Longevity Wiki - User contributions [en-GB]

Handbook:Vision and Action Plan

2021-09-12T15:50:40Z

SV: Added Outcomes table

== Theory of Change ==
{| class="wikitable"
|+
! rowspan="2" |Inputs
! rowspan="2" |Activities
! rowspan="2" |Outputs
! colspan="3" |Outcomes
|-
!Short-term
!Mid-term
!Long-term
|-
| colspan="6" |'''Main goal:''' Produce high-qualitative, accessible articles on longevity research with the purpose of increasing awareness and funding to the field.
|-
|Core team
| rowspan="7" |1.1. Attract scientific researchers in the field of longevity research to contribute to our articles.

1.2. Keep and build an active, sustainable community that is engaged and willing to produce and maintain content.

1.3. Produce new high-qualitative accessible articles on longevity topics in pace with new research, and maintain the ones already existing.
| rowspan="7" |''Non-direct project impact''
1.1.a)

1.2.a) Awareness of Longevity research increases among researchers and the public

1.2.b) Credibility of Longevity research increases among research institutions and news sources

''Direct project impact''

2.1.a) Awareness of Longevity Wiki increases

2.1.b) Credibility of Longevity Wiki increases

2.1.c) Accessibility of Longevity Wiki increases

2.1.d) Number of articles on Longevity Wiki increases
| rowspan="7" |''Non-direct project impact''
1.1. Funding for researchers and research institutions that focus on longevity increase.

1.2. Awareness of the importance, existence and credibility of longevity research increase among researchers and the public.

2.1 Longevity Wiki is a well-known, science-based, sense-making, trustworthy and reliable source of information on longevity.
| rowspan="7" |Longevity research is an '''established research field''', with '''several institutions''' around the world having longevity as a research focus, and more researchers continually come into the field, with the '''number of scientific research papers''' steadily '''increasing'''.

Longevity Wiki is the '''primary''' Internet source of knowledge in longevity research.
| rowspan="7" |Significant '''increase''' in '''average/maximum human health- and/or lifespan''' in the next '''100 years''' and life extension therapies are accessible all over the world.
|-
|Contributors
|-
|LongevityWiki Community
|-
|Advisory Board
|-
|Financial Resources
|-
|Partnerships (e.g. Effective Altruist organizations)
|-
|Global Longevity Community (e.g. subreddit, researchers, etc.)
|-
| colspan="6" |Our vision is a world in which humans live physically healthy lives until the day they die, and that death is a choice, not an obligation.
|}
{| class="wikitable"
|+
!
!Output
!Indicators
!Target Year 2022
|-
|1.1.a)
|
|
|
|-
|1.2.a)
|Awareness of Longevity research increases
|Number of articles written on longevity in scientific journals
Number of news articles on longevity written in (non-)scientific journals

Number of funding applications for longevity research
|
|-
|1.2.b)
|Credibility of Longevity research increases
|
|
|-
|2.1.a)
|Awareness of Longevity Wiki increases
|Number of readers per month
Number of new web links per month
|
|-
|2.1.b)
|Credibility of Longevity Wiki increases
|Number of citations in notable journals
Number of researchers in the field contributing to the Wiki

Amount of money received in funding for the Wiki
|
|-
|2.1.c)
|Accessibility of Longevity Wiki increases
|Number of people interacting with our mini-widgets
Number of mini-widgets

Google Search queries where we place top 5
|
|-
|2.1.d)
|Number of articles on Longevity Wiki increases
|Number of finished articles
Number of articles in progress

Number of active content writers
|
|}
{| class="wikitable"
|+
!
!Outcome
!Indicators
!Target Year 2022
!Data source
|-
|1.1.
|Funding for researchers and research institutions that focus on longevity increase.
|Amount of funding (in $) given to researchers for longevity-related projects.
Number of grants given to research in longevity-related projects.
|
|
|-
|1.2.
|Awareness of the importance, existence and credibility of longevity research increase.
|Number of university students who write their Bachelor/Master/PhD thesis within a subject closely related to longevity research.
Number of research institutions doing longevity-related research.

Number of researchers doing longevity-related research.

Percentage change in number of published scientific research papers on longevity.
|
|
|-
|2.1.
|Longevity Wiki is a well-known, science-based, sense-making, trustworthy and reliable source of information on longevity.
|
|
|
|}

Handbook:Vision and Action Plan

2021-09-11T15:57:06Z

SV: Added Outputs table

Handbook:Vision and Action Plan

2021-09-11T15:39:09Z

SV: Created the Theory of Change

Handbook:Handbook

2021-08-25T18:16:38Z

SV: /* Organization */ minor

== Organizational Mission==
Longevity Wiki is an open-access project to create the go-to platform for the science of longevity. The wiki was borne from the need for high quality scientific content on aging and longevity to be freely available and accessible. The Wiki ultimately aims to cover the following topics in detail:

*Longevity drugs and the evidence supportin them
*Personal longevity strategies/advice
*Hallmarks of aging/biology of aging
*Animal models of aging
*Laboratories working in geroscience, and their focus
*Longevity biotech (companies, development pipeline)
*Biology of aging + diseases of aging connection

== About ==

=== What is Longevity Wiki? ===
Longevity Wiki is the world’s first open access longevity education platform. It is a global non-profit wiki created to democratize information on research efforts in aging biology. The Wiki will be launched in late 2021.

=== What is the purpose of Longevity Wiki? ===
Longevity Wiki exists to bridge the knowledge gap between doctors, scientists and the public with aging biology research.

Aging is the largest cause of death and suffering worldwide, accounting for more than 70% of deaths globally. However, there is widespread lack of understanding about biological aging and its critical role in age-related diseases such as cancer, Alzheimer's, and cardiovascular disease. This is a bottleneck towards accelerating the rate of geroscience research - a nascent field of medicine that seeks to understand how the underlying biological mechanisms of aging can be targeted to prevent and treat age-related diseases.

Longevity Wiki provides clear, concise information and empowers readers to contribute to this field. Our goal is to progress the longevity field by providing free educational material in the form of informative articles.

=== Why a Wiki? ===
The major benefit of using the MediaWiki platform - the same platform as Wikipedia - is that it allows many users to contribute. The longevity field is vast, and having a system that allows users to easily amend and update content is crucial to ensuring the continuation of the Wiki.

=== Where does Longevity Wiki fit into the Longevity Ecosystem? ===
Currently, although there are various longevity news outlets (e.g. [https://www.longevity.technology/ longevity.technology], [https://www.lifespan.io/ lifespan.io], [https://www.fightaging.org/ fightaging.org]) there is no centralized hub of longevity information. Longevity Wiki fills this gap by consolidating information and presenting it in an accessible way.

=== Who is the target audience? ===
We plan to target both specialists and non-specialists. The wiki will cater to both groups through having multiple layers of content.

=== Who is involved? ===
Longevity Wiki consists of a team of content writers, engineers and UX specialists. The project is open-access and anyone can contribute. The core team members are listed below:

'''Co-Founder - Jack Harley'''

Jack Harley is a neuroscientist trained at the University of Oxford. He is the author of the popular article, [https://www.lesswrong.com/posts/RcifQCKkRc9XTjxC2/anti-aging-state-of-the-art Anti-Aging: State of the Art] published on the rationality forum, [https://www.lesswrong.com/ LessWrong]. Jack is the former Vice President of the Oxford Society of Ageing and Longevity and has 8+ years’ experience in for-profit roles in Biotech and non-for-profit roles in the Effective Altruism community.

'''CTO and Co-Founder - Bogdan Dziewierz'''

Bogdan Dziewierz is software architect and engineer with a specialisation in digital, web and mobile. He has 15+ years experience architecting and building multi-tiered, distributed web and mobile applications.

'''Head of UX - Marc Smeehuijzen'''

Marc Smeehuijzen is a User Experience designer with over 15 years experience in web design and usability. He has worked for a variety of international companies trying to make their technology easier to use.

'''Head of Content - Benjamin Wu'''

Benjamin Wu is an Australian healthcare professional working in primary eye care, serving a predominantly geriatric patient base. He is chiefly interested in the biology of aging, translational medicine, and advancing the geroscience hypothesis.

==How to edit the Wiki==
=== Let us know first ===
If you want to help with the Longevity Wiki in any way, please [[Contact|contact us]] first, so we can help you get started. You can also join our [https://discord.gg/jBR5aRcpfV Discord Server] (a free chat platform) which is used for most internal communication in the wiki team.

=== Create content ===
Longevity Wiki uses the [[mediawikiwiki:MediaWiki|MediaWiki]] platform - the same as Wikipedia. This is the software that makes it possible to store all content, edit articles, track changes and more.

==== Create an account ====
If you want to edit the wiki, it's a good idea to create an account first. That way it's easier to keep track of your work and you get some extra functionality. To create an account, in the menu click the Account icon on the right (the 'little person') and click '''Create account''' and follow the instructions. Creating an account is not mandatory however for editing.

==== Create a page ====
To create a new article on the wiki, go to the menu and click '''Contribute''' and then '''Create new page'''. You will then be prompted to select a title for your article. After that, the Edit toolbar appears at the top and you can start writing. The Edit toolbar provides you with standard edit functions like making headings, bold text, insert links, insert images and much more.

When adding a new page related to longevity to the wiki, please make sure to categorize it as 'Longevity' so that it automatically appears in the [[Articles]] listing. (Save Changes -> Categories)

==== Edit a page ====
To edit an existing article, lookup the article, go to the menu and click '''Contribute''' and then (under 'This page...') click '''Edit'''. Then the Edit toolbar will open at the top, and you can start writing.
[[File:Text editor.png|none|thumb|732x732px|The '''Edit''' toolbar]]

==== Images ====
Often it's a good idea to include images in your article. Just make sure that if you use an image of someone else, you are not violating any copyright. In general, you are free to use images with a [https://creativecommons.org/ Creative Commons] license, but don't forget to use the right [https://creativecommons.org/use-remix/ attribution]. If you need help creating an image yourself, let us know in the Images channel on our [https://discord.gg/jBR5aRcpfV Discord Server], and we can help you create a unique and copyright-free image.

==== Referencing ====
For referencing to external sources (e.g. a journal article), Longevity Wiki uses the [[wikipedia:APA_style|APA referencing style]] - the same as Wikipedia. To create a reference, click '''Cite''' on the Edit toolbar. There are a few useful resources for creating citations, such as [https://zbib.org/ Zoterobib].

==== Writing style ====
The aim of the Wiki is to create '''comprehensive''', '''scientifically accurate''' and '''accessible''' content on longevity. The writing style we are aiming for is essentially the same as Wikipedia, in balancing technical and non-technical content. Here is our '''[[Writing tips for easy reading|writing guide]]''' to help you get started. More information on Wikipedia's writing style can be found in [[wikipedia:Wikipedia:Manual_of_Style|Wikipedia's Manual of Style]].

==Strategy==
Instead of producing as much content as possible, we’re going to focus on creating 5 pillar articles written by experts on the topic. These articles will demonstrate the knowledge and quality of our initiative, and then we will build out the wiki from there.

As for the 5 pillar articles, if you have a post-grad (MSc, PhD, MD) in a related area to one of the articles below, and want to help, please [[Contact|let us know]].

#'''Epigenetic reprogramming'''
#'''Aging and Neurodegeneration'''
#'''Rapamycin'''
#'''Biomarkers of healthspan'''
#'''COVID-19 and Aging'''

In conjunction with these articles, we are going to create a Glossary page of key terms in the longevity space, along with a short (2-3 sentence definition). This Glossary is the major area where we will need help from any interested content writers. We also will need people to help with marketing, and with the administration/organization of the wiki.

==Organization==
This Handbook is the source of truth for the wiki, but we use a few other platforms for communicating and sharing resources. Like the wiki itself, they are all publicly accessible and transparent.

=== Discord Server ===
We mostly communicate via the [https://discord.gg/UDKmjcnjye Longevity Wiki Discord Server]. It serves as a day-to-day message board, as well as the host of our meetings. Meetings take place every week at 08:30 GMT.

=== Google Drive ===
Our [https://drive.google.com/drive/folders/19Ol2wcRd2IWUt_gOC5j5Ff7FjSzPVuBf Drive folder] is used for sharing many useful documents, such as draft ideas, spreadsheets, or useful non-wiki resources.

===Engineering Team===

*Source code: [https://github.com/longevitywiki Github]
*Task management: [https://longevitywiki.atlassian.net/jira/software/projects/LW/boards/1 Jira]
*Documentation & roadmap: [https://longevitywiki.atlassian.net/wiki/spaces/LW/overview Confluence]

==Available Roles and Projects for the Wiki==
Longevity Wiki is an open access, collaborative project and we invite all volunteers to contribute! The goal of the Wiki is to create a trusted, high quality platform of longevity science content.

This chapter lists the current projects we are working on, and how you can get involved.

===Pillar article writing===
'''Role: Senior content writer'''

'''Minimum requirements: Masters or PhD training, ideally in a relevant field to content being written'''

We are seeking those with strong scientific backgrounds to help our initial offering of 5 ‘pillar’ articles that will form the initial content on the Wiki.

These articles are designed to be long-form (1.5-2.5k words) articles summarizing the relevant literature as it pertains to aging biology. The style we are aiming for is similar to a literature review, but with a simplified writing style that is accessible to non-specialist readers.

An example is our article on [[Rapamycin]], however, the style and structure of the article may vary by topic.

The following topics have been selected:

*'''Epigenetic reprogramming'''
*'''Aging and Neurodegeneration'''
*'''Rapamycin'''
*'''Biomarkers of healthspan'''
*'''COVID-19 and Aging'''

If you are interested in volunteering to help research or write these articles, please [[Contact|contact us]].

===Glossary expansion===
'''Role: Junior content writer'''

'''Minimum requirements: High school level biology'''

We are building a glossary of relevant terminology to expand the scope of the Wiki. The glossary will be accessible from an article through the use of so called ‘hovercards’ which makes it possible to display the meaning of a difficult term without leaving the article page.

The list of glossary terms is being populated based on the pillar articles. A full list of glossary terms can be found here (ADD LINK).

To contribute to the glossary, simply choose a term that has not yet been defined, and write a concise, and scientifically accurate definition.

Some guidelines:

*All references should be cited using APA referencing

*All links to internal articles should be linked
*Definitions should be clear and comprehensible to non-specialist audiences
*Definitions can be up to 270 characters in length

An example of a glossary term (ADD LINK).

===Life extension tool database===
'''Role: Researcher'''

'''Minimum requirements: Undergraduate biology, ability to comprehend the longevity data and research'''

We are creating a ‘life extension tool’ that provides an up to date overview of the life extension achieved for different animals with different interventions.

A [https://zpl.io/bePZGJl sample of the tool] can be viewed on our design platform Zeplin.

In order to populate data for the tool, we require assistance in reviewing the literature to identify the lifespan extension associated with different drugs and species, and the original publication in which this was published.

Our current database: [https://docs.google.com/spreadsheets/d/14OLhV4WWSUGomEY-3zko1o8zHHrJwt5YipGbjxhracM/edit?usp=sharing Life Extension Tool Data].

===Software engineering support===
'''Role: Engineer'''

'''Minimum requirements: Interest in software engineering'''

As the wiki grows, we need to ensure that the automation and infrastructure develops. We are especially looking for people with the following abilities:

* AWS reliability engineering/DevOps (people to manage infrastructure and deploy apps)
* PHP
* Front-end development
* Technical product ownership
* A scrum master/iteration manager

===Marketing===
'''Role: Based on experience and performance'''

'''Minimum requirements: Past experience in marketing, splendid communicator and creative individual who is eager to learn'''

Our marketing department is expanding. If you are a creative individual who loves communicating, you could get a lot of significant responsibilities.

As our platform expands, our marketing efforts must do the same. Are you are eager to learn and would love to help us grow as quick as humanly possible?

Then, [[Contact|let’s talk]].

=== Graphic design ===
'''Role: Illustrator, data visualization'''

'''Minimum requirements: Experience with graphic design'''

We are looking for individuals with graphic design skills to help us create and re-work pictures, scientific diagrams and graphs to communicate information to non-technical audiences. You will work closely with our content writers to produce high-impact, engaging visuals to accompany the written content.

=== Other roles ===
'''Role: Translator'''

We are looking for individuals with language skills to translate articles into other languages to reach a broader audience - particularly languages spoken commonly around the world. This will be done with the assistance of tools such as Google Translate.

'''Role: UX specialist'''

We are seeking expertise in user experience (UX) to help us design an intuitive and engaging platform. The goal is to create a satisfying experience for our users. You will work with the Head of UX in this role.

==Meeting minutes==
We're committed to being an open-access platform, and as such, we share the minutes of our weekly meetings. The meetings consist of our sprint planning sessions and mid-sprint meetings, which occur on alternating weeks.

Check out the [https://en.longevitywiki.org/wiki/Handbook:Meeting_Minutes?venotify=created Meeting Minutes] if you want to catch up on the current state of the wiki's development.

==Organizational Constitution==
==Contact information==
[[Contact|Contact information]]

Handbook:Handbook

2021-08-25T18:06:15Z

SV: /* Meeting minutes */ Added an explanation paragraph. /* Organization */ Reordered for clarity.

== Organizational Mission==
Longevity Wiki is an open-access project to create the go-to platform for the science of longevity. The wiki was borne from the need for high quality scientific content on aging and longevity to be freely available and accessible. The Wiki ultimately aims to cover the following topics in detail:

*Longevity drugs and the evidence supportin them
*Personal longevity strategies/advice
*Hallmarks of aging/biology of aging
*Animal models of aging
*Laboratories working in geroscience, and their focus
*Longevity biotech (companies, development pipeline)
*Biology of aging + diseases of aging connection

== About ==

=== What is Longevity Wiki? ===
Longevity Wiki is the world’s first open access longevity education platform. It is a global non-profit wiki created to democratize information on research efforts in aging biology. The Wiki will be launched in late 2021.

=== What is the purpose of Longevity Wiki? ===
Longevity Wiki exists to bridge the knowledge gap between doctors, scientists and the public with aging biology research.

Aging is the largest cause of death and suffering worldwide, accounting for more than 70% of deaths globally. However, there is widespread lack of understanding about biological aging and its critical role in age-related diseases such as cancer, Alzheimer's, and cardiovascular disease. This is a bottleneck towards accelerating the rate of geroscience research - a nascent field of medicine that seeks to understand how the underlying biological mechanisms of aging can be targeted to prevent and treat age-related diseases.

Longevity Wiki provides clear, concise information and empowers readers to contribute to this field. Our goal is to progress the longevity field by providing free educational material in the form of informative articles.

=== Why a Wiki? ===
The major benefit of using the MediaWiki platform - the same platform as Wikipedia - is that it allows many users to contribute. The longevity field is vast, and having a system that allows users to easily amend and update content is crucial to ensuring the continuation of the Wiki.

=== Where does Longevity Wiki fit into the Longevity Ecosystem? ===
Currently, although there are various longevity news outlets (e.g. [https://www.longevity.technology/ longevity.technology], [https://www.lifespan.io/ lifespan.io], [https://www.fightaging.org/ fightaging.org]) there is no centralized hub of longevity information. Longevity Wiki fills this gap by consolidating information and presenting it in an accessible way.

=== Who is the target audience? ===
We plan to target both specialists and non-specialists. The wiki will cater to both groups through having multiple layers of content.

=== Who is involved? ===
Longevity Wiki consists of a team of content writers, engineers and UX specialists. The project is open-access and anyone can contribute. The core team members are listed below:

'''Co-Founder - Jack Harley'''

Jack Harley is a neuroscientist trained at the University of Oxford. He is the author of the popular article, [https://www.lesswrong.com/posts/RcifQCKkRc9XTjxC2/anti-aging-state-of-the-art Anti-Aging: State of the Art] published on the rationality forum, [https://www.lesswrong.com/ LessWrong]. Jack is the former Vice President of the Oxford Society of Ageing and Longevity and has 8+ years’ experience in for-profit roles in Biotech and non-for-profit roles in the Effective Altruism community.

'''CTO and Co-Founder - Bogdan Dziewierz'''

Bogdan Dziewierz is software architect and engineer with a specialisation in digital, web and mobile. He has 15+ years experience architecting and building multi-tiered, distributed web and mobile applications.

'''Head of UX - Marc Smeehuijzen'''

Marc Smeehuijzen is a User Experience designer with over 15 years experience in web design and usability. He has worked for a variety of international companies trying to make their technology easier to use.

'''Head of Content - Benjamin Wu'''

Benjamin Wu is an Australian healthcare professional working in primary eye care, serving a predominantly geriatric patient base. He is chiefly interested in the biology of aging, translational medicine, and advancing the geroscience hypothesis.

==How to edit the Wiki==
=== Let us know first ===
If you want to help with the Longevity Wiki in any way, please [[Contact|contact us]] first, so we can help you get started. You can also join our [https://discord.gg/jBR5aRcpfV Discord Server] (a free chat platform) which is used for most internal communication in the wiki team.

=== Create content ===
Longevity Wiki uses the [[mediawikiwiki:MediaWiki|MediaWiki]] platform - the same as Wikipedia. This is the software that makes it possible to store all content, edit articles, track changes and more.

==== Create an account ====
If you want to edit the wiki, it's a good idea to create an account first. That way it's easier to keep track of your work and you get some extra functionality. To create an account, in the menu click the Account icon on the right (the 'little person') and click '''Create account''' and follow the instructions. Creating an account is not mandatory however for editing.

==== Create a page ====
To create a new article on the wiki, go to the menu and click '''Contribute''' and then '''Create new page'''. You will then be prompted to select a title for your article. After that, the Edit toolbar appears at the top and you can start writing. The Edit toolbar provides you with standard edit functions like making headings, bold text, insert links, insert images and much more.

When adding a new page related to longevity to the wiki, please make sure to categorize it as 'Longevity' so that it automatically appears in the [[Articles]] listing. (Save Changes -> Categories)

==== Edit a page ====
To edit an existing article, lookup the article, go to the menu and click '''Contribute''' and then (under 'This page...') click '''Edit'''. Then the Edit toolbar will open at the top, and you can start writing.
[[File:Text editor.png|none|thumb|732x732px|The '''Edit''' toolbar]]

==== Images ====
Often it's a good idea to include images in your article. Just make sure that if you use an image of someone else, you are not violating any copyright. In general, you are free to use images with a [https://creativecommons.org/ Creative Commons] license, but don't forget to use the right [https://creativecommons.org/use-remix/ attribution]. If you need help creating an image yourself, let us know in the Images channel on our [https://discord.gg/jBR5aRcpfV Discord Server], and we can help you create a unique and copyright-free image.

==== Referencing ====
For referencing to external sources (e.g. a journal article), Longevity Wiki uses the [[wikipedia:APA_style|APA referencing style]] - the same as Wikipedia. To create a reference, click '''Cite''' on the Edit toolbar. There are a few useful resources for creating citations, such as [https://zbib.org/ Zoterobib].

==== Writing style ====
The aim of the Wiki is to create '''comprehensive''', '''scientifically accurate''' and '''accessible''' content on longevity. The writing style we are aiming for is essentially the same as Wikipedia, in balancing technical and non-technical content. Here is our '''[[Writing tips for easy reading|writing guide]]''' to help you get started. More information on Wikipedia's writing style can be found in [[wikipedia:Wikipedia:Manual_of_Style|Wikipedia's Manual of Style]].

==Strategy==
Instead of producing as much content as possible, we’re going to focus on creating 5 pillar articles written by experts on the topic. These articles will demonstrate the knowledge and quality of our initiative, and then we will build out the wiki from there.

As for the 5 pillar articles, if you have a post-grad (MSc, PhD, MD) in a related area to one of the articles below, and want to help, please [[Contact|let us know]].

#'''Epigenetic reprogramming'''
#'''Aging and Neurodegeneration'''
#'''Rapamycin'''
#'''Biomarkers of healthspan'''
#'''COVID-19 and Aging'''

In conjunction with these articles, we are going to create a Glossary page of key terms in the longevity space, along with a short (2-3 sentence definition). This Glossary is the major area where we will need help from any interested content writers. We also will need people to help with marketing, and with the administration/organization of the wiki.

==Organization==
This Handbook is the ''source of truth'' for the wiki, but we use a few other platforms for communicating and sharing resources. Like the wiki itself, they are all publicly accessible and transparent.

=== Discord Server ===
We mostly communicate via the [https://discord.gg/UDKmjcnjye Longevity Wiki Discord Server]. It serves as a day-to-day message board, as well as the host of our meetings. Meetings take place every week at 08:30 GMT.

=== Google Drive ===
Our [https://drive.google.com/drive/folders/19Ol2wcRd2IWUt_gOC5j5Ff7FjSzPVuBf Drive folder] is used for sharing many useful documents, such as draft ideas, spreadsheets, or useful non-wiki resources.

===Engineering Team===

*Source code: [https://github.com/longevitywiki Github]
*Task management: [https://longevitywiki.atlassian.net/jira/software/projects/LW/boards/1 Jira]
*Documentation & roadmap: [https://longevitywiki.atlassian.net/wiki/spaces/LW/overview Confluence]

==Available Roles and Projects for the Wiki==
Longevity Wiki is an open access, collaborative project and we invite all volunteers to contribute! The goal of the Wiki is to create a trusted, high quality platform of longevity science content.

This chapter lists the current projects we are working on, and how you can get involved.

===Pillar article writing===
'''Role: Senior content writer'''

'''Minimum requirements: Masters or PhD training, ideally in a relevant field to content being written'''

We are seeking those with strong scientific backgrounds to help our initial offering of 5 ‘pillar’ articles that will form the initial content on the Wiki.

These articles are designed to be long-form (1.5-2.5k words) articles summarizing the relevant literature as it pertains to aging biology. The style we are aiming for is similar to a literature review, but with a simplified writing style that is accessible to non-specialist readers.

An example is our article on [[Rapamycin]], however, the style and structure of the article may vary by topic.

The following topics have been selected:

*'''Epigenetic reprogramming'''
*'''Aging and Neurodegeneration'''
*'''Rapamycin'''
*'''Biomarkers of healthspan'''
*'''COVID-19 and Aging'''

If you are interested in volunteering to help research or write these articles, please [[Contact|contact us]].

===Glossary expansion===
'''Role: Junior content writer'''

'''Minimum requirements: High school level biology'''

We are building a glossary of relevant terminology to expand the scope of the Wiki. The glossary will be accessible from an article through the use of so called ‘hovercards’ which makes it possible to display the meaning of a difficult term without leaving the article page.

The list of glossary terms is being populated based on the pillar articles. A full list of glossary terms can be found here (ADD LINK).

To contribute to the glossary, simply choose a term that has not yet been defined, and write a concise, and scientifically accurate definition.

Some guidelines:

*All references should be cited using APA referencing

*All links to internal articles should be linked
*Definitions should be clear and comprehensible to non-specialist audiences
*Definitions can be up to 270 characters in length

An example of a glossary term (ADD LINK).

===Life extension tool database===
'''Role: Researcher'''

'''Minimum requirements: Undergraduate biology, ability to comprehend the longevity data and research'''

We are creating a ‘life extension tool’ that provides an up to date overview of the life extension achieved for different animals with different interventions.

A [https://zpl.io/bePZGJl sample of the tool] can be viewed on our design platform Zeplin.

In order to populate data for the tool, we require assistance in reviewing the literature to identify the lifespan extension associated with different drugs and species, and the original publication in which this was published.

Our current database: [https://docs.google.com/spreadsheets/d/14OLhV4WWSUGomEY-3zko1o8zHHrJwt5YipGbjxhracM/edit?usp=sharing Life Extension Tool Data].

===Software engineering support===
'''Role: Engineer'''

'''Minimum requirements: Interest in software engineering'''

As the wiki grows, we need to ensure that the automation and infrastructure develops. We are especially looking for people with the following abilities:

* AWS reliability engineering/DevOps (people to manage infrastructure and deploy apps)
* PHP
* Front-end development
* Technical product ownership
* A scrum master/iteration manager

===Marketing===
'''Role: Based on experience and performance'''

'''Minimum requirements: Past experience in marketing, splendid communicator and creative individual who is eager to learn'''

Our marketing department is expanding. If you are a creative individual who loves communicating, you could get a lot of significant responsibilities.

As our platform expands, our marketing efforts must do the same. Are you are eager to learn and would love to help us grow as quick as humanly possible?

Then, [[Contact|let’s talk]].

=== Graphic design ===
'''Role: Illustrator, data visualization'''

'''Minimum requirements: Experience with graphic design'''

We are looking for individuals with graphic design skills to help us create and re-work pictures, scientific diagrams and graphs to communicate information to non-technical audiences. You will work closely with our content writers to produce high-impact, engaging visuals to accompany the written content.

=== Other roles ===
'''Role: Translator'''

We are looking for individuals with language skills to translate articles into other languages to reach a broader audience - particularly languages spoken commonly around the world. This will be done with the assistance of tools such as Google Translate.

'''Role: UX specialist'''

We are seeking expertise in user experience (UX) to help us design an intuitive and engaging platform. The goal is to create a satisfying experience for our users. You will work with the Head of UX in this role.

==Meeting minutes==
We're committed to being an open-access platform, and as such, we share the minutes of our weekly meetings. The meetings consist of our sprint planning sessions and mid-sprint meetings, which occur on alternating weeks.

Check out the [https://en.longevitywiki.org/wiki/Handbook:Meeting_Minutes?venotify=created Meeting Minutes] if you want to catch up on the current state of the wiki's development.

==Organizational Constitution==
==Contact information==
[[Contact|Contact information]]

Handbook:Handbook

2021-08-19T06:25:29Z

SV: Merged with the About page

== Organizational Mission==
Being the go-to platform on all scientific areas related to longevity:

*Personal longevity strategies/advice
*Hallmarks of aging/biology of aging
*Longevity drugs
*Animal models of aging
*Laboratories working in geroscience, and their focus
*Longevity biotech (companies, development pipeline)
*Biology of aging + diseases of aging connection

== About ==

=== What is Longevity Wiki? ===
Longevity Wiki is the world’s first open access longevity education platform. It is a global non-profit wiki created to democratize information on research efforts in aging biology. The Wiki will be launched in late 2021.

=== What is the purpose of Longevity Wiki? ===
Longevity Wiki exists to bridge the knowledge gap between doctors, scientists and the public with aging biology research.

Aging is the largest cause of death and suffering worldwide, accounting for more than 70% of deaths globally. However, there is widespread lack of understanding about biological aging and its critical role in age-related diseases such as cancer, Alzheimer's, and cardiovascular disease. This is a bottleneck towards accelerating the rate of geroscience research - a nascent field of medicine that seeks to understand how the underlying biological mechanisms of aging can be targeted to prevent and treat age-related diseases.

Longevity Wiki provides clear, concise information and empowers readers to contribute to this field. Our goal is to progress the longevity field by providing free educational material in the form of informative articles.

=== Why a Wiki? ===
The major benefit of using the MediaWiki platform - the same platform as Wikipedia - is that it allows many users to contribute. The longevity field is vast, and having a system that allows users to easily amend and update content is crucial to ensuring the continuation of the Wiki.

=== Where does Longevity Wiki fit into the Longevity Ecosystem? ===
Currently, although there are various longevity news outlets (e.g. [https://www.longevity.technology/ longevity.technology], [https://www.lifespan.io/ lifespan.io], [https://www.fightaging.org/ fightaging.org]) there is no centralized hub of longevity information. Longevity Wiki fills this gap by consolidating information and presenting it in an accessible way.

=== Who is the target audience? ===
We plan to target both specialists and non-specialists. The wiki will cater to both groups through having multiple layers of content.

=== Who is involved? ===
Longevity Wiki consists of an all-star team of writers, engineers and UX specialists. The organization structure is listed below:

'''CEO and Co-Founder - Jack Harley'''

Jack Harley is a neuroscientist trained at the University of Oxford. He is the author of the popular article, [https://www.lesswrong.com/posts/RcifQCKkRc9XTjxC2/anti-aging-state-of-the-art Anti-Aging: State of the Art] published on the rationality forum, [https://www.lesswrong.com/ LessWrong]. Jack is the former Vice President of the Oxford Society of Ageing and Longevity and has 8+ years’ experience in for-profit roles in Biotech and non-for-profit roles in the Effective Altruism community.

'''CTO and Co-Founder - Bogdan Dziewierz'''

Bogdan Dziewierz is software architect and engineer with a specialisation in digital, web and mobile. He has 15+ years experience architecting and building multi-tiered, distributed web and mobile applications.

'''Head of UX - Marc Smeehuijzen'''

Marc Smeehuijzen is a User Experience designer with over 10 years experience in web design and usability. He has worked for a variety of international companies trying to make their technology a bit easier to use.

'''Head of Content - Benjamin Wu'''

Benjamin Wu is an Australian healthcare professional working in primary eye care, serving a predominantly geriatric patient base. He is chiefly interested in the biology of aging, translational medicine, and advancing the geroscience hypothesis.

'''Content Writer - Sophia Moss'''

'''Content Writer - Aleksandr Petukhov'''

'''Board Advisor - Dr. Aubrey de Grey'''

==How to edit the Wiki==
=== Let us know first ===
If you want to help with the Longevity Wiki in any way, it's a good idea to [[Contact|contact us]] first, so we can help you get started. You can also join our [https://discord.gg/jBR5aRcpfV Discord Server] (a free chat platform) which is used for most internal communication in the wiki team.

=== Create content ===
Longevity Wiki uses the [[mediawikiwiki:MediaWiki|MediaWiki]] platform - the same as Wikipedia. This is the software that makes it possible to store all content, edit articles, track changes and more.

==== Create an account ====
If you want to edit the wiki, it's a good idea to create an account first. That way it's easier to keep track of your work and you get some extra functionality. To create an account, in the menu click the Account icon on the right (the 'little person') and click '''Create account''' and follow the instructions. Creating an account is not mandatory however for editing.

==== Create a page ====
To create a new article on the wiki, go to the menu and click '''Contribute''' and then '''Create new page'''. You will then be prompted to select a title for your article. After that, the Edit toolbar appears at the top and you can start writing. The Edit toolbar provides you with standard edit functions like making headings, bold text, insert links, insert images and much more.

When adding a new page related to longevity to the wiki, please make sure to categorize it as 'Longevity' so that it automatically appears in the Articles listing. (Save Changes -> Categories)

==== Edit a page ====
To edit an existing article, lookup the article, go to the menu and click '''Contribute''' and then (under 'This page...') click '''Edit'''. Then the Edit toolbar will open at the top, and you can start writing.
[[File:Text editor.png|none|thumb|732x732px|The '''Edit''' toolbar]]

==== Images ====
Often it's a good idea to include images in your article. Just make sure that if you use an image of someone else, you are not violating any copyright. In general, you are free to use images with a [https://creativecommons.org/ Creative Commons] license, but don't forget to use the right [https://creativecommons.org/use-remix/ attribution]. If you need help creating an image yourself, let us know in the Images channel on our [https://discord.gg/jBR5aRcpfV Discord Server], and we can help you create a unique and copyright-free image.

==== Referencing ====
For referencing to external sources (e.g. a journal article), Longevity Wiki uses the [[wikipedia:APA_style|APA referencing style]] - the same as Wikipedia. To create a reference, click '''Cite''' on the Edit toolbar. There are a few useful resources for creating citations, such as [https://zbib.org/ this one].

==== Writing style ====
The aim of the Wiki is to create '''comprehensive''', '''scientifically accurate''' and '''accessible''' content on longevity. The writing style we are aiming for is essentially the same as Wikipedia, in balancing technical and non-technical content. Here is our '''[[Writing tips for easy reading|writing guide]]''' to help you get started. More information on Wikipedia's writing style can be found in [[wikipedia:Wikipedia:Manual_of_Style|Wikipedia's Manual of Style]].

==Strategy==
Instead of producing as much content as possible, we’re going to focus on creating 5 pillar articles written by experts on the topic. These articles will demonstrate the knowledge and quality of our initiative, and then we will build out the wiki from there.

As for the 5 pillar articles, if you have a post-grad (MSc, PhD, MD) in a related area to one of the articles below, please rech

#'''Epigenetic reprogramming'''
#'''Aging and Neurodegeneration'''
#'''Rapamycin'''
#'''Biomarkers of healthspan'''
#'''COVID-19 and Aging'''

In conjunction with these articles, we are going to create a Glossary page of key terms in the longevity space, along with a short (2-3 sentence definition). This Glossary is the major area where we will need help from any interested content writers. We also will need people to help with marketing, and with the administration/organization of the wiki.

==Organization==

===General===

*Communications: Organizational discord server can be found [https://discord.gg/UDKmjcnjye here].
*Weekly Meetings, 10:30 a.m. (CET) on the Discord Server ''(TODO: other meetings, public calendar links for people to add?)''

*This wiki (Handbook namespace) as the source of truth for the organization
*Trello for Content Writers Task Management (In the future could be the Wiki itself): [https://trello.com/b/mfwbyEB6/content-creators Content creator board]
* Google Drive for presentations and unordered thoughts to share: [https://drive.google.com/drive/folders/19Ol2wcRd2IWUt_gOC5j5Ff7FjSzPVuBf Drive Link (public)]

===Engineering Team===

*Source code: [https://github.com/longevitywiki Github]
*Task management: [https://longevitywiki.atlassian.net/jira/software/projects/LW/boards/1 Jira]
*Documentation & roadmap: [https://longevitywiki.atlassian.net/wiki/spaces/LW/overview Confluence]

==Available Roles and Projects for the Wiki==
Longevity Wiki is an open access, collaborative project and we invite all volunteers to contribute! The goal of the Wiki is to create a trusted, high quality platform of longevity science content.

This chapter lists the current projects we are working on, and how you can get involved.

===Pillar article writing===
'''Role: Senior content writer'''

'''Minimum requirements: Masters or PhD training, ideally in a relevant field to content being written'''

We are seeking those with strong scientific backgrounds to help our initial offering of 20 ‘pillar’ articles that will form the initial content on the Wiki.

These articles are designed to be long-form (1.5-2.5k words) articles summarizing the relevant literature as it pertains to aging biology. The style we are aiming for is similar to a literature review, but with a simplified writing style that is accessible to non-specialist readers.

An example article is [[Rapamycin|here]], however, the style and structure of the article may vary by topic.

The following topics have been selected:

*Biomarkers of Healthspan
*Brain aging and neurodegeneration

If you are interested in volunteering to help research or write these articles, please contact Jack Harley at [[Mailto:jtt.harley@gmail.com|jtt.harley@gmail.com]] or Max Schons at [[Mailto:Maxxsschons@gmail.com|Mxschons@gmail.com]].

===Glossary expansion===
'''Role: Junior content writer'''

'''Minimum requirements: High school level biology'''

We are building a glossary of relevant terminology to expand the scope of the Wiki. This will be used to allow users to use the ‘hovercard’ feature to define any words they are unfamiliar with.

The list of glossary terms is being populated based on the pillar articles. A full list of glossary terms can be found here.

To contribute to the glossary, simply choose a term that has not yet been defined, and write a concise, and scientifically accurate definition.

*All references should be cited using APA referencing

*All links to internal articles should be linked
*Technical advice on how to edit the Wiki can be found [[Contribute|here]]
*Definitions are clear and comprehensible to non-specialist audiences.
*Definitions are up to 270 characters in length

An example of a glossary term can be found here.

===Life extension tool database===
'''Role: Researcher'''

'''Minimum requirements: Undergraduate biology, ability to comprehend data and research'''

We are creating a ‘life extension tool’ that allows the lifespan extension of certain drugs on various model organisms to be visualised.

A sample of the tool can be viewed here. In order to populate data for the tool, we require assistance in reviewing the literature to identify the lifespan extension associated with different drugs, and the original publication in which this was published.

The current database of life-extension data can be viewed and edited here.

===Software engineering support===
'''Role: Engineer'''

'''Minimum requirements: Interest in software engineering'''

As the wiki grows, we need to ensure that the automation and infrastructure develops. We are especially looking for people with the following abilities:

* AWS reliability engineering/DevOps (people to manage infrastructure and deploy apps)
* PHP
* Front-end development
* Technical product ownership
* A scrum master/iteration manager

===Marketing===
'''Role: Based on experience and performance'''

'''Minimum requirements: Past experience in marketing, splendid communicator and creative individual who is eager to learn.'''

Our marketing department is expanding. If you are a creative individual who loves communicating, you could get a lot of significant responsibilities.

As our platform expands, our marketing efforts must do the same. Are you are eager to learn and would love to help us grow as quick as humanly possible?

Then, let’s talk: andreasdmelhede@gmail.com

=== Graphic design ===
'''Role: Illustrator, data visualization'''

'''Minimum requirements: Experience with graphic design'''

We are looking for individuals with graphic design skills to help us create and re-work pictures, scientific diagrams and graphs to communicate information to non-technical audiences. You will work closely with our content writers to produce high-impact, engaging visuals to accompany the written content.

=== Other roles ===
'''Role: Translator'''

We are looking for individuals with language skills to translate articles into other languages to reach a broader audience - particularly languages spoken commonly around the world. This will be done with the assistance of tools such as Google Translate.

'''Role: UX specialist'''

We are seeking expertise in user experience (UX) to help us design an intuitive and engaging platform. The goal is to create a satisfying experience for our users. You will work with the Head of UX in this role.

==Meeting minutes==
All meeting minutes can be viewed [https://en.longevitywiki.org/wiki/Handbook:Meeting_Minutes?venotify=created here].

==Organizational Constitution==

Handbook:Handbook

2021-08-18T18:05:37Z

SV: Merged Handbook and How to contribute pages

''Should be merged with the About page: [[About]] (Note: Should be an editable wiki-page)''

== Organizational Mission==
Being the go-to platform on all scientific areas related to longevity:

*Personal longevity strategies/advice
*Hallmarks of aging/biology of aging
*Longevity drugs
*Animal models of aging
*Laboratories working in geroscience, and their focus
*Longevity biotech (companies, development pipeline)
*Biology of aging + diseases of aging connection

==How to edit the Wiki==
The complete technical guide to editing the Wiki can be found [[How to contribute|here]].

=== Let us know first ===
If you want to help with the Longevity Wiki in any way, it's a good idea to [[Contact|contact us]] first, so we can help you get started. You can also join our [https://discord.gg/jBR5aRcpfV Discord Server] (a free chat platform) which is used for most internal communication in the wiki team.

=== Create content ===
Longevity Wiki uses the [[mediawikiwiki:MediaWiki|MediaWiki]] platform - the same as Wikipedia. This is the software that makes it possible to store all content, edit articles, track changes and more.

==== Create an account ====
If you want to edit the wiki, it's a good idea to create an account first. That way it's easier to keep track of your work and you get some extra functionality. To create an account, in the menu click the Account icon on the right (the 'little person') and click '''Create account''' and follow the instructions. Creating an account is not mandatory however for editing.

==== Create a page ====
To create a new article on the wiki, go to the menu and click '''Contribute''' and then '''Create new page'''. You will then be prompted to select a title for your article. After that, the Edit toolbar appears at the top and you can start writing. The Edit toolbar provides you with standard edit functions like making headings, bold text, insert links, insert images and much more.

When adding a new page related to longevity to the wiki, please make sure to categorize it as 'Longevity' so that it automatically appears in the Articles listing. (Save Changes -> Categories)

==== Edit a page ====
To edit an existing article, lookup the article, go to the menu and click '''Contribute''' and then (under 'This page...') click '''Edit'''. Then the Edit toolbar will open at the top, and you can start writing.
[[File:Text editor.png|none|thumb|732x732px|The '''Edit''' toolbar]]

==== Images ====
Often it's a good idea to include images in your article. Just make sure that if you use an image of someone else, you are not violating any copyright. In general, you are free to use images with a [https://creativecommons.org/ Creative Commons] license, but don't forget to use the right [https://creativecommons.org/use-remix/ attribution]. If you need help creating an image yourself, let us know in the Images channel on our [https://discord.gg/jBR5aRcpfV Discord Server], and we can help you create a unique and copyright-free image.

==== Referencing ====
For referencing to external sources (e.g. a journal article), Longevity Wiki uses the [[wikipedia:APA_style|APA referencing style]] - the same as Wikipedia. To create a reference, click '''Cite''' on the Edit toolbar. There are a few useful resources for creating citations, such as [https://zbib.org/ this one].

==== Writing style ====
The aim of the Wiki is to create '''comprehensive''', '''scientifically accurate''' and '''accessible''' content on longevity. The writing style we are aiming for is essentially the same as Wikipedia, in balancing technical and non-technical content. Here is our '''[[Writing tips for easy reading|writing guide]]''' to help you get started. More information on Wikipedia's writing style can be found in [[wikipedia:Wikipedia:Manual_of_Style|Wikipedia's Manual of Style]].

==Strategy==
Instead of producing as much content as possible, we’re going to focus on creating 5 pillar articles written by experts on the topic. These articles will demonstrate the knowledge and quality of our initiative, and then we will build out the wiki from there.

As for the 5 pillar articles, if you have a post-grad (MSc, PhD, MD) in a related area to one of the articles below, please rech

#'''Epigenetic reprogramming'''
#'''Aging and Neurodegeneration'''
#'''Rapamycin'''
#'''Biomarkers of healthspan'''
#'''COVID-19 and Aging'''

In conjunction with these articles, we are going to create a Glossary page of key terms in the longevity space, along with a short (2-3 sentence definition). This Glossary is the major area where we will need help from any interested content writers. We also will need people to help with marketing, and with the administration/organization of the wiki.

==Organization==

===General===

*Communications: Organizational discord server can be found [https://discord.gg/UDKmjcnjye here].
*Weekly Meetings, 10:30 a.m. (CET) on the Discord Server ''(TODO: other meetings, public calendar links for people to add?)''

*This wiki (Handbook namespace) as the source of truth for the organization
*Trello for Content Writers Task Management (In the future could be the Wiki itself): [https://trello.com/b/mfwbyEB6/content-creators Content creator board]
* Google Drive for presentations and unordered thoughts to share: [https://drive.google.com/drive/folders/19Ol2wcRd2IWUt_gOC5j5Ff7FjSzPVuBf Drive Link (public)]

===Engineering Team===

*Source code: [https://github.com/longevitywiki Github]
*Task management: [https://longevitywiki.atlassian.net/jira/software/projects/LW/boards/1 Jira]
*Documentation & roadmap: [https://longevitywiki.atlassian.net/wiki/spaces/LW/overview Confluence]

==Available Roles and Projects for the Wiki==
Longevity Wiki is an open access, collaborative project and we invite all volunteers to contribute! The goal of the Wiki is to create a trusted, high quality platform of longevity science content.

This chapter lists the current projects we are working on, and how you can get involved.

===Pillar article writing===
'''Role: Senior content writer'''

'''Minimum requirements: Masters or PhD training, ideally in a relevant field to content being written'''

We are seeking those with strong scientific backgrounds to help our initial offering of 20 ‘pillar’ articles that will form the initial content on the Wiki.

These articles are designed to be long-form (1.5-2.5k words) articles summarizing the relevant literature as it pertains to aging biology. The style we are aiming for is similar to a literature review, but with a simplified writing style that is accessible to non-specialist readers.

An example article is [[Rapamycin|here]], however, the style and structure of the article may vary by topic.

The following topics have been selected:

*Biomarkers of Healthspan
*Brain aging and neurodegeneration

If you are interested in volunteering to help research or write these articles, please contact Jack Harley at [[Mailto:jtt.harley@gmail.com|jtt.harley@gmail.com]] or Max Schons at [[Mailto:Maxxsschons@gmail.com|Mxschons@gmail.com]].

===Glossary expansion===
'''Role: Junior content writer'''

'''Minimum requirements: High school level biology'''

We are building a glossary of relevant terminology to expand the scope of the Wiki. This will be used to allow users to use the ‘hovercard’ feature to define any words they are unfamiliar with.

The list of glossary terms is being populated based on the pillar articles. A full list of glossary terms can be found here.

To contribute to the glossary, simply choose a term that has not yet been defined, and write a concise, and scientifically accurate definition.

*All references should be cited using APA referencing

*All links to internal articles should be linked
*Technical advice on how to edit the Wiki can be found [[Contribute|here]]
*Definitions are clear and comprehensible to non-specialist audiences.
*Definitions are up to 270 characters in length

An example of a glossary term can be found here.

===Life extension tool database===
'''Role: Researcher'''

'''Minimum requirements: Undergraduate biology, ability to comprehend data and research'''

We are creating a ‘life extension tool’ that allows the lifespan extension of certain drugs on various model organisms to be visualised.

A sample of the tool can be viewed here. In order to populate data for the tool, we require assistance in reviewing the literature to identify the lifespan extension associated with different drugs, and the original publication in which this was published.

The current database of life-extension data can be viewed and edited here.

===Software engineering support===
'''Role: Engineer'''

'''Minimum requirements: Interest in software engineering'''

As the wiki grows, we need to ensure that the automation and infrastructure develops. We are especially looking for people with the following abilities:

* AWS reliability engineering/DevOps (people to manage infrastructure and deploy apps)
* PHP
* Front-end development
* Technical product ownership
* A scrum master/iteration manager

===Marketing===
'''Role: Based on experience and performance'''

'''Minimum requirements: Past experience in marketing, splendid communicator and creative individual who is eager to learn.'''

Our marketing department is expanding. If you are a creative individual who loves communicating, you could get a lot of significant responsibilities.

As our platform expands, our marketing efforts must do the same. Are you are eager to learn and would love to help us grow as quick as humanly possible?

Then, let’s talk: andreasdmelhede@gmail.com

=== Graphic design ===
'''Role: Illustrator, data visualization'''

'''Minimum requirements: Experience with graphic design'''

We are looking for individuals with graphic design skills to help us create and re-work pictures, scientific diagrams and graphs to communicate information to non-technical audiences. You will work closely with our content writers to produce high-impact, engaging visuals to accompany the written content.

=== Other roles ===
'''Role: Translator'''

We are looking for individuals with language skills to translate articles into other languages to reach a broader audience - particularly languages spoken commonly around the world. This will be done with the assistance of tools such as Google Translate.

'''Role: UX specialist'''

We are seeking expertise in user experience (UX) to help us design an intuitive and engaging platform. The goal is to create a satisfying experience for our users. You will work with the Head of UX in this role.

==Meeting minutes==
All meeting minutes can be viewed [https://en.longevitywiki.org/wiki/Handbook:Meeting_Minutes?venotify=created here].

==Organizational Constitution==

Handbook:Meeting Minutes

2021-08-18T17:07:20Z

SV: Minor language edits

== 18/08/2021 ==

=== 🧍 Attending ===
* Jack Harley
* Bogdan Dziewierz
* Max Schulz
* Andreas Melhede
* Sam Voigt
* Marc Smeehujizen
* Heye Groß

=== 📣 Updates Roundtable ===
Jack Harley

* India times article is being finalised, to be released next week or week after. New co-author [https://medicine.nus.edu.sg/bch/faculty/brian-kennedy/ Brian Kennedy] joined

* More contributors interested to join the project. There is a need for people to help with on-boarding new contributors

* Gave a talk in EA group in Melbourne. This was followed up with an invitation to the medical conference in Melbourne.

* Handbook work is progressing'''.''' We need to make it more prominent and visible in the menu.

''Bogdan Dziewierz''

* Custom namespace "Handbook" created on the Wiki
* Engineering iteration meeting needs to be scheduled. Created new #engineering channel in Discord to help with coordination of such activities.
* Slowly progressing on Life Extension tool

''Heye Groß''

* Will get more involved in Longevity Wiki over next weeks. More clear on working hours.
* Discussed whether Longevity is a topic that is / should be on the agenda for EA compared to other existential risks and how EA can be used as spread-the-word or funding platform for Longevity effectively.
* Open Philantropy: Donates to the most effective areas but have a pessimistic view of longevity research. We think their evaluation is limited because they haven’t done cost / benefits calculation of investing into geroscience. Can be low-hanging fruit for donations, provided cost / benefit calculation is done for them.

''Jack Harley''

* Let’s try to organise symposium or conference once we get funding. EA could be convinced to fund this initiative.

''Max Schulz''

* Meeting Organization in general: I also like the process of always having a pre-created meeting topics from participants file for the next meeting
** Every participant plan can add his points already (I personally like to do this), then the meeting owner already has an idea in advance what people want to talk about and how to potentially structure it (Jack Harley in this case?)
* Updated the about page with pillar articles and ongoing projects suggestion ([[Handbook:Handbook]]). Some open points on my side (see page)
** 5 or 20 pillar articles to start with? Saw conflicting information
** Content should be merged with: [[About]], [[How to contribute]] (Especially "Other Roles")
** In the visual editor, there are quite some "paragraphs" that I can't delete, they don't show up in the source editor ...?
** Open calendar links for meetings would be good (also are there other meetings to know of...?)
* How do you currently navigate the articles on the wiki? For example, how do you find the handbook article? (Any ongoing efforts on the navigation side?)
* There are article drafts shared on Discord with Google Docs, we should encourage everybody to directly write to the Wiki so this work doesn't get lost (e.g. [https://docs.google.com/document/d/1gSJjEJbP_A1Qs_uewoWjkSFUhsyfN1IUNUYIVuxDb7E/edit link]) (The "core articles" that we want to work on should just be categorized accordingly IMHO)
** Similarly, with the glossary suggestion - better if it would be already added to the wiki instead: [https://docs.google.com/document/d/1q2dlsLK76bAXyU3ZPZ_eWn_oI3UFQEtie_8D2nRH5cQ/edit#heading=h.lhdrp4ijtcd2 google docs]
* What is the status of the vision and action plan? ([https://docs.google.com/presentation/d/1rlPZyncQGRW6koCunM23msQyVWEQ0CVyGMnMAUSaE8U/edit#slide=id.g655cbd83be_0_18 Google Slides])
* Idea to try get some funding from the upcoming Gitcoin round from VitaDAO? I know that the high quality articles would make the case stronger, on the other hand they explicitly want to also go for early projects and "open science": [https://docs.google.com/document/d/13rjnkgxCdQ63V1M69cE-moeY6ktRfo5XIF8E9nwaeIU/edit Quadratic Funding Round Document]
* Last week, the process of registering a non-profit was quickly discussed but it's not in the minutes (I don't remember what was discussed)

''Heye Groß / Jack Harley / Bogdan Dziewierz''

* There is need to think about what we need money for so that we can start participating in funding rounds / grants / etc.

''Andres Melhede''

* Waiting for India article so that it can be used as a source for more content to be used on Social Media

{| class="wikitable"
|
=== ✅ Action Items ===

* Jack: There is a need for volunteers to help with on-boarding new contributors

* Bogdan: We need to make it more prominent and visible in the menu
* Bogdan: How to contribute menu item needs to be replaced with Handbook
* Jack: We need to brainstorm and document what we need the funds for so that we can start participating in funding rounds / grants / etc.
* Jack: Let’s try to organise symposium or conference once we get funding.
* Max: Max to follow up with VitaDAO to find out if we can participate in their Gitcoin round.
|}

== 11/08/2021 ==

=== Purpose ===
Regular weekly meeting

=== 🧍 Attending ===

* Jack Harley, Co-Founder
* Bogdan Dziewierz, Co-founder & Head of Engineering
* Max Schons, Content Writer
* Max Schulz, Engineering Team Member and Organisational Consultant
* Ben Wu, Head of Content
* Andreas Melhede, Head of Marketing
* Sharon Wong, Content Translator

=== 📣 Updates Roundtable ===

# Name: Max Schulz
## Discussed benefits of the ‘handbook-first’ approach, such as convenience in onboarding new volunteers to the organisation, and having a centralized knowledge base for strategy and roadmap documents. Brought up the need for a central landing page upon which organisational links are easily accessible.
## Discussed platforms for hosting the Handbook, such as Confluence.
# Name Bogdan
## Suggested using the Wiki itself as the ‘Handbook’, and Confluence for the engineering activities. The rest of the team agreed. Offered to create a namespace using MediaWiki for the handbook and landing page.
## Life extension tool is a work in progress.
# Name Jack
## Discussed the role of content writer manager, and suggested Max Schulz be introduced to this role.
## Once content writers are on board with the new content writing strategy, those with a biology background can be tasked with adding data to the life extension tool.
# ‍Name Max Schons
## Outlined briefly the content strategy of creating a few high quality articles then seeking the endorsement of experts in the field, to attract more high quality contributors.
## Provided example of meeting minutes layouts in a handbook: <nowiki>https://github.com/mermaid-js/mermaid/releases</nowiki>
# Name Ben
## Provided update on the Times of India article, which will be published in the coming 1-2 weeks. The article will mention Longevity Wiki in the authors’ biographies section.
# Name Sharon
## Offered to review meeting minutes, and provided suggestions for the minutes - including key references and links at the beginning of the minutes.
# Name Andreas
## Provided updates on social media accounts.
## Did several edits and suggestions for the Aging Article for the Indian News Site.

{| class="wikitable"
|
=== ✅ Action Items ===

* Bogdan to create namespace for Handbook, and Handbook landing page
* Jack follow up on Max’s organizational wiki suggestions
* Jack to follow up with Max Schulz regarding content writers management
* Jack to assign organizational document writing to other members
* Bogdan to organize an Engineering team spring meeting
* Jack to create and share a document of organizational processes
* Max Schulz to forward exemplary handbook to Jack
* Max Schons to continue working on Biomarkers of Healthspan article
* Ben Wu to continue working on Aging Epigenetics article
|}

== 04/08/2021 ==

=== 🧍 Attending ===

* Jack Harley, Co-Founder
* Bogdan Dziewierz, Co-founder & Head of Engineering
* Marc Smeehuijzen, Head of UX
* Ben Wu, Head of Content
* Andreas Melhede, Head of Marketing

=== 📣 Updates Roundtable ===

# Name: Bogdan
## Had the kick-off engineering meeting 30 July 2021 with Sam Voigt, Maximilian Schulz and Mark Whitlock. He setup Jira and Confluence. (These are popular project management tools in IT development). The engineering cards on Trello will be moved to Jira. For more details on this meeting, see the minutes on Confluence. (If you don’t have access to Confluence, ask Bogdan).
## Suggestion: split weekly meetings per department (so engineering, marketing, content, etc. all have their own weekly meeting instead of everybody in the same meeting).
## Suggestion: we could move the draft articles that we’re working on from Google Docs to the wiki itself. This way visitors can see the wiki is alive and check recent changes of the articles.
## Continue working on the Life Extension Tool and a glossary extension for the wiki, among other things. We might develop other tools in the future. Jack for instance suggested an interactive roadmap for longevity laboratories in the world.
# Name Ben
## There is a little delay in writing the India Times article on longevity. But it’s 90% done. He will see if we can get a famous professor as co author (e.g. David Sinclair). On Google Docs there’s a draft of the article and members of the team are welcome to provide feedback
# Name Jack
## Talked to Maximillian Schulz who made a number of interesting organizational suggestions for the wiki (see Jack’s email from 4 Aug. 2021). There is a need for organizational docs to be made transparently accessible on the Wiki, and we proposed this be in the form of pages on the Wiki categorized accordingly.
## New marketing expert is interested in joining the project, could work alongside Andreas
## Plan to reach out to expert in Rapamycin (Mikhail Blagosklonny) to seek a review/endorsement for this article on the Wiki.
## Looking for someone who can manage the content writers.
# ‍Name Marc
## Updated the design for the Life Extension Tool. There are now two modes: 1. you can see per species what % life extension has been achieved per intervention and 2. you can see per intervention what % life extension has been achieved per species. The designs can be found on Zeplin. (If you don’t have access to Zeplin, please send Marc your email address so he can add you). He also posted some screenshots of the designs in the UX channel on our Discord server.
## Made English to Dutch translations of the interface elements of the wiki (document is on Google Drive).
# Name Andreas
## Made some social media posts on the 5 key articles that we’re working on.
## Engagement and sharing relevant content on the various social media platforms (especially focused on Twitter)

{| class="wikitable"
|
=== ✅ Action Items ===

* Ben looks for famous professor as co author for India Times article
* Jack follow up on Maximillian’s organizational wiki suggestions
* Jack looks for someone to manage the content writers
* Jack to assign organizational document writing to other members
* Marc joins the engineering team and moves his Trello cards to Jira
|}

== 29/07/2021 ==

=== 🧍 Attending ===

* Jack Harley, Co-Founder
* Andreas Melhede, Head of Marketing
* Ben Wu, Head of Content

=== 🙌 Celebrate wins ===

* New software developer, Mark Whitlock, will join the IT team to help develop the technical side
* Database for the Life Extension Tool (the UX design for which can be viewed here) has been created

=== 💬 Discussion Topics ===

* Who are we trying to target with content? Discussed the need for content that appeals to the masses to fill a gap in content in this space. While we hope to create content that scientists will read, and for credibility most will likely stick with reading review articles so we should bear in mind our target audience of non-specialists.

=== 📣 Updates Roundtable ===

# Name: Jack
## A new contributor, Max Schultz, who has written blog posts about knowledge databases has provided a report on the state of the Wiki, offering avenues for expanding the Wiki. The notes for his meeting agenda with me are attached below this document.
## We have created an excel spreadsheet of data for the Life extension tool, and are encouraging contributors to help expand the data.
## Have created a new folder in the Google Drive called ‘Weekly Meetings’ wherein this Meeting Minutes and future minutes can be saved.
## Discussed the need to update content writers with a new approach of creating a glossary for pillar articles.
# Name Ben
## Joao Pedro’s database contains an extensive list of drugs and their life extension effects, which we can draw from for our own tool. <nowiki>https://genomics.senescence.info/drugs/browse.php</nowiki>

<nowiki>https://genomics.senescence.info/drugs/</nowiki>

We should aim to create a more user-friendly, and simplified version for our tool, focusing on ~20 key drugs that are most relevant to today’s life extension protocols.

# We should focus on data from the ITP (NIA’s Intervention Testing Program) as this is a rigorous and reliable test.

# Name Andreas
## Clarifying the target audience as primarily those who are non-specialists
## Clarified the style of social media posts, as evidence-based and reliable, as advised by Ben.

‍
{| class="wikitable"
|
=== ✅ Action Items ===

* Jack meeting with Max Shulz to discuss further collaboration ideas
* Ben to add list of drugs of interest to lifespan extension tool database
* Ben to add relevant sources to the database for content writers - E.g. ITP
* Assign content writers / other team members with science background to assist with completing data for the life extension tool
* Andreas to create Discord channel for meeting minutes
* Communicate to content writers the new deliverables of expanding the glossary associated with the ‘pillar’ articles
|}

Metformin

2021-06-25T09:20:25Z

SV: Edited the reference I added (to APA)

Metformin is an approved medication<ref name=":0">''Metformin: Medicine to treat type 2 diabetes''. (2019, February 25). NHS. https://www.nhs.uk/medicines/metformin/</ref> used to treat type 2 diabetes. It has been proposed as having longevity benefits based on data suggesting that it extends lifespan in people with diabetes more than in those without it. For this reason, it is currently being considered in the first large-scale human longevity trial - the TAME trial.<ref name=":1" />[[File:Metformin.svg.png|thumb|The chemical structure of Metformin]]

== Use in Medicine ==

Metformin is a common, inexpensive drug that has been used to treat and prevent type 2 diabetes for over 60 years. It is known to reduce the amount of sugar the liver releases into the blood and helps the body respond better to insulin.<ref>''Metformin: Medicine to treat type 2 diabetes''. (2019, February 25). NHS.https://www.nhs.uk/medicines/metformin/#:~:text=Metformin%20works%20by%20reducing%20the,to%20reduce%20the%20side%20effects.</ref> Metformin is also used to treat metabolic syndrome, which is a combination of obesity, high blood pressure and diabetes, and is sometimes used for polycystic ovary syndrome (PCOS).<ref name=":0" />
== Life extension effects ==
=== Life extension in model organisms ===
In animal trials, metformin has been found to extend the lifespan of worms, mice, fruit flies and yeast from 5-50%.<ref>Lamming, D. W., Sabatini, D. M., & Baur, J. A. (2012). Pharmacologic means of extending lifespan. ''Journal of Clinical & Experimental Pathology'', ''Suppl 4''. https://doi.org/10.4172/2161-0681.S4-002</ref>

=== Life extension in humans ===
Research undertaken since metformin was approved by the FDA in 1994 has found that people who take metformin tend to be healthier than those who take another diabetes-related drug.<ref>Saraei, P., Asadi, I., Kakar, M. A., & Moradi-Kor, N. (2019). The beneficial effects of metformin on cancer prevention and therapy: A comprehensive review of recent advances. ''Cancer Management and Research'', ''11'', 3295–3313. https://doi.org/10.2147/CMAR.S200059</ref> They live longer, have fewer cardiovascular issues, get cancer less often, and tend to outlive other people with both diabetes and cancer on different medications.

In a retrospective observational study of 90,400 subjects with diabetes who took metformin, compared to those taking another diabetes drug, and a matched control group of subjects without diabetes, it was found that metformin patients not only outlived the other subjects with diabetes but also lived longer than the subjects in the control group.<ref>Bannister, C. A., Holden, S. E., Jenkins-Jones, S., Morgan, C. L., Halcox, J. P., Schernthaner, G., Mukherjee, J., & Currie, C. J. (2014). Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. ''Diabetes, Obesity and Metabolism'', ''16''(11), 1165–1173. https://doi.org/https://doi.org/10.1111/dom.12354</ref> While there are various criticisms of the methodology of this paper, this has led scientists at the forefront of longevity to consider metformin as a drug with the potential to extend healthy lifespans – which could help people to not just live longer, but live more healthily for longer.

== Mechanism ==
Metformin mimics the processes involved with dietary restriction without the person having to restrict their diet.<ref>Lee, S.-H., & Min, K.-J. (2013). Caloric restriction and its mimetics. ''BMB Reports'', ''46''(4), 181–187. https://doi.org/10.5483/BMBRep.2013.46.4.033</ref> Pathways involved in longevity signaling in human cells are increased with metformin, which can help reduce the harmful effects of sugar and fat storage, and prevent hardening of the arteries.

Both type 1 and type 2 diabetes are regarded by aging biology researchers as diseases of accelerated aging. They lead to premature morbidity and mortality due to frailty, cancer, stroke, heart disease, dementia, kidney disease, diabetic retinopathy, peripheral neuropathy, and many other age-related diseases.

As metformin is known to inhibit complex I of the mitochondria to activate AMPK and reduce mTOR signaling, which are molecular pathways associated with aging, there is biological rationale for repurposing this diabetes drug as a potential drug for healthy aging in people without diabetes.<ref>Vial, G., Detaille, D., & Guigas, B. (2019). Role of mitochondria in the mechanism(s) of action of metformin. ''Frontiers in Endocrinology'', ''10''. https://doi.org/10.3389/fendo.2019.00294</ref>

== The TAME Trial ==
Studies have shown that metformin can delay the effects of aging in animals, and it seems fairly likely that these benefits may extend to humans as well. The Targeting Aging with Metformin (TAME) trials are a series of clinical trials at 14 leading research institutions in the United States. They are looking to study whether metformin can delay the development or progression of age-related diseases (such as dementia and cancer) in 3,000 65-to-79-year-olds over six years.<ref name=":1">''TAME – Targeting Aging with Metformin''. (n.d.). American Federation for Aging Research. https://www.afar.org/tame-trial </ref>

== Side effects ==
Common side effects (which affect 1 in 100 people) include feeling or being sick, stomach ache, loss of appetite and/or a metallic taste in the mouth.

Serious side effects are very rare and affect less than 1 in 10,000 people. These can include severe tiredness, a slow heart rate, liver problems, or a rash. It is also possible to have a serious allergic reaction (anaphylaxis) to metformin if one is allergic to its active ingredients.

== References ==

Resveratrol

2021-06-24T13:26:42Z

SV: Added doi links

[[File:Resveratrol.png|thumb|200x200px|The chemical structure of trans-resveratrol.]]
Resveratrol (trans‐3,5,4′‐trihydroxystilbene) is a compound produced naturally by various plants in response to injury or microbial infection. Its main dietary sources include grapes, blueberry, cranberry, peanuts, and legumes.<ref>Tian, B., & Liu, J. (2020). Resveratrol: A review of plant sources, synthesis, stability, modification and food application. ''Journal of the Science of Food and Agriculture'', ''100''(4), 1392-1404. https://doi.org/10.1002/jsfa.10152</ref> Resveratrol has gained widespread scientific attention after reports of its lifespan extension properties in a range of model organisms.<ref>Bhullar, K. S., & Hubbard, B. P. (2015). Lifespan and healthspan extension by resveratrol. ''Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease'', ''1852''(6), 1209-1218. https://doi.org/10.1016/j.bbadis.2015.01.012</ref> Resveratrol is currently considered a dietary supplement and is not an approved medicine.

== Evidence of lifespan extension ==
Resveratrol has been shown to extend healthy lifespan in yeast, worms, fruit flies, bees, and fish by 10-70%. <ref>Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., ... & Sinclair, D. A. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. ''Nature'', ''425''(6954), 191-196. https://doi.org/10.1038/nature01960</ref><ref>Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M., & Sinclair, D. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. ''Nature'', ''430''(7000), 686-689. https://doi.org/10.1038/nature02789</ref><ref>Rascón, B., Hubbard, B. P., Sinclair, D. A., & Amdam, G. V. (2012). The lifespan extension effects of resveratrol are conserved in the honey bee and may be driven by a mechanism related to caloric restriction. ''Aging (Albany NY)'', ''4''(7), 499. https://doi.org/10.18632/aging.100474</ref><ref>Valenzano, D. R., Terzibasi, E., Genade, T., Cattaneo, A., Domenici, L., & Cellerino, A. (2006). Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. ''Current biology'', ''16''(3), 296-300. https://doi.org/10.1016/j.cub.2005.12.038</ref><ref>Yu, X., & Li, G. (2012). Effects of resveratrol on longevity, cognitive ability and aging-related histological markers in the annual fish Nothobranchius guentheri. ''Experimental gerontology'', ''47''(12), 940-949. https://doi.org/10.1016/j.exger.2012.08.009</ref> In mice on a high-calorie diet, resveratrol reduced the risk of death from the diet by 31%.<ref>Baur, J. A., Pearson, K. J., Price, N. L., Jamieson, H. A., Lerin, C., Kalra, A., ... & Sinclair, D. A. (2006). Resveratrol improves health and survival of mice on a high-calorie diet. ''Nature'', ''444''(7117), 337-342. https://dx.doi.org/10.1038/nature05354</ref> No lifespan extension has been observed in healthy mice and rats.<ref>Pearson, K. J., Baur, J. A., Lewis, K. N., Peshkin, L., Price, N. L., Labinskyy, N., ... & de Cabo, R. (2008). Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. ''Cell metabolism'', ''8''(2), 157-168. https://doi.org/10.1016/j.cmet.2008.06.011</ref><ref>Miller, R. A., Harrison, D. E., Astle, C. M., Baur, J. A., Boyd, A. R., De Cabo, R., ... & Strong, R. (2011). Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. ''The Journals of Gerontology: Series A'', ''66''(2), 191-201. https://doi.org/10.1093/gerona/glq178</ref><ref>Strong, R., Miller, R. A., Astle, C. M., Baur, J. A., De Cabo, R., Fernandez, E., ... & Harrison, D. E. (2013). Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''68''(1), 6-16. https://dx.doi.org/10.1093/gerona/gls070</ref><ref>da Luz, P. L., Tanaka, L., Brum, P. C., Dourado, P. M. M., Favarato, D., Krieger, J. E., & Laurindo, F. R. M. (2012). Red wine and equivalent oral pharmacological doses of resveratrol delay vascular aging but do not extend life span in rats. ''Atherosclerosis'', ''224''(1), 136-142. https://doi.org/10.1016/j.atherosclerosis.2012.06.007</ref>

== Human clinical trials ==
A range of clinical trials investigating the health benefits of resveratrol supplementation has been performed, some carrying conflicting results.<ref name=":0" /><ref name=":1" /> Resveratrol has been shown to improve glucose control and insulin sensitivity in persons with type 2 diabetes, and modulate some cancer-related genes.<ref>Liu, K., Zhou, R., Wang, B., & Mi, M. T. (2014). Effect of resveratrol on glucose control and insulin sensitivity: a meta-analysis of 11 randomized controlled trials. ''The American journal of clinical nutrition'', ''99''(6), 1510-1519. https://doi.org/10.3945/ajcn.113.082024</ref><ref>Zhu, X., Wu, C., Qiu, S., Yuan, X., & Li, L. (2017). Effects of resveratrol on glucose control and insulin sensitivity in subjects with type 2 diabetes: Systematic review and meta-analysis. ''Nutrition & metabolism'', ''14''(1), 1-10. https://doi.org/10.1186/s12986-017-0217-z</ref><ref>Ko, J. H., Sethi, G., Um, J. Y., Shanmugam, M. K., Arfuso, F., Kumar, A. P., ... & Ahn, K. S. (2017). The role of resveratrol in cancer therapy. ''International journal of molecular sciences'', ''18''(12), 2589. https://dx.doi.org/10.3390/ijms18122589</ref> Resveratrol supplementation in postmenopausal women (150 mg per day for 12 months) resulted in improvement of overall cognitive performance.<ref>Zaw, J. J. T., Howe, P. R., & Wong, R. H. (2020). Sustained cerebrovascular and cognitive benefits of resveratrol in postmenopausal women. ''Nutrients'', ''12''(3), 828. https://doi.org/10.3390/nu12030828</ref> The study concluded that resveratrol supplementation could potentially reverse cognitive ageing by up to 10 years.

== Safety and bioavailability ==
It has been shown that resveratrol is generally safe in humans.<ref name=":0">Singh, A. P., Singh, R., Verma, S. S., Rai, V., Kaschula, C. H., Maiti, P., & Gupta, S. C. (2019). Health benefits of resveratrol: Evidence from clinical studies. ''Medicinal research reviews'', ''39''(5), 1851-1891. https://doi.org/10.1002/med.21565</ref><ref name=":1">Bitterman, J. L., & Chung, J. H. (2015). Metabolic effects of resveratrol: addressing the controversies. ''Cellular and Molecular Life Sciences'', ''72''(8), 1473-1488. https://doi.org/10.1007/s00018-014-1808-8</ref> Mild adverse effects such as nausea, diarrhea, and abdominal pain have been reported with doses of 1 g per day and higher.<ref>Brown, V. A., Patel, K. R., Viskaduraki, M., Crowell, J. A., Perloff, M., Booth, T. D., ... & Brenner, D. E. (2010). Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis. ''Cancer research'', ''70''(22), 9003-9011. https://doi.org/10.1158/0008-5472.can-10-2364</ref><ref>Patel, K. R., Scott, E., Brown, V. A., Gescher, A. J., Steward, W. P., & Brown, K. (2011). Clinical trials of resveratrol. ''Annals of the New York Academy of Sciences'', ''1215''(1), 161-169. https://doi.org/10.1111/j.1749-6632.2010.05853.x</ref>

Resveratrol is quickly metabolized and is poorly absorbed in the human body, which limits its potential for clinical use.<ref>Muñoz, O., Muñoz, R., & Bustamante, S. (2015). Pharmacological properties of resveratrol. A pre-clinical and clinical review. ''Biochem Pharmacol (Los Angel)'', ''4''(184), 2167-0501.</ref>

== Mechanism ==
Resveratrol can most likely act through multiple mechanisms in the cell.<ref name=":1" /> One of its crucial targets is Silent Information Regulator 1 (SIRT1), a protein proposed to mediate the beneficial effects of caloric restriction, as well as regulate pathways involved in mitochondrial biogenesis and inflammation. <ref name=":0" />

== References ==

Epigenetic clock

2021-06-24T13:06:56Z

SV: Fixing my own bad referencing

Biological age is a measure of a person's position along their lifespan. '''Epigenetic clocks''' are one way to measure biological age, and are based on a subject's DNA methylation (DNAm) status, also often referred to as ''DNAm age'' or ''epigenetic age''. These clocks have been shown to predict all-cause mortality better than chronological age and traditional risk factors.<ref>Chen, B. H., Marioni, R. E., Colicino, E., Peters, M. J., Ward-Caviness, C. K., Tsai, P.-C., Roetker, N. S., Just, A. C., Demerath, E. W., Guan, W., Bressler, J., Fornage, M., Studenski, S., Vandiver, A. R., Moore, A. Z., Tanaka, T., Kiel, D. P., Liang, L., Vokonas, P., … Horvath, S. (2016). DNA methylation-based measures of biological age: meta-analysis predicting time to death. ''Aging (Albany NY)'', ''8''(9), 1844–1859. https://doi.org/10.18632/aging.101020</ref>

By measuring biological age, researchers can identify people who exhibit accelerated aging and would therefore benefit the most from an anti-aging drug, and determine whether an aging intervention slows or even reverses aging.<ref>Ferrucci, L., Gonzalez-Freire, M., Fabbri, E., Simonsick, E., Tanaka, T., Moore, Z., Salimi, S., Sierra, F., & Cabo, R. de. (2020). Measuring biological aging in humans: A quest. ''Aging Cell'', ''19''(2), e13080. https://doi.org/https://doi.org/10.1111/acel.13080</ref> Quantifying biological age is considered important for longevity research because it would be less feasible to run clinical trials over several decades to know whether human life has been extended. Instead, it would be more practical to use biological aging clocks to predict if a therapy is likely to extend healthspan and lifespan within a shorter timeframe.
== Mechanism ==
The epigenetic clock works by measuring DNA methylation levels, i.e., the number and distribution of methyl groups attached to the DNA molecule. These ‘tags’ signal genes to be turned on or off.

Epigenetic clocks appear to measure a universal feature of aging across species. The same algorithm, based on the same set of biomarkers (DNAm) has been shown to strongly predict chronological age in hundreds of animals, including mice, bats, and humans. Notably, the residual or unexplained variance of epigenetic clocks (such as GrimAge) for prediction of chronological age appears to further capture biological age.<ref name=":0">Lu, A. T., Quach, A., Wilson, J. G., Reiner, A. P., Aviv, A., Raj, K., Hou, L., Baccarelli, A. A., Li, Y., Stewart, J. D., Whitsel, E. A., Assimes, T. L., Ferrucci, L., & Horvath, S. (2019). DNA methylation GrimAge strongly predicts lifespan and healthspan. ''Aging'', ''11''(2), 303–327. https://doi.org/10.18632/aging.101684</ref> For GrimAge, this aspect is referred to as AgeAccelGrim, where the regression of DNA GrimAge on chronological age predicts whether biological age is greater or lesser than chronological age.<ref name=":0" /> In other words, epigenetic clocks accurately predict one's age based on various DNAm biomarkers, but the error in prediction reflects the differences in rates of biological aging between individuals.

[[wikipedia:DNA_methylation|DNA methylation]] is the attachment of a methyl group to one of the “links” in the DNA strain (specifically, cytosine nucleotide). This does not affect the content of the DNA itself, but it does affect how it is read and used by the cell. This is one of the group of changes called epigenetics – changes in the organism's physical function which do not alter the DNA sequence itself, but can be inherited under certain conditions.

There have been a number of studies showing that as humans (and other mammals) age, patterns of methylation in their DNA change in certain ways.<ref>Fransquet, P. D., Wrigglesworth, J., Woods, R. L., Ernst, M. E., & Ryan, J. (2019). The epigenetic clock as a predictor of disease and mortality risk: A systematic review and meta-analysis. ''Clinical Epigenetics'', ''11''(1), 62. https://doi.org/10.1186/s13148-019-0656-7</ref> The exact patterns of change are quite complex and not yet fully described, but broadly, two tendencies have been detected. First, the global level of methylation decreases, unequally in different tissues (for example, in mice, methylation levels decreased in the brain, heart, and spleen, but not in the lungs or liver). Secondly, the local methylation levels increase in certain locations: CpG islands (regions on a DNA strain where the sequence cytosine-guanine occurs with high frequency) and bivalent chromatin domain promoters (a promoter is a DNA sequence which initiates the transcription of the gene following it).

These changes can be used to estimate the biological age of the organism, and there are a [[wikipedia:Epigenetic_clock#Other_age_estimators_based_on_DNA_methylation_levels|number of approaches]] to achieving this measurement, the most common being the Horvath’s clock, developed by Horvath et al. in 2013.<ref>Bocklandt, S., Lin, W., Sehl, M. E., Sánchez, F. J., Sinsheimer, J. S., Horvath, S., & Vilain, E. (2011). Epigenetic predictor of age. ''PLOS ONE'', ''6''(6), e14821. https://doi.org/10.1371/journal.pone.0014821</ref> They used publicly available datasets of methylation data collected on [[wikipedia:Illumina,_Inc.|Illumina]] chips, and analyzed 21,369 CpG sites available on both 27k and 450k chips (the number referring to the total number of sites that the chip analyzes). The team then used a penalized regression model (elastic net regularization, which is essentially a linear combination of lasso and ridge regularization penalties, which thus drives the model to have both smaller coefficients and fewer of them) to identify 353 sites providing the most signals, of which 193 correlated with age positively, and the remaining 160 negatively. The clock then applies a calibration function to the weighted average of these 353 sites methylation levels to determine the biological age.

== Discovery ==
Changes in methylation levels with aging have been observed for some time. The first work using epigenetic changes as a basis for biological clocks was published in 2009 by Schumacher.<ref>Schumacher, A. (2009). ''An epigenetic clock: Anticorrelation & DNA methylation as biomarker for aging.'' https://doi.org/10.13140/RG.2.2.12457.83042</ref> In 2013, the labs of Trey Ideker and Kang Zhang at the University of California, San Diego published the Hannum epigenetic clock, which consisted of 71 markers which accurately estimate age based on blood methylation levels.<ref>Hannum, G., Guinney, J., Zhao, L., Zhang, L., Hughes, G., Sadda, S., Klotzle, B., Bibikova, M., Fan, J.-B., Gao, Y., Deconde, R., Chen, M., Rajapakse, I., Friend, S., Ideker, T., & Zhang, K. (2013). Genome-wide methylation profiles reveal quantitative views of human aging rates. ''Molecular Cell'', ''49''(2), 359–367. https://doi.org/10.1016/j.molcel.2012.10.016</ref> In the same year, the first multi-tissue epigenetic clock was developed by Steve Horvath, a professor of human genetics and of biostatistics at UCLA.<ref>Horvath, S. (2013). DNA methylation age of human tissues and cell types. ''Genome Biology'', ''14''(10), 3156. https://doi.org/10.1186/gb-2013-14-10-r115</ref> Horvath’s clock allows the measurement of the age of different tissues of the same organism with the same clock, so it is the most widely used in aging research today.

== Epigenetic clocks and aging ==

It is not fully known whether epigenetic changes are a cause or consequence of other aging processes. Several theories have been proposed, and are explained below:

=== Link with Hallmarks of Aging ===
There is evidence that changed methylation patterns can be linked to some of the [[Hallmarks of Aging|hallmarks of aging]]: loss of proteostasis, mitochondrial dysfunction, stem cell exhaustion, and immunosenescence.<ref>Jiang, S., & Guo, Y. (2020, July 8). ''Epigenetic clock: DNA methylation in aging'' [Review Article]. Stem Cells International. https://doi.org/https://doi.org/10.1155/2020/1047896</ref> Lu, Yuancheng, et al. were able to reverse age-induced loss of sight from glaucoma, and even regenerate a mechanically damaged eye nerve, by manipulating methylation patterns in mice.<ref name=":1">Lu, Y., Brommer, B., Tian, X., Krishnan, A., Meer, M., Wang, C., Vera, D. L., Zeng, Q., Yu, D., Bonkowski, M. S., Yang, J.-H., Zhou, S., Hoffmann, E. M., Karg, M. M., Schultz, M. B., Kane, A. E., Davidsohn, N., Korobkina, E., Chwalek, K., … Sinclair, D. A. (2020). Reprogramming to recover youthful epigenetic information and restore vision. ''Nature'', ''588''(7836), 124–129. https://doi.org/10.1038/s41586-020-2975-4</ref> They used three out of the four so-called 'Yamanaka factors', which are proteins necessary for reprogramming adult somatic cells back to pluripotent stem cells. Using the factors in live organisms for prolonged periods of time is known to cause cancer by boosting up cell division. But, with the exclusion of one of these factors (c-Myc), that is known to be oncogenic. The other three factors were kept active in mice for over a year without inducing any tumors.

The induction of these factors allowed the mice to regrow a mechanically damaged optic nerve. Normally, a mouse's optic nerve can regrow during early development, but then loses this ability a few days after birth. In this experiment, adult mice were able to re-obtain a similar regenerative ability and regained around half of their lost visual acuity.

Another result achieved using the Yamanaka factors was the restoration of the vision of healthy, middle-aged (one-year-old) mice. Before treatment, these mice scored worse than the younger mice on tests of visual acuity, but one month after treatment, they had similar results

=== Information theory of aging ===
Another theory, popularised by Professor David Sinclair, is that epigenetic changes might be the master regulator of aging - known as [https://hplus.club/blog/a-summary-of-david-sinclairs-information-theory-of-aging/ the information theory of aging].

Since DNA is identical in every somatic cell, each cell needs to “know” which genes to read in order to differentiate itself from a stem cell and perform its function. For example, a neuron cell only expresses (i.e. uses) genes relevant for being a neuron, and not a muscle cell or a skin cell. This is achieved through methylation and other epigenetic mechanisms.

The theory goes that aging is fundamentally caused by the accumulation of the effects of errors in this process, eventually causing a cell to stop functioning normally and either become cancerous or die.

== Relevance for longevity research ==

=== Smoking ===
Research shows that smoking increases epigenetic age of buccal cells, airway cells, esophagus tissue, and lung tissue. Quitting smoking causes the epigenetic age acceleration in airway cells (but not in lung tissue) to revert to the level of non-smokers.<ref>Wu, X., Huang, Q., Javed, R., Zhong, J., Gao, H., & Liang, H. (2019). Effect of tobacco smoking on the epigenetic age of human respiratory organs. ''Clinical Epigenetics'', ''11''(1), 183. https://doi.org/10.1186/s13148-019-0777-z</ref>

=== Obesity ===
Obesity (defined as increased BMI) has been shown to correlate with increased epigenetic age in a number of tissues. For liver tissue, one study found an average increase of approximately 2.2 years of epigenetic age for each 10 BMI units.<ref>Horvath, S., Erhart, W., Brosch, M., Ammerpohl, O., von Schönfels, W., Ahrens, M., Heits, N., Bell, J. T., Tsai, P.-C., Spector, T. D., Deloukas, P., Siebert, R., Sipos, B., Becker, T., Röcken, C., Schafmayer, C., & Hampe, J. (2014). Obesity accelerates epigenetic aging of human liver. ''Proceedings of the National Academy of Sciences'', ''111''(43), 15538–15543. https://doi.org/10.1073/pnas.1412759111</ref> There was no correlation for blood cells, however. Another study found an increase of approximately 2.3 years per 10 BMI points for visceral adipose tissue (visceral fat).<ref>de Toro-Martín, J., Guénard, F., Tchernof, A., Hould, F.-S., Lebel, S., Julien, F., Marceau, S., & Vohl, M.-C. (2019). Body mass index is associated with epigenetic age acceleration in the visceral adipose tissue of subjects with severe obesity. ''Clinical Epigenetics'', ''11''(1), 172. https://doi.org/10.1186/s13148-019-0754-6</ref>

=== Depression ===
Major depressive disorder (MDD) was also found to be associated with increased epigenetic age. One study found increased epigenetic age in blood cells associated with symptoms of MDD and childhood trauma scores.<ref>Han, L. K. M., Aghajani, M., Clark, S. L., Chan, R. F., Hattab, M. W., Shabalin, A. A., Zhao, M., Kumar, G., Xie, L. Y., Jansen, R., Milaneschi, Y., Dean, B., Aberg, K. A., van den Oord, E. J. C. G., & Penninx, B. W. J. H. (2018). Epigenetic aging in major depressive disorder. ''American Journal of Psychiatry'', ''175''(8), 774–782. https://doi.org/10.1176/appi.ajp.2018.17060595</ref> They also analyzed brain cells (collected post mortem) and found that increased epigenetic age correlated with MDD symptoms.

=== Centenarians ===
Those who live past the age of 100 have reduced DNAm levels, with a pattern of methylation that appears to correlate less in neighboring [[wikipedia:CpG_site|cytosine-phosphate-guanine (CpG) sites]] of the DNA of newborns, which were more homogenous.<ref>Heyn, H., Li, N., Ferreira, H. J., Moran, S., Pisano, D. G., Gomez, A., Diez, J., Sanchez-Mut, J. V., Setien, F., Carmona, F. J., Puca, A. A., Sayols, S., Pujana, M. A., Serra-Musach, J., Iglesias-Platas, I., Formiga, F., Fernandez, A. F., Fraga, M. F., Heath, S. C., … Esteller, M. (2012). Distinct DNA methylomes of newborns and centenarians. ''Proceedings of the National Academy of Sciences'', ''109''(26), 10522–10527. https://doi.org/10.1073/pnas.1120658109</ref>

=== Partial Epigenetic Reprogramming ===
Lu, Yuancheng, et al. were able to reverse age-induced loss of sight, and even regenerate a mechanically damaged eye nerve, by manipulating methylation patterns in mice.<ref name=":1" /> In addition to the vision restoration mentioned above, they were able to improve locomotive and cognitive performance in aged mice, and also shift the clocks forward, making the mice biologically older than they should be.<ref>Palliyaguru, D. L., Minor, R. K., Mitchell, S. J., Palacios, H. H., Licata, J. J., Ward, T. M., Abulwerdi, G., Elliott, P., Westphal, C., Ellis, J. L., Sinclair, D. A., Price, N. L., Bernier, M., & de Cabo, R. (2020a). Combining a high dose of metformin with the SIRT1 activator, SRT1720, reduces life span in aged mice fed a high-fat diet. ''The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences'', ''75''(11), 2037–2041. https://doi.org/10.1093/gerona/glaa148</ref> This is not particularly useful in practice, but necessary to confirm that their model of aging works.
== Other uses ==
Epigenetic clock also has many other [[wikipedia:Epigenetic_clock#Motivation_for_biological_clocks|applications]]:

* Testing the validity of various theories of biological aging
* Diagnosing various age related diseases and for defining cancer subtypes
* Predicting/prognosticating the onset of various diseases
* Serving as surrogate markers for evaluating therapeutic interventions including rejuvenation approaches,
* Studying developmental biology and cell differentiation
* Forensic applications, e.g. to estimate the age of a suspect based on blood left at a crime scene

== References ==

Resveratrol

2021-06-24T12:42:31Z

SV: Minor language edits

[[File:Resveratrol.png|thumb|200x200px|The chemical structure of trans-resveratrol.]]
Resveratrol (trans‐3,5,4′‐trihydroxystilbene) is a compound produced naturally by various plants in response to injury or microbial infection. Its main dietary sources include grapes, blueberry, cranberry, peanuts, and legumes.<ref>Tian, B., & Liu, J. (2020). Resveratrol: A review of plant sources, synthesis, stability, modification and food application. ''Journal of the Science of Food and Agriculture'', ''100''(4), 1392-1404.</ref> Resveratrol has gained widespread scientific attention after reports of its lifespan extension properties in a range of model organisms.<ref>Bhullar, K. S., & Hubbard, B. P. (2015). Lifespan and healthspan extension by resveratrol. ''Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease'', ''1852''(6), 1209-1218.</ref> Resveratrol is currently considered a dietary supplement and is not an approved medicine.

== Evidence of lifespan extension ==
Resveratrol has been shown to extend healthy lifespan in yeast, worms, fruit flies, bees, and fish by 10-70%. <ref>Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., ... & Sinclair, D. A. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. ''Nature'', ''425''(6954), 191-196.</ref><ref>Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M., & Sinclair, D. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. ''Nature'', ''430''(7000), 686-689.</ref><ref>Rascón, B., Hubbard, B. P., Sinclair, D. A., & Amdam, G. V. (2012). The lifespan extension effects of resveratrol are conserved in the honey bee and may be driven by a mechanism related to caloric restriction. ''Aging (Albany NY)'', ''4''(7), 499.</ref><ref>Valenzano, D. R., Terzibasi, E., Genade, T., Cattaneo, A., Domenici, L., & Cellerino, A. (2006). Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. ''Current biology'', ''16''(3), 296-300.</ref><ref>Yu, X., & Li, G. (2012). Effects of resveratrol on longevity, cognitive ability and aging-related histological markers in the annual fish Nothobranchius guentheri. ''Experimental gerontology'', ''47''(12), 940-949.</ref> In mice on a high-calorie diet, resveratrol reduced the risk of death from the diet by 31%.<ref>Baur, J. A., Pearson, K. J., Price, N. L., Jamieson, H. A., Lerin, C., Kalra, A., ... & Sinclair, D. A. (2006). Resveratrol improves health and survival of mice on a high-calorie diet. ''Nature'', ''444''(7117), 337-342.</ref> No lifespan extension has been observed in healthy mice and rats.<ref>Pearson, K. J., Baur, J. A., Lewis, K. N., Peshkin, L., Price, N. L., Labinskyy, N., ... & de Cabo, R. (2008). Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. ''Cell metabolism'', ''8''(2), 157-168.</ref><ref>Miller, R. A., Harrison, D. E., Astle, C. M., Baur, J. A., Boyd, A. R., De Cabo, R., ... & Strong, R. (2011). Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. ''The Journals of Gerontology: Series A'', ''66''(2), 191-201.</ref><ref>Strong, R., Miller, R. A., Astle, C. M., Baur, J. A., De Cabo, R., Fernandez, E., ... & Harrison, D. E. (2013). Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice. ''Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences'', ''68''(1), 6-16.</ref><ref>da Luz, P. L., Tanaka, L., Brum, P. C., Dourado, P. M. M., Favarato, D., Krieger, J. E., & Laurindo, F. R. M. (2012). Red wine and equivalent oral pharmacological doses of resveratrol delay vascular aging but do not extend life span in rats. ''Atherosclerosis'', ''224''(1), 136-142.</ref>

== Human clinical trials ==
A range of clinical trials investigating the health benefits of resveratrol supplementation has been performed, some carrying conflicting results.<ref name=":0" /><ref name=":1" /> Resveratrol has been shown to improve glucose control and insulin sensitivity in persons with type 2 diabetes, and modulate some cancer-related genes.<ref>Liu, K., Zhou, R., Wang, B., & Mi, M. T. (2014). Effect of resveratrol on glucose control and insulin sensitivity: a meta-analysis of 11 randomized controlled trials. ''The American journal of clinical nutrition'', ''99''(6), 1510-1519.</ref><ref>Zhu, X., Wu, C., Qiu, S., Yuan, X., & Li, L. (2017). Effects of resveratrol on glucose control and insulin sensitivity in subjects with type 2 diabetes: Systematic review and meta-analysis. ''Nutrition & metabolism'', ''14''(1), 1-10.</ref><ref>Ko, J. H., Sethi, G., Um, J. Y., Shanmugam, M. K., Arfuso, F., Kumar, A. P., ... & Ahn, K. S. (2017). The role of resveratrol in cancer therapy. ''International journal of molecular sciences'', ''18''(12), 2589.</ref> Resveratrol supplementation in postmenopausal women (150 mg per day for 12 months) resulted in improvement of overall cognitive performance.<ref>Zaw, J. J. T., Howe, P. R., & Wong, R. H. (2020). Sustained cerebrovascular and cognitive benefits of resveratrol in postmenopausal women. ''Nutrients'', ''12''(3), 828.</ref> The study concluded that resveratrol supplementation could potentially reverse cognitive ageing by up to 10 years.

== Safety and bioavailability ==
It has been shown that resveratrol is generally safe in humans.<ref name=":0">Singh, A. P., Singh, R., Verma, S. S., Rai, V., Kaschula, C. H., Maiti, P., & Gupta, S. C. (2019). Health benefits of resveratrol: Evidence from clinical studies. ''Medicinal research reviews'', ''39''(5), 1851-1891.</ref><ref name=":1">Bitterman, J. L., & Chung, J. H. (2015). Metabolic effects of resveratrol: addressing the controversies. ''Cellular and Molecular Life Sciences'', ''72''(8), 1473-1488.</ref> Mild adverse effects such as nausea, diarrhea, and abdominal pain have been reported with doses of 1 g per day and higher.<ref>Brown, V. A., Patel, K. R., Viskaduraki, M., Crowell, J. A., Perloff, M., Booth, T. D., ... & Brenner, D. E. (2010). Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin-like growth factor axis. ''Cancer research'', ''70''(22), 9003-9011.</ref><ref>Patel, K. R., Scott, E., Brown, V. A., Gescher, A. J., Steward, W. P., & Brown, K. (2011). Clinical trials of resveratrol. ''Annals of the New York Academy of Sciences'', ''1215''(1), 161-169.</ref>

Resveratrol is quickly metabolized and is poorly absorbed in the human body, which limits its potential for clinical use.<ref>Muñoz, O., Muñoz, R., & Bustamante, S. (2015). Pharmacological properties of resveratrol. A pre-clinical and clinical review. ''Biochem Pharmacol (Los Angel)'', ''4''(184), 2167-0501.</ref>

== Mechanism ==
Resveratrol can most likely act through multiple mechanisms in the cell.<ref name=":1" /> One of its crucial targets is Silent Information Regulator 1 (SIRT1), a protein proposed to mediate the beneficial effects of caloric restriction, as well as regulate pathways involved in mitochondrial biogenesis and inflammation. <ref name=":0" />

== References ==

Epigenetic clock

2021-06-24T09:33:03Z

SV: Reordering chapters

Biological age is a measure of a person's position along their lifespan. '''Epigenetic clocks''' are one way to measure biological age, and are based on a subject's DNA methylation (DNAm) status, also often referred to as ''DNAm age'' or ''epigenetic age''. These clocks have been shown to predict all-cause mortality better than chronological age and traditional risk factors.<ref>Chen, Brian H., et al. “DNA Methylation-Based Measures of Biological Age: Meta-Analysis Predicting Time to Death.” ''Aging (Albany NY)'', vol. 8, no. 9, Sept. 2016, pp. 1844–59. ''[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5076441/ PubMed Central]'', doi:[https://www.aging-us.com/article/101020/text 10.18632/aging.101020].</ref>

By measuring biological age, researchers can identify people who exhibit accelerated aging and would therefore benefit the most from an anti-aging drug, and determine whether an aging intervention slows or even reverses aging.<ref>Ferrucci, Luigi, et al. “Measuring Biological Aging in Humans: A Quest.” ''Aging Cell'', vol. 19, no. 2, 2020, p. e13080. ''Wiley Online Library'', doi:https://doi.org/10.1111/acel.13080.</ref> Quantifying biological age is considered important for longevity research because it would be less feasible to run clinical trials over several decades to know whether human life has been extended. Instead, it would be more practical to use biological aging clocks to predict if a therapy is likely to extend healthspan and lifespan within a shorter timeframe.
== Mechanism ==
The epigenetic clock works by measuring DNA methylation levels, i.e., the number and distribution of methyl groups attached to the DNA molecule. These ‘tags’ signal genes to be turned on or off.

Epigenetic clocks appear to measure a universal feature of aging across species. The same algorithm, based on the same set of biomarkers (DNAm) has been shown to strongly predict chronological age in hundreds of animals, including mice, bats, and humans. Notably, the residual or unexplained variance of epigenetic clocks (such as GrimAge) for prediction of chronological age appears to further capture biological age.<ref name=":0">Lu, Ake T., et al. “DNA Methylation GrimAge Strongly Predicts Lifespan and Healthspan.” ''Aging'', vol. 11, no. 2, Jan. 2019, pp. 303–27. ''[https://pubmed.ncbi.nlm.nih.gov/30669119/ PubMed]'', doi:[https://www.aging-us.com/article/101684/text 10.18632/aging.101684].</ref> For GrimAge, this aspect is referred to as AgeAccelGrim, where the regression of DNA GrimAge on chronological age predicts whether biological age is greater or lesser than chronological age.<ref name=":0" /> In other words, epigenetic clocks accurately predict one's age based on various DNAm biomarkers, but the error in prediction reflects the differences in rates of biological aging between individuals.

[[wikipedia:DNA_methylation|DNA methylation]] is the attachment of a methyl group to one of the “links” in the DNA strain (specifically, cytosine nucleotide). This does not affect the content of the DNA itself, but it does affect how it is read and used by the cell. This is one of the group of changes called epigenetics – changes in the organism's physical function which do not alter the DNA sequence itself, but can be inherited under certain conditions.

There have been a number of studies showing that as humans (and other mammals) age, patterns of methylation in their DNA change in certain ways.<ref>Fransquet, Peter D., et al. “The Epigenetic Clock as a Predictor of Disease and Mortality Risk: A Systematic Review and Meta-Analysis.” ''Clinical Epigenetics'', vol. 11, no. 1, Apr. 2019, p. 62. ''BioMed Central'', doi:[https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0656-7 10.1186/s13148-019-0656-7].</ref> The exact patterns of change are quite complex and not yet fully described, but broadly, two tendencies have been detected. First, the global level of methylation decreases, unequally in different tissues (for example, in mice, methylation levels decreased in the brain, heart, and spleen, but not in the lungs or liver). Secondly, the local methylation levels increase in certain locations: CpG islands (regions on a DNA strain where the sequence cytosine-guanine occurs with high frequency) and bivalent chromatin domain promoters (a promoter is a DNA sequence which initiates the transcription of the gene following it).

These changes can be used to estimate the biological age of the organism, and there are a [[wikipedia:Epigenetic_clock#Other_age_estimators_based_on_DNA_methylation_levels|number of approaches]] to achieving this measurement, the most common being the Horvath’s clock, developed by Horvath et al. in 2013.<ref>Bocklandt, Sven, et al. “Epigenetic Predictor of Age.” ''PLOS ONE'', vol. 6, no. 6, June 2011, p. e14821. ''PLoS Journals'', doi:[https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0014821 10.1371/journal.pone.0014821].</ref> They used publicly available datasets of methylation data collected on [[wikipedia:Illumina,_Inc.|Illumina]] chips, and analyzed 21,369 CpG sites available on both 27k and 450k chips (the number referring to the total number of sites that the chip analyzes). The team then used a penalized regression model (elastic net regularization, which is essentially a linear combination of lasso and ridge regularization penalties, which thus drives the model to have both smaller coefficients and fewer of them) to identify 353 sites providing the most signals, of which 193 correlated with age positively, and the remaining 160 negatively. The clock then applies a calibration function to the weighted average of these 353 sites methylation levels to determine the biological age.

== Discovery ==
Changes in methylation levels with aging have been observed for some time. The first work using epigenetic changes as a basis for biological clocks was published in 2009 by Schumacher.<ref>Schumacher, Axel. ''An Epigenetic Clock: Anticorrelation &amp; DNA Methylation as Biomarker for Aging.'' 2009. ''DOI.org (Datacite)'', doi:[https://www.researchgate.net/publication/344399255_An_epigenetic_clock_Anticorrelation_DNA_methylation_as_biomarker_for_aging?channel=doi&linkId=5f70f837458515b7cf5402bc&showFulltext=true 10.13140/RG.2.2.12457.83042].</ref> In 2013, the labs of Trey Ideker and Kang Zhang at the University of California, San Diego published the Hannum epigenetic clock, which consisted of 71 markers which accurately estimate age based on blood methylation levels.<ref>Hannum, Gregory, et al. “Genome-Wide Methylation Profiles Reveal Quantitative Views of Human Aging Rates.” ''Molecular Cell'', vol. 49, no. 2, Jan. 2013, pp. 359–67. ''www.cell.com'', doi:[https://www.cell.com/molecular-cell/fulltext/S1097-2765(12)00893-3?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1097276512008933%3Fshowall%3Dtrue 10.1016/j.molcel.2012.10.016].</ref> In the same year, the first multi-tissue epigenetic clock was developed by Steve Horvath, a professor of human genetics and of biostatistics at UCLA.<ref>Horvath, Steve. “DNA Methylation Age of Human Tissues and Cell Types.” ''Genome Biology'', vol. 14, no. 10, Dec. 2013, p. 3156. ''BioMed Central'', doi:[https://genomebiology.biomedcentral.com/articles/10.1186/gb-2013-14-10-r115 10.1186/gb-2013-14-10-r115].</ref> Horvath’s clock allows the measurement of the age of different tissues of the same organism with the same clock, so it is the most widely used in aging research today.

== Epigenetic clocks and aging ==

It is not fully known whether epigenetic changes are a cause or consequence of other aging processes. Several theories have been proposed, and are explained below:

=== Link with Hallmarks of Aging ===
There is evidence that changed methylation patterns can be linked to some of the [[Hallmarks of Aging|hallmarks of aging]]: loss of proteostasis, mitochondrial dysfunction, stem cell exhaustion, and immunosenescence.<ref>Jiang, Shuang, and Yuchen Guo. “Epigenetic Clock: DNA Methylation in Aging.” ''Stem Cells International'', 8 July 2020, doi:https://doi.org/10.1155/2020/1047896.</ref> Lu, Yuancheng, et al. were able to reverse age-induced loss of sight from glaucoma, and even regenerate a mechanically damaged eye nerve, by manipulating methylation patterns in mice.<ref name=":1">Lu, Yuancheng, et al. “Reprogramming to Recover Youthful Epigenetic Information and Restore Vision.” ''Nature'', vol. 588, no. 7836, Dec. 2020, pp. 124–29. ''[https://pubmed.ncbi.nlm.nih.gov/33268865/ PubMed]'', doi:[https://www.nature.com/articles/s41586-020-2975-4 10.1038/s41586-020-2975-4].</ref> They used three out of the four so-called 'Yamanaka factors', which are proteins necessary for reprogramming adult somatic cells back to pluripotent stem cells. Using the factors in live organisms for prolonged periods of time is known to cause cancer by boosting up cell division. But, with the exclusion of one of these factors (c-Myc), that is known to be oncogenic. The other three factors were kept active in mice for over a year without inducing any tumors.

The induction of these factors allowed the mice to regrow a mechanically damaged optic nerve. Normally, a mouse's optic nerve can regrow during early development, but then loses this ability a few days after birth. In this experiment, adult mice were able to re-obtain a similar regenerative ability and regained around half of their lost visual acuity.

Another result achieved using the Yamanaka factors was the restoration of the vision of healthy, middle-aged (one-year-old) mice. Before treatment, these mice scored worse than the younger mice on tests of visual acuity, but one month after treatment, they had similar results

=== Information theory of aging ===
Another theory, popularised by Professor David Sinclair, is that epigenetic changes might be the master regulator of aging - known as [https://hplus.club/blog/a-summary-of-david-sinclairs-information-theory-of-aging/ the information theory of aging].

Since DNA is identical in every somatic cell, each cell needs to “know” which genes to read in order to differentiate itself from a stem cell and perform its function. For example, a neuron cell only expresses (i.e. uses) genes relevant for being a neuron, and not a muscle cell or a skin cell. This is achieved through methylation and other epigenetic mechanisms.

The theory goes that aging is fundamentally caused by the accumulation of the effects of errors in this process, eventually causing a cell to stop functioning normally and either become cancerous or die.

== Relevance for longevity research ==

=== Smoking ===
Research shows that smoking increases epigenetic age of buccal cells, airway cells, esophagus tissue, and lung tissue. Quitting smoking causes the epigenetic age acceleration in airway cells (but not in lung tissue) to revert to the level of non-smokers.<ref>Wu, Xiaohui, et al. “Effect of Tobacco Smoking on the Epigenetic Age of Human Respiratory Organs.” ''Clinical Epigenetics'', vol. 11, no. 1, Dec. 2019, p. 183. ''BioMed Central'', doi:[https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0777-z 10.1186/s13148-019-0777-z].</ref>

=== Obesity ===
Obesity (defined as increased BMI) has been shown to correlate with increased epigenetic age in a number of tissues. For liver tissue, one study found an average increase of approximately 2.2 years of epigenetic age for each 10 BMI units.<ref>Horvath, Steve, et al. “[https://www.pnas.org/content/111/43/15538 Obesity Accelerates Epigenetic Aging of Human Liver.]” ''Proceedings of the National Academy of Sciences'', vol. 111, no. 43, Oct. 2014, pp. 15538–43.</ref> There was no correlation for blood cells, however. Another study found an increase of approximately 2.3 years per 10 BMI points for visceral adipose tissue (visceral fat).<ref>de Toro-Martín, Juan, et al. “Body Mass Index Is Associated with Epigenetic Age Acceleration in the Visceral Adipose Tissue of Subjects with Severe Obesity.” ''Clinical Epigenetics'', vol. 11, no. 1, Dec. 2019, p. 172. ''BioMed Central'', doi:[https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0754-6 10.1186/s13148-019-0754-6].</ref>

=== Depression ===
Major depressive disorder (MDD) was also found to be associated with increased epigenetic age. One study found increased epigenetic age in blood cells associated with symptoms of MDD and childhood trauma scores.<ref>Han, Laura K. M., et al. “Epigenetic Aging in Major Depressive Disorder.” ''American Journal of Psychiatry'', vol. 175, no. 8, Apr. 2018, pp. 774–82. ''ajp.psychiatryonline.org (Atypon)'', doi:[https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2018.17060595 10.1176/appi.ajp.2018.17060595].</ref> They also analyzed brain cells (collected post mortem) and found that increased epigenetic age correlated with MDD symptoms.

=== Centenarians ===
Those who live past the age of 100 have reduced DNAm levels, with a pattern of methylation that appears to correlate less in neighboring [[wikipedia:CpG_site|cytosine-phosphate-guanine (CpG) sites]] of the DNA of newborns, which were more homogenous.<ref>Heyn, Holger, et al. “[https://www.pnas.org/content/109/26/10522 Distinct DNA Methylomes of Newborns and Centenarians.]” ''Proceedings of the National Academy of Sciences'', vol. 109, no. 26, June 2012, pp. 10522–27.</ref>

=== Partial Epigenetic Reprogramming ===
Lu, Yuancheng, et al. were able to reverse age-induced loss of sight, and even regenerate a mechanically damaged eye nerve, by manipulating methylation patterns in mice.<ref name=":1" /> In addition to the vision restoration mentioned above, they were able to improve locomotive and cognitive performance in aged mice, and also shift the clocks forward, making the mice biologically older than they should be.<ref>Palliyaguru, Dushani L., et al. “Combining a High Dose of Metformin With the SIRT1 Activator, SRT1720, Reduces Life Span in Aged Mice Fed a High-Fat Diet.” ''The Journals of Gerontology: Series A'', vol. 75, no. 11, Oct. 2020, pp. 2037–41. ''Silverchair'', doi:[https://academic.oup.com/biomedgerontology/article/75/11/2037/5859153 10.1093/gerona/glaa148].</ref> This is not particularly useful in practice, but necessary to confirm that their model of aging works.
== Other uses ==
Epigenetic clock also has many other [[wikipedia:Epigenetic_clock#Motivation_for_biological_clocks|applications]]:

* Testing the validity of various theories of biological aging
* Diagnosing various age related diseases and for defining cancer subtypes
* Predicting/prognosticating the onset of various diseases
* Serving as surrogate markers for evaluating therapeutic interventions including rejuvenation approaches,
* Studying developmental biology and cell differentiation
* Forensic applications, e.g. to estimate the age of a suspect based on blood left at a crime scene

== References ==

Epigenetic clock

2021-06-24T09:31:56Z

SV: Grammar, sentence structure, reference changes

Biological age is a measure of a person's position along their lifespan. '''Epigenetic clocks''' are one way to measure biological age, and are based on a subject's DNA methylation (DNAm) status, also often referred to as ''DNAm age'' or ''epigenetic age''. These clocks have been shown to predict all-cause mortality better than chronological age and traditional risk factors.<ref>Chen, Brian H., et al. “DNA Methylation-Based Measures of Biological Age: Meta-Analysis Predicting Time to Death.” ''Aging (Albany NY)'', vol. 8, no. 9, Sept. 2016, pp. 1844–59. ''[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5076441/ PubMed Central]'', doi:[https://www.aging-us.com/article/101020/text 10.18632/aging.101020].</ref>

By measuring biological age, researchers can identify people who exhibit accelerated aging and would therefore benefit the most from an anti-aging drug, and determine whether an aging intervention slows or even reverses aging.<ref>Ferrucci, Luigi, et al. “Measuring Biological Aging in Humans: A Quest.” ''Aging Cell'', vol. 19, no. 2, 2020, p. e13080. ''Wiley Online Library'', doi:https://doi.org/10.1111/acel.13080.</ref> Quantifying biological age is considered important for longevity research because it would be less feasible to run clinical trials over several decades to know whether human life has been extended. Instead, it would be more practical to use biological aging clocks to predict if a therapy is likely to extend healthspan and lifespan within a shorter timeframe.

== Relevance for longevity research ==

=== Smoking ===
Research shows that smoking increases epigenetic age of buccal cells, airway cells, esophagus tissue, and lung tissue. Quitting smoking causes the epigenetic age acceleration in airway cells (but not in lung tissue) to revert to the level of non-smokers.<ref>Wu, Xiaohui, et al. “Effect of Tobacco Smoking on the Epigenetic Age of Human Respiratory Organs.” ''Clinical Epigenetics'', vol. 11, no. 1, Dec. 2019, p. 183. ''BioMed Central'', doi:[https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0777-z 10.1186/s13148-019-0777-z].</ref>

=== Obesity ===
Obesity (defined as increased BMI) has been shown to correlate with increased epigenetic age in a number of tissues. For liver tissue, one study found an average increase of approximately 2.2 years of epigenetic age for each 10 BMI units.<ref>Horvath, Steve, et al. “[https://www.pnas.org/content/111/43/15538 Obesity Accelerates Epigenetic Aging of Human Liver.]” ''Proceedings of the National Academy of Sciences'', vol. 111, no. 43, Oct. 2014, pp. 15538–43.</ref> There was no correlation for blood cells, however. Another study found an increase of approximately 2.3 years per 10 BMI points for visceral adipose tissue (visceral fat).<ref>de Toro-Martín, Juan, et al. “Body Mass Index Is Associated with Epigenetic Age Acceleration in the Visceral Adipose Tissue of Subjects with Severe Obesity.” ''Clinical Epigenetics'', vol. 11, no. 1, Dec. 2019, p. 172. ''BioMed Central'', doi:[https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0754-6 10.1186/s13148-019-0754-6].</ref>

=== Depression ===
Major depressive disorder (MDD) was also found to be associated with increased epigenetic age. One study found increased epigenetic age in blood cells associated with symptoms of MDD and childhood trauma scores.<ref>Han, Laura K. M., et al. “Epigenetic Aging in Major Depressive Disorder.” ''American Journal of Psychiatry'', vol. 175, no. 8, Apr. 2018, pp. 774–82. ''ajp.psychiatryonline.org (Atypon)'', doi:[https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2018.17060595 10.1176/appi.ajp.2018.17060595].</ref> They also analyzed brain cells (collected post mortem) and found that increased epigenetic age correlated with MDD symptoms.

=== Centenarians ===
Those who live past the age of 100 have reduced DNAm levels, with a pattern of methylation that appears to correlate less in neighboring [[wikipedia:CpG_site|cytosine-phosphate-guanine (CpG) sites]] of the DNA of newborns, which were more homogenous.<ref>Heyn, Holger, et al. “[https://www.pnas.org/content/109/26/10522 Distinct DNA Methylomes of Newborns and Centenarians.]” ''Proceedings of the National Academy of Sciences'', vol. 109, no. 26, June 2012, pp. 10522–27.</ref>

=== Partial Epigenetic Reprogramming ===
Lu, Yuancheng, et al. were able to reverse age-induced loss of sight, and even regenerate a mechanically damaged eye nerve, by manipulating methylation patterns in mice.<ref name=":1">Lu, Yuancheng, et al. “Reprogramming to Recover Youthful Epigenetic Information and Restore Vision.” ''Nature'', vol. 588, no. 7836, Dec. 2020, pp. 124–29. ''[https://pubmed.ncbi.nlm.nih.gov/33268865/ PubMed]'', doi:[https://www.nature.com/articles/s41586-020-2975-4 10.1038/s41586-020-2975-4].</ref> In addition to the vision restoration mentioned above, they were able to improve locomotive and cognitive performance in aged mice, and also shift the clocks forward, making the mice biologically older than they should be.<ref>Palliyaguru, Dushani L., et al. “Combining a High Dose of Metformin With the SIRT1 Activator, SRT1720, Reduces Life Span in Aged Mice Fed a High-Fat Diet.” ''The Journals of Gerontology: Series A'', vol. 75, no. 11, Oct. 2020, pp. 2037–41. ''Silverchair'', doi:[https://academic.oup.com/biomedgerontology/article/75/11/2037/5859153 10.1093/gerona/glaa148].</ref> This is not particularly useful in practice, but necessary to confirm that their model of aging works.
== Mechanism ==
The epigenetic clock works by measuring DNA methylation levels, i.e., the number and distribution of methyl groups attached to the DNA molecule. These ‘tags’ signal genes to be turned on or off.

Epigenetic clocks appear to measure a universal feature of aging across species. The same algorithm, based on the same set of biomarkers (DNAm) has been shown to strongly predict chronological age in hundreds of animals, including mice, bats, and humans. Notably, the residual or unexplained variance of epigenetic clocks (such as GrimAge) for prediction of chronological age appears to further capture biological age.<ref name=":0">Lu, Ake T., et al. “DNA Methylation GrimAge Strongly Predicts Lifespan and Healthspan.” ''Aging'', vol. 11, no. 2, Jan. 2019, pp. 303–27. ''[https://pubmed.ncbi.nlm.nih.gov/30669119/ PubMed]'', doi:[https://www.aging-us.com/article/101684/text 10.18632/aging.101684].</ref> For GrimAge, this aspect is referred to as AgeAccelGrim, where the regression of DNA GrimAge on chronological age predicts whether biological age is greater or lesser than chronological age.<ref name=":0" /> In other words, epigenetic clocks accurately predict one's age based on various DNAm biomarkers, but the error in prediction reflects the differences in rates of biological aging between individuals.

[[wikipedia:DNA_methylation|DNA methylation]] is the attachment of a methyl group to one of the “links” in the DNA strain (specifically, cytosine nucleotide). This does not affect the content of the DNA itself, but it does affect how it is read and used by the cell. This is one of the group of changes called epigenetics – changes in the organism's physical function which do not alter the DNA sequence itself, but can be inherited under certain conditions.

There have been a number of studies showing that as humans (and other mammals) age, patterns of methylation in their DNA change in certain ways.<ref>Fransquet, Peter D., et al. “The Epigenetic Clock as a Predictor of Disease and Mortality Risk: A Systematic Review and Meta-Analysis.” ''Clinical Epigenetics'', vol. 11, no. 1, Apr. 2019, p. 62. ''BioMed Central'', doi:[https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0656-7 10.1186/s13148-019-0656-7].</ref> The exact patterns of change are quite complex and not yet fully described, but broadly, two tendencies have been detected. First, the global level of methylation decreases, unequally in different tissues (for example, in mice, methylation levels decreased in the brain, heart, and spleen, but not in the lungs or liver). Secondly, the local methylation levels increase in certain locations: CpG islands (regions on a DNA strain where the sequence cytosine-guanine occurs with high frequency) and bivalent chromatin domain promoters (a promoter is a DNA sequence which initiates the transcription of the gene following it).

These changes can be used to estimate the biological age of the organism, and there are a [[wikipedia:Epigenetic_clock#Other_age_estimators_based_on_DNA_methylation_levels|number of approaches]] to achieving this measurement, the most common being the Horvath’s clock, developed by Horvath et al. in 2013.<ref>Bocklandt, Sven, et al. “Epigenetic Predictor of Age.” ''PLOS ONE'', vol. 6, no. 6, June 2011, p. e14821. ''PLoS Journals'', doi:[https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0014821 10.1371/journal.pone.0014821].</ref> They used publicly available datasets of methylation data collected on [[wikipedia:Illumina,_Inc.|Illumina]] chips, and analyzed 21,369 CpG sites available on both 27k and 450k chips (the number referring to the total number of sites that the chip analyzes). The team then used a penalized regression model (elastic net regularization, which is essentially a linear combination of lasso and ridge regularization penalties, which thus drives the model to have both smaller coefficients and fewer of them) to identify 353 sites providing the most signals, of which 193 correlated with age positively, and the remaining 160 negatively. The clock then applies a calibration function to the weighted average of these 353 sites methylation levels to determine the biological age.

== Discovery ==
Changes in methylation levels with aging have been observed for some time. The first work using epigenetic changes as a basis for biological clocks was published in 2009 by Schumacher.<ref>Schumacher, Axel. ''An Epigenetic Clock: Anticorrelation &amp; DNA Methylation as Biomarker for Aging.'' 2009. ''DOI.org (Datacite)'', doi:[https://www.researchgate.net/publication/344399255_An_epigenetic_clock_Anticorrelation_DNA_methylation_as_biomarker_for_aging?channel=doi&linkId=5f70f837458515b7cf5402bc&showFulltext=true 10.13140/RG.2.2.12457.83042].</ref> In 2013, the labs of Trey Ideker and Kang Zhang at the University of California, San Diego published the Hannum epigenetic clock, which consisted of 71 markers which accurately estimate age based on blood methylation levels.<ref>Hannum, Gregory, et al. “Genome-Wide Methylation Profiles Reveal Quantitative Views of Human Aging Rates.” ''Molecular Cell'', vol. 49, no. 2, Jan. 2013, pp. 359–67. ''www.cell.com'', doi:[https://www.cell.com/molecular-cell/fulltext/S1097-2765(12)00893-3?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1097276512008933%3Fshowall%3Dtrue 10.1016/j.molcel.2012.10.016].</ref> In the same year, the first multi-tissue epigenetic clock was developed by Steve Horvath, a professor of human genetics and of biostatistics at UCLA.<ref>Horvath, Steve. “DNA Methylation Age of Human Tissues and Cell Types.” ''Genome Biology'', vol. 14, no. 10, Dec. 2013, p. 3156. ''BioMed Central'', doi:[https://genomebiology.biomedcentral.com/articles/10.1186/gb-2013-14-10-r115 10.1186/gb-2013-14-10-r115].</ref> Horvath’s clock allows the measurement of the age of different tissues of the same organism with the same clock, so it is the most widely used in aging research today.

== Epigenetic clocks and aging ==

It is not fully known whether epigenetic changes are a cause or consequence of other aging processes. Several theories have been proposed, and are explained below:

=== Link with Hallmarks of Aging ===
There is evidence that changed methylation patterns can be linked to some of the [[Hallmarks of Aging|hallmarks of aging]]: loss of proteostasis, mitochondrial dysfunction, stem cell exhaustion, and immunosenescence.<ref>Jiang, Shuang, and Yuchen Guo. “Epigenetic Clock: DNA Methylation in Aging.” ''Stem Cells International'', 8 July 2020, doi:https://doi.org/10.1155/2020/1047896.</ref> Lu, Yuancheng, et al. were able to reverse age-induced loss of sight from glaucoma, and even regenerate a mechanically damaged eye nerve, by manipulating methylation patterns in mice.<ref name=":1" /> They used three out of the four so-called 'Yamanaka factors', which are proteins necessary for reprogramming adult somatic cells back to pluripotent stem cells. Using the factors in live organisms for prolonged periods of time is known to cause cancer by boosting up cell division. But, with the exclusion of one of these factors (c-Myc), that is known to be oncogenic. The other three factors were kept active in mice for over a year without inducing any tumors.

The induction of these factors allowed the mice to regrow a mechanically damaged optic nerve. Normally, a mouse's optic nerve can regrow during early development, but then loses this ability a few days after birth. In this experiment, adult mice were able to re-obtain a similar regenerative ability and regained around half of their lost visual acuity.

Another result achieved using the Yamanaka factors was the restoration of the vision of healthy, middle-aged (one-year-old) mice. Before treatment, these mice scored worse than the younger mice on tests of visual acuity, but one month after treatment, they had similar results

=== Information theory of aging ===
Another theory, popularised by Professor David Sinclair, is that epigenetic changes might be the master regulator of aging - known as [https://hplus.club/blog/a-summary-of-david-sinclairs-information-theory-of-aging/ the information theory of aging].

Since DNA is identical in every somatic cell, each cell needs to “know” which genes to read in order to differentiate itself from a stem cell and perform its function. For example, a neuron cell only expresses (i.e. uses) genes relevant for being a neuron, and not a muscle cell or a skin cell. This is achieved through methylation and other epigenetic mechanisms.

The theory goes that aging is fundamentally caused by the accumulation of the effects of errors in this process, eventually causing a cell to stop functioning normally and either become cancerous or die.

== Other uses ==
Epigenetic clock also has many other [[wikipedia:Epigenetic_clock#Motivation_for_biological_clocks|applications]]:

* Testing the validity of various theories of biological aging
* Diagnosing various age related diseases and for defining cancer subtypes
* Predicting/prognosticating the onset of various diseases
* Serving as surrogate markers for evaluating therapeutic interventions including rejuvenation approaches,
* Studying developmental biology and cell differentiation
* Forensic applications, e.g. to estimate the age of a suspect based on blood left at a crime scene

== References ==

User talk:SV

2021-06-24T08:51:19Z

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2021-06-24T08:50:37Z

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Epigenetic clock

2021-06-24T08:47:18Z

SV: Added the rest of the references and edited some links

Biological age is a measure of a person's position along their lifespan. '''Epigenetic clocks''' are one way to measure biological age, and are based on a subject's DNA methylation (DNAm) status, also often referred to as ''DNAm age'' or ''epigenetic age''. These clocks have been shown to predict all-cause mortality better than chronological age and traditional risk factors.<ref>Chen, Brian H., et al. “DNA Methylation-Based Measures of Biological Age: Meta-Analysis Predicting Time to Death.” ''Aging (Albany NY)'', vol. 8, no. 9, Sept. 2016, pp. 1844–59. ''[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5076441/ PubMed Central]'', doi:[https://www.aging-us.com/article/101020/text 10.18632/aging.101020].</ref>

By measuring biological age, researchers can identify people who exhibit accelerated aging and would therefore benefit the most from an anti-aging drug, and determine whether an aging intervention slows or even reverses aging.<ref>Ferrucci, Luigi, et al. “Measuring Biological Aging in Humans: A Quest.” ''Aging Cell'', vol. 19, no. 2, 2020, p. e13080. ''Wiley Online Library'', doi:https://doi.org/10.1111/acel.13080.</ref> Quantifying biological age is considered important for longevity research because it would be less feasible to run clinical trials over several decades to know whether human life has been extended. Instead, it would be more practical to use biological aging clocks to predict if a therapy is likely to extend healthspan and lifespan within a shorter timeframe.

== Relevance for longevity research ==

=== Smoking ===
Research shows that smoking increases epigenetic age of buccal cells, airway cells, esophagus tissue, and lung tissue. Quitting smoking caused the epigenetic age acceleration in airway cells (but not in lung tissue) to revert to the level of non-smokers.<ref>Wu, Xiaohui, et al. “Effect of Tobacco Smoking on the Epigenetic Age of Human Respiratory Organs.” ''Clinical Epigenetics'', vol. 11, no. 1, Dec. 2019, p. 183. ''BioMed Central'', doi:[https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0777-z 10.1186/s13148-019-0777-z].</ref>

=== Obesity ===
Obesity (defined as increased BMI) has been shown to correlate with increased epigenetic age in a number of tissues. For liver tissue, one study found the average increase of ~2.2 years of epigenetic age for each 10 BMI units.<ref>Horvath, Steve, et al. “[https://www.pnas.org/content/111/43/15538 Obesity Accelerates Epigenetic Aging of Human Liver.]” ''Proceedings of the National Academy of Sciences'', vol. 111, no. 43, Oct. 2014, pp. 15538–43.</ref> There was no correlation for blood cells however. Another study found an increase of ~2.3 years per 10 BMI points for visceral adipose tissue (visceral fat).<ref>de Toro-Martín, Juan, et al. “Body Mass Index Is Associated with Epigenetic Age Acceleration in the Visceral Adipose Tissue of Subjects with Severe Obesity.” ''Clinical Epigenetics'', vol. 11, no. 1, Dec. 2019, p. 172. ''BioMed Central'', doi:[https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0754-6 10.1186/s13148-019-0754-6].</ref>

=== Depression ===
Major depressive disorder (MDD) was also found to be associated with increased epigenetic age. A study by Han et al. found increased epigenetic age in blood cells associated with symptoms of MDD and childhood trauma scores.<ref>Han, Laura K. M., et al. “Epigenetic Aging in Major Depressive Disorder.” ''American Journal of Psychiatry'', vol. 175, no. 8, Apr. 2018, pp. 774–82. ''ajp.psychiatryonline.org (Atypon)'', doi:[https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2018.17060595 10.1176/appi.ajp.2018.17060595].</ref> They also analyzed brain cells (collected post mortem) and found that increased epigenetic age correlated with MDD symptoms.

=== Centenarians ===
Those who live past the age of 100 have reduced DNAm levels, with a pattern of methylation that appears to correlate less in neighboring [[wikipedia:CpG_site|cytosine-phosphate-guanine (CpG) sites]] of the DNA of newborns, which were more homogenous.<ref>Heyn, Holger, et al. “[https://www.pnas.org/content/109/26/10522 Distinct DNA Methylomes of Newborns and Centenarians.]” ''Proceedings of the National Academy of Sciences'', vol. 109, no. 26, June 2012, pp. 10522–27.</ref>

=== Partial Epigenetic Reprogramming ===
David Sinclair et al. were able to reverse age-induced loss of sight and even regenerate a mechanically damaged eye nerve by manipulating methylation patterns in mice.<ref name=":1">Lu, Yuancheng, et al. “Reprogramming to Recover Youthful Epigenetic Information and Restore Vision.” ''Nature'', vol. 588, no. 7836, Dec. 2020, pp. 124–29. ''[https://pubmed.ncbi.nlm.nih.gov/33268865/ PubMed]'', doi:[https://www.nature.com/articles/s41586-020-2975-4 10.1038/s41586-020-2975-4].</ref> In addition to vision restoration mentioned above they were able to [https://pubmed.ncbi.nlm.nih.gov/33268865/ improve] locomotive and cognitive performance in aged mice, and they also were able to shift the clocks forward, making the mice biologically older than it should be.<ref>Palliyaguru, Dushani L., et al. “Combining a High Dose of Metformin With the SIRT1 Activator, SRT1720, Reduces Life Span in Aged Mice Fed a High-Fat Diet.” ''The Journals of Gerontology: Series A'', vol. 75, no. 11, Oct. 2020, pp. 2037–41. ''Silverchair'', doi:[https://academic.oup.com/biomedgerontology/article/75/11/2037/5859153 10.1093/gerona/glaa148].</ref> This is not particularly useful in practice, but necessary to confirm that their model of aging works.
== Mechanism ==
Epigenetic clock works by measuring DNA methylation levels, i.e. the number and distribution of methyl groups attached to the DNA molecule. These ‘tags’ signal to genes to be turned on or off.

Epigenetic clocks appear to measure a universal feature of aging across species. The same algorithm that is based on the same set of biomarkers (DNAm) has been shown to strongly predict chronological age in hundreds of animals, ranging from mice, bats, and to humans. Notably, the residual or unexplained variance of epigenetic clocks (such as 'GrimAge)' for prediction of chronological age, appears to further capture biological age.<ref name=":0">Lu, A. T., Quach, A., Wilson, J. G., Reiner, A. P., Aviv, A., Raj, K., ... & Horvath, S. (2019). DNA methylation GrimAge strongly predicts lifespan and healthspan. ''Aging (Albany NY)'', ''11''(2), 303.</ref> For GrimAge, this aspect is referred to as AgeAccelGrim, where regression of DNA GrimAge on chronological age predicts whether biological age is greater or lesser than chronological age.<ref name=":0" /> In other words, epigenetic clocks accurately predict one's age based on various DNAm biomarkers, but the error in prediction (which is an expected outcome), reflects the differences in rates of biological aging between individuals.

[[wikipedia:DNA_methylation|DNA methylation]] is attachment of a methyl group to one of the “links” in the DNA strain (specifically, cytosine nucleotide). This does not affect the content of the DNA itself, but it does affect how it’s being read and used by the cell. This is one of the group of changes called epigenetics - changes in the organism's physical function which do not alter the DNA sequence itself, but - under certain conditions - can be inherited.

There has been a number of studies showing that as humans (and other mammals) age, patterns of methylation in their DNA change in certain ways.<ref>Fransquet, Peter D., et al. “The Epigenetic Clock as a Predictor of Disease and Mortality Risk: A Systematic Review and Meta-Analysis.” ''Clinical Epigenetics'', vol. 11, no. 1, Apr. 2019, p. 62. ''BioMed Central'', doi:[https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0656-7 10.1186/s13148-019-0656-7].</ref> The exact patterns of change are quite complex and not yet fully described, but broadly, there were two tendencies detected. First, the global level of methylation decreases, unequally in different tissues (for example, in mice methylation levels decreased in brain, heart and spleen, but not in lungs or liver). Secondly, the local methylation level increases in certain locations: CpG islands (regions on a DNA strain where the sequence cytosine-guanine occurs with high frequency) and bivalent chromatin domain promoters (promoter is a sequence in DNA which initiates transcription of the gene following it).

These changes can be used to estimate the biological age of the organism, and there’s a [[wikipedia:Epigenetic_clock#Other_age_estimators_based_on_DNA_methylation_levels|number of approaches]] to that, most common being the Horvath’s clock, developed by Horvath et al. in 2013.<ref>Bocklandt, Sven, et al. “Epigenetic Predictor of Age.” ''PLOS ONE'', vol. 6, no. 6, June 2011, p. e14821. ''PLoS Journals'', doi:[https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0014821 10.1371/journal.pone.0014821].</ref> They used publicly available datasets of methylation data collected on [[wikipedia:Illumina,_Inc.|Illumina]] chips, and analyzed 21,369 CpG sites available on both 27k and 450k chips (the number referring to the total number of sites the chip analyzes). The team then used a penalized regression model (Elastic net regularization, which is essentially a linear combination of lasso and ridge regularization penalties which thus drives the model to have both smaller coefficients and fewer of them) to identify 353 sites providing the most signal, of which 193 correlated with age positively and the remaining 160 negatively. The clock then applies a calibration function to the weighted average of these 353 sites methylation levels to determine the biological age.

== Discovery ==
Changes in methylation levels with aging have been observed for some time. First work using epigenetic changes as a basis for biological clocks was published in 2009 by Schumacher.<ref>Schumacher, Axel. ''An Epigenetic Clock: Anticorrelation &amp; DNA Methylation as Biomarker for Aging.'' 2009. ''DOI.org (Datacite)'', doi:[https://www.researchgate.net/publication/344399255_An_epigenetic_clock_Anticorrelation_DNA_methylation_as_biomarker_for_aging?channel=doi&linkId=5f70f837458515b7cf5402bc&showFulltext=true 10.13140/RG.2.2.12457.83042].</ref> In 2013, the labs of Trey Ideker and Kang Zhang at the University of California, San Diego published the Hannum epigenetic clock, which consisted of 71 markers that accurately estimate age based on blood methylation levels.<ref>Hannum, Gregory, et al. “Genome-Wide Methylation Profiles Reveal Quantitative Views of Human Aging Rates.” ''Molecular Cell'', vol. 49, no. 2, Jan. 2013, pp. 359–67. ''www.cell.com'', doi:[https://www.cell.com/molecular-cell/fulltext/S1097-2765(12)00893-3?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1097276512008933%3Fshowall%3Dtrue 10.1016/j.molcel.2012.10.016].</ref> In the same year the first multi-tissue epigenetic clock was developed by Steve Horvath, a professor of human genetics and of biostatistics at UCLA.<ref>Horvath, Steve. “DNA Methylation Age of Human Tissues and Cell Types.” ''Genome Biology'', vol. 14, no. 10, Dec. 2013, p. 3156. ''BioMed Central'', doi:[https://genomebiology.biomedcentral.com/articles/10.1186/gb-2013-14-10-r115 10.1186/gb-2013-14-10-r115].</ref> Horvath’s clock allows to measure the age of different tissues of the same organism with the same clock, so it is most widely used in aging research today.

== Epigenetic clocks and aging ==

It is not fully known whether epigenetic changes are a cause or consequence of other aging processes. Several theories have been proposed, and are explained below:

=== Link with Hallmarks of Aging ===
There is evidence that changed methylation patterns can be linked to some of the [[Hallmarks of Aging|hallmarks of aging]]: loss of proteostasis, mitochondrial dysfunction, stem cell exhaustion, and immunosenescence.<ref>Jiang, Shuang, and Yuchen Guo. “Epigenetic Clock: DNA Methylation in Aging.” ''Stem Cells International'', 8 July 2020, doi:https://doi.org/10.1155/2020/1047896.</ref> David Sinclair et al. were able to reverse age-induced loss of sight from glaucoma, and even regenerate a mechanically damaged eye nerve by manipulating methylation patterns in mice.<ref name=":1" /> They used three out of four so-called 'Yamanaka factors' which are proteins necessary for reprogramming adult somatic cells back to pluripotent stem cells. Using the factors in live organisms for prolonged periods of time is known to cause cancer by boosting up cell division. But with exclusion of one of these factors (c-Myc), that is known to be oncogenic, the other three factors were kept active in mice for over a year without inducing any tumors.

The induction of these factors allowed the mice to regrow a mechanically damaged optic nerve. Normally, a mouse's optic nerve can regrow during early development, but then loses this ability a few days after birth. In this experiment, adult mice were able to re-obtain a similar regenerative ability and regained around half of their lost visual acuity.

Another result achieved using Yamanaka factors was restoring vision of healthy, middle-aged (one-year-old) mice. These mice scored worse on the tests of visual acuity before treatment than the younger mice, but one month after treatment they had similar results

=== Information theory of aging ===
Another theory, popularised by Professor David Sinclair, is that epigenetic changes might be the master regulator aging - known as [https://hplus.club/blog/a-summary-of-david-sinclairs-information-theory-of-aging/ the information theory of aging].

Since DNA is identical in every somatic cell, each cell in order to differentiate from a stem cell and then perform its function needs to “know” which genes to read, so that e.g. a neuron cell only expresses (i.e. uses) genes relevant for being a neuron, and not a muscle cell or a skin cell. This is achieved through methylation and other epigenetic mechanisms.

The theory goes that aging is fundamentally caused by errors in this process accumulating, eventually causing a cell to stop functioning normally and either become cancerous or die.

== Other uses ==
Epigenetic clock also has many other [[wikipedia:Epigenetic_clock#Motivation_for_biological_clocks|applications]]:

* Testing the validity of various theories of biological aging
* Diagnosing various age related diseases and for defining cancer subtypes
* Predicting/prognosticating the onset of various diseases
* Serving as surrogate markers for evaluating therapeutic interventions including rejuvenation approaches,
* Studying developmental biology and cell differentiation
* Forensic applications, e.g. to estimate the age of a suspect based on blood left at a crime scene

== References ==

Epigenetic clock

2021-06-24T07:31:55Z

SV: Added references category and started adding references (replacing links). "Intro" and "Relevance for longevity" chapters have citations, will do the rest later.

Biological age is a measure of a person's position along their lifespan. '''Epigenetic clocks''' are one way to measure biological age, and are based on a subject's DNA methylation (DNAm) status, also often referred to as ''DNAm age'' or ''epigenetic age''. These clocks have been shown to predict all-cause mortality better than chronological age and traditional risk factors.<ref>Chen, B. H., Marioni, R. E., Colicino, E., Peters, M. J., Ward-Caviness, C. K., Tsai, P. C., ... & Horvath, S. (2016). DNA methylation-based measures of biological age: meta-analysis predicting time to death. ''Aging (Albany NY)'', ''8''(9), 1844.</ref>

By measuring biological age, researchers can identify people who exhibit accelerated aging and would therefore benefit the most from an anti-aging drug, and determine whether an aging intervention slows or even reverses aging.<ref>[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13080 Ferrucci, L., Gonzalez‐Freire, M., Fabbri, E., Simonsick, E., Tanaka, T., Moore, Z., ... & de Cabo, R. (2020). Measuring biological aging in humans: A quest. ''Aging Cell'', ''19''(2), e13080.]</ref> Quantifying biological age is considered important for longevity research because it would be less feasible to run clinical trials over several decades to know whether human life has been extended. Instead, it would be more practical to use biological aging clocks to predict if a therapy is likely to extend healthspan and lifespan within a shorter timeframe.

== Relevance for longevity research ==

=== Smoking ===
Research shows that smoking increases epigenetic age of buccal cells, airway cells, esophagus tissue, and lung tissue. Quitting smoking caused the epigenetic age acceleration in airway cells (but not in lung tissue) to revert to the level of non-smokers.<ref>Wu, Xiaohui, et al. “Effect of Tobacco Smoking on the Epigenetic Age of Human Respiratory Organs.” ''Clinical Epigenetics'', vol. 11, no. 1, Dec. 2019, p. 183. ''BioMed Central'', doi:[https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0777-z 10.1186/s13148-019-0777-z].</ref>

=== Obesity ===
Obesity (defined as increased BMI) has been shown to correlate with increased epigenetic age in a number of tissues. For liver tissue, one study found the average increase of ~2.2 years of epigenetic age for each 10 BMI units.<ref>Horvath, Steve, et al. “[https://www.pnas.org/content/111/43/15538 Obesity Accelerates Epigenetic Aging of Human Liver.]” ''Proceedings of the National Academy of Sciences'', vol. 111, no. 43, Oct. 2014, pp. 15538–43.</ref> There was no correlation for blood cells however. Another study found an increase of ~2.3 years per 10 BMI points for visceral adipose tissue (visceral fat).<ref>de Toro-Martín, Juan, et al. “Body Mass Index Is Associated with Epigenetic Age Acceleration in the Visceral Adipose Tissue of Subjects with Severe Obesity.” ''Clinical Epigenetics'', vol. 11, no. 1, Dec. 2019, p. 172. ''BioMed Central'', doi:[https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0754-6 10.1186/s13148-019-0754-6].</ref>

=== Depression ===
Major depressive disorder (MDD) was also found to be associated with increased epigenetic age. A study by Han et al. found increased epigenetic age in blood cells associated with symptoms of MDD and childhood trauma scores.<ref>Han, Laura K. M., et al. “Epigenetic Aging in Major Depressive Disorder.” ''American Journal of Psychiatry'', vol. 175, no. 8, Apr. 2018, pp. 774–82. ''ajp.psychiatryonline.org (Atypon)'', doi:[https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2018.17060595 10.1176/appi.ajp.2018.17060595].</ref> They also analyzed brain cells (collected post mortem) and found that increased epigenetic age correlated with MDD symptoms.

=== Centenarians ===
Those who live past the age of 100 have reduced DNAm levels, with a pattern of methylation that appears to correlate less in neighboring [[wikipedia:CpG_site|cytosine-phosphate-guanine (CpG) sites]] of the DNA of newborns, which were more homogenous.<ref>Heyn, Holger, et al. “[https://www.pnas.org/content/109/26/10522 Distinct DNA Methylomes of Newborns and Centenarians.]” ''Proceedings of the National Academy of Sciences'', vol. 109, no. 26, June 2012, pp. 10522–27.</ref>

=== Partial Epigenetic Reprogramming ===
David Sinclair et al. were able to reverse age-induced loss of sight and even regenerate a mechanically damaged eye nerve by manipulating methylation patterns in mice.<ref>Lu, Yuancheng, et al. “Reprogramming to Recover Youthful Epigenetic Information and Restore Vision.” ''Nature'', vol. 588, no. 7836, Dec. 2020, pp. 124–29. ''[https://pubmed.ncbi.nlm.nih.gov/33268865/ PubMed]'', doi:[https://www.nature.com/articles/s41586-020-2975-4 10.1038/s41586-020-2975-4].</ref> In addition to vision restoration mentioned above they were able to [https://pubmed.ncbi.nlm.nih.gov/33268865/ improve] locomotive and cognitive performance in aged mice, and they also were able to shift the clocks forward, making the mice biologically older than it should be.<ref>Palliyaguru, Dushani L., et al. “Combining a High Dose of Metformin With the SIRT1 Activator, SRT1720, Reduces Life Span in Aged Mice Fed a High-Fat Diet.” ''The Journals of Gerontology: Series A'', vol. 75, no. 11, Oct. 2020, pp. 2037–41. ''Silverchair'', doi:[https://academic.oup.com/biomedgerontology/article/75/11/2037/5859153 10.1093/gerona/glaa148].</ref> This is not particularly useful in practice, but necessary to confirm that their model of aging works.
== Mechanism ==
Epigenetic clock works by measuring DNA methylation levels, i.e. the number and distribution of methyl groups attached to the DNA molecule. These ‘tags’ signal to genes to be turned on or off.

Epigenetic clocks appear to measure a universal feature of aging across species. The same algorithm that is based on the same set of biomarkers (DNAm) has been shown to strongly predict chronological age in hundreds of animals, ranging from mice, bats, and to humans. Notably, the residual or unexplained variance of epigenetic clocks (such as 'GrimAge)' for prediction of chronological age, appears to further capture biological age.<ref name=":0">Lu, A. T., Quach, A., Wilson, J. G., Reiner, A. P., Aviv, A., Raj, K., ... & Horvath, S. (2019). DNA methylation GrimAge strongly predicts lifespan and healthspan. ''Aging (Albany NY)'', ''11''(2), 303.</ref> For GrimAge, this aspect is referred to as AgeAccelGrim, where regression of DNA GrimAge on chronological age predicts whether biological age is greater or lesser than chronological age.<ref name=":0" /> In other words, epigenetic clocks accurately predict one's age based on various DNAm biomarkers, but the error in prediction (which is an expected outcome), reflects the differences in rates of biological aging between individuals.

[[wikipedia:DNA_methylation|DNA methylation]] is attachment of a methyl group to one of the “links” in the DNA strain (specifically, cytosine nucleotide). This does not affect the content of the DNA itself, but it does affect how it’s being read and used by the cell. This is one of the group of changes called epigenetics - changes in the organism's physical function which do not alter the DNA sequence itself, but - under certain conditions - can be inherited.

There has been a [https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0656-7 number of studies] showing that as humans (and other mammals) age, patterns of methylation in their DNA change in certain ways. The exact patterns of change are quite complex and not yet fully described, but broadly there were two tendencies detected. First, the global level of methylation decreases, unequally in different tissues (for example in mice methylation levels decreased in brain, heart and spleen, but not in lungs or liver). Secondly, the local methylation level increases in certain locations: CpG islands (regions on a DNA strain where the sequence cytosine-guanine occurs with high frequency) and bivalent chromatin domain promoters (promoter is a sequence in DNA which initiates transcription of the gene following it).

These changes can be used to estimate the biological age of the organism, and there’s a [[wikipedia:Epigenetic_clock#Other_age_estimators_based_on_DNA_methylation_levels|number of approaches]] to that, most common being the Horvath’s clock, developed by [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120753/ Horvath et al. in 2013]. They used publicly available datasets of methylation data collected on [[wikipedia:Illumina,_Inc.|Illumina]] chips, and analyzed 21,369 CpG sites available on both 27k and 450k chips (the number referring to the total number of sites the chip analyzes). The team then used a penalized regression model (Elastic net regularization, which is essentially a linear combination of lasso and ridge regularization penalties which thus drives the model to have both smaller coefficients and fewer of them) to identify 353 sites providing the most signal, of which 193 correlated with age positively and the remaining 160 negatively. The clock then applies a calibration function to the weighted average of these 353 sites methylation levels to determine the biological age.

== Discovery ==
Changes in methylation levels with aging have been observed for some time. First work using epigenetic changes as a basis for biological clocks was [https://www.researchgate.net/publication/344399255_An_epigenetic_clock_Anticorrelation_DNA_methylation_as_biomarker_for_aging?channel=doi&linkId=5f70f837458515b7cf5402bc&showFulltext=true published] in 2009 by Schumacher. In 2013, the labs of Trey Ideker and Kang Zhang at the University of California, San Diego published the Hannum epigenetic clock ([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3780611/ Hannum 2013]), which consisted of 71 markers that accurately estimate age based on blood methylation levels, and in the same year the first multi-tissue epigenetic clock, was developed by Steve Horvath, a professor of human genetics and of biostatistics at UCLA ([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015143/ Horvath 2013]) Horvath’s clock allows to measure the age of different tissues of the same organism with the same clock, so it is most widely used in aging research today.

== Epigenetic clocks and aging ==

It is not fully known whether epigenetic changes are a cause or consequence of other aging processes. Several theories have been proposed, and are explained below:

=== Link with Hallmarks of Aging ===
There is [https://www.hindawi.com/journals/sci/2020/1047896/ evidence] that changed methylation patterns can be linked to some of the [[Hallmarks of Aging|hallmarks of aging]]: loss of proteostasis, mitochondrial dysfunction, stem cell exhaustion and immunosenescence. [https://pubmed.ncbi.nlm.nih.gov/33268865/ David Sinclair et al.] were able to reverse age-induced loss of sight from glaucoma, and even regenerate a mechanically damaged eye nerve by manipulating methylation patterns in mice. They used three out of four so-called 'Yamanaka factors' which are proteins necessary for reprogramming adult somatic cells back to pluripotent stem cells. Using the factors in live organisms for prolonged periods of time is known to cause cancer by boosting up cell division. But with exclusion of one of these factors (c-Myc), that is known to be oncogenic, the other three factors were kept active in mice for over a year without inducing any tumors.

The induction of these factors allowed the mice to regrow a mechanically damaged optic nerve. Normally, a mouse's optic nerve can regrow during early development, but then loses this ability a few days after birth. In this experiment, adult mice were able to re-obtain a similar regenerative ability and regained around half of their lost visual acuity.

Another result achieved using Yamanaka factors was restoring vision of healthy, middle-aged (one-year-old) mice. These mice scored worse on the tests of visual acuity before treatment than the younger mice, but one month after treatment they had similar results

=== Information theory of aging ===
Another theory, popularised by Professor David Sinclair, is that epigenetic changes might be the master regulator aging - known as [https://hplus.club/blog/a-summary-of-david-sinclairs-information-theory-of-aging/ the information theory of aging].

Since DNA is identical in every somatic cell, each cell in order to differentiate from a stem cell and then perform its function needs to “know” which genes to read, so that e.g. a neuron cell only expresses (i.e. uses) genes relevant for being a neuron, and not a muscle cell or a skin cell. This is achieved through methylation and other epigenetic mechanisms.

The theory goes that aging is fundamentally caused by errors in this process accumulating, eventually causing a cell to stop functioning normally and either become cancerous or die.

== Other uses ==
Epigenetic clock also has many other [[wikipedia:Epigenetic_clock#Motivation_for_biological_clocks|applications]]:

* Testing the validity of various theories of biological aging
* Diagnosing various age related diseases and for defining cancer subtypes
* Predicting/prognosticating the onset of various diseases
* Serving as surrogate markers for evaluating therapeutic interventions including rejuvenation approaches,
* Studying developmental biology and cell differentiation
* Forensic applications, e.g. to estimate the age of a suspect based on blood left at a crime scene

== References ==

Aging and cancer

2021-06-14T10:06:25Z

SV: Edited for sentence structure

Cancer is characterised by uncontrolled somatic cell growth, often related to genetic mutations in the proteins responsible for preventing tumor cell proliferation or the regulation of cell growth.

=== How is Aging Relevant to Cancer? ===
[[File:CancerRisk Adaptation.png|alt=Age is the major risk factor for cancer|thumb|685x685px|Age is the major risk factor for cancer]]
Aging is the largest risk factor for cancer, and dwarfs all other environmental risk factors, such as with smoking, alcohol, and diet. From an epidemiological perspective, this suggests that targeting the fundamental biological mechanisms of aging may yield larger cancer prevention effects than addressing other cancer risk factors.

Aging is permissive for the development of cancer due to multiple biological mechanisms, including reduced cancer cell surveillance from immune system aging (immunosenescence), systemic low-grade age-related inflammation (inflammaging) that promotes a pro-cancer environment, as well as age-associated accumulation of DNA mutations and genome instability, among various others mechanisms that promote cancer induction and growth.<ref>De Magalhães, J. P. (2013). How ageing processes influence cancer. ''Nature Reviews Cancer'', ''13''(5), 357-365.</ref>

Cancer is regarded as an age-related disease. While there exist many exceptions, such as in childhood cancers which are often associated with monogenic hereditary mutations, most cancers occur in the elderly. The median age of cancer diagnosis in the United States (US) is 66, and is a leading cause of morbidity and death. Case and mortality dynamics of the exponential increase in cancer incidence with age is not unique to the US, being shared across different countries, but is generally a greater cause of death in developed countries.<ref>Fitzmaurice, C., Abate, D., Abbasi, N., Abbastabar, H., Abd-Allah, F., Abdel-Rahman, O., ... & Derakhshani, A. (2019). Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: a systematic analysis for the global burden of disease study. ''JAMA oncology'', ''5''(12), 1749-1768.</ref> This apparent demographic difference is partly related to longer life expectancies in developed countries, which allows people to live long enough to develop cancer.

This problem of increased cancer mortality in developed countries suggests that if population aging is not slowed (to delay the onset of all age-related diseases, including cancer), increased life expectancy may lead to a greater cancer burden and mortality. This issue is not unique to cancer, and may apply to any age-related disease. The reason such a problem arises is because the incidence of all age-related diseases increases exponentially.
[[File:Aging as a risk factor.png|alt=Incidence of all age-related diseases increases exponentially with age|thumb|359x359px|Incidence of all age-related diseases increases exponentially with age]]

Importantly, the mortality doubling rate of cancer approximates that of the Gompertz-Makeham law of mortality, which shows that disease mortality doubles every 8 years, reflecting how cancer is an age-related disease.

This shows that the emphasis on an aging population must be made for the burden of cancer, which has implications for policy, clinical trial strategy, public and private sector investment, and society in general.

A systematic analyses of the Global Burden of Disease Study for cancer show that population aging is a significant contributor to the rise in cancer cases from 1990 to 2017.<ref>[https://jamanetwork.com/journals/jamaoncology/fullarticle/2752381 Fitzmaurice, C., Abate, D., Abbasi, N., Abbastabar, H., Abd-Allah, F., Abdel-Rahman, O., ... & Derakhshani, A. (2019). Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: a systematic analysis for the global burden of disease study. ''JAMA oncology'', ''5''(12), 1749-1768.]
</ref>

[[File:Age as -1 risk factor for cancer.jpg|alt=Age as a risk factor for cancer|thumb|[https://elifesciences.org/articles/39950 Age as a risk factor for cancer]]]

=== Citations ===

Fisetin

2021-06-14T09:53:31Z

SV: I edited the article for grammar and readability. I also added some useful doi links in the references section.

Fisetin is a potent flavonol polyphenol compound found to reduce [[Senolytics|senescence]] markers in human and animal tissues.<ref name=":0">[https://pubmed.ncbi.nlm.nih.gov/30279143/ Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., Ling, Y. Y., Melos, K. I., Pirtskhalava, T., Inman, C. L., McGuckian, C., Wade, E. A., Kato, J. I., Grassi, D., Wentworth, M., Burd, C. E., Arriaga, E. A., Ladiges, W. L., Tchkonia, T., Kirkland, J. L., … Niedernhofer, L. J. (2018). Fisetin is a senotherapeutic that extends health and lifespan. ''EBioMedicine'', ''36'', 18–28. https://doi.org/10.1016/j.ebiom.2018.09.015]</ref> It can be extracted from most vegetables and fruits, such as strawberries, onions, and cucumbers.<ref>Kim, H. J., Kim, S. H., & Yun, J. M. (2012). Fisetin inhibits hyperglycemia-induced proinflammatory cytokine production by epigenetic mechanisms. ''Evidence-based complementary and alternative medicine : eCAM'', ''2012'', 639469. https://doi.org/10.1155/2012/639469.</ref> Among the therapeutic advantages of fisetin are anti-inflammatory, antiangiogenic, cardioprotective, and neuroprotective benefits.<ref>Mehta, P., Pawar, A., Mahadik, K., & Bothiraja C. (2018). Emerging novel drug delivery strategies for bioactive flavonol fisetin in biomedicine. ''Biomedicine & Pharmacotherapy'', ''106'', 1282-1291. https://doi.org/10.1016/j.biopha.2018.07.079</ref>

== Evidence of lifespan extension ==
The primary advantage of fisetin treatment is that it targets senescent cells (SCs). These cells have accumulated DNA damage or other stressors, and this leads to changes in chromatin and secretome protein levels, which prevents the cell from replicating or apoptosis.<ref name=":0" /> This mechanism is designed to prevent the cell from becoming a cancer cell; however, SCs can instead develop senescence-associated secretory phenotypes (SASPs) which induce inflammatory cytokines, chemokines, and extracellular degrading proteins. This is problematic because, even with low levels of SCs, it can cause tissue dysfunction.<ref name=":0" /> These cells are closely linked to age since they usually increase in abundance with age in several tissues, such as adipose tissue, skeletal muscle, kidney, and skin.<ref>Herbig, U., Ferreira, M., Condel, L., Carey, D., & Sedivy, J. M. (2006). Cellular senescence in aging primates. ''Science'', ''311''(5765), 1257-1257. ''science.sciencemag.org'', [https://science.sciencemag.org/content/311/5765/1257 doi:10.1126/science.1122446].</ref> Fisetin is a well-suited treatment option to destroy such cells and this has thus been investigated in mice and in humans.

=== Mice ===
[[File:Yousefzadeh et al. (2018) results.jpg|thumb|MEFs and IMR90 comparison in flovanoid polyphenols in Yousefzadeh et al. (2018)'s study. ]]
[[File:FisetinDietAdvantage.jpg|thumb|Fisetin diet advantages in Ercc1−/∆ mice with the p16Ink4a-luciferase transgene. ]]
Yousefzadeh et al. (2018) found that fisetin was the most effective [[Senolytics|senolytic]] out of 10 flavonoids.<ref name=":0" /> In vitro, the defective DNA repair gene Ercc1−/− in the embryonic stem cell line was targeted to induce senescence. The mutant Ercc1−/− mice cells had the greatest improvement when treated with fisetin. In vitro, they used Ercc1−/∆ mice with the p16Ink4a-luciferase transgene to evoke accelerating accumulation of senscent cells. The mice were then living on a diet from 6-8 to 10-12 weeks of age, with fisetin supplements adiminstered in every 500 mg/kg. They found that luciferase Ercc1−/∆;p16Ink4a signal was significantly suppressed following the diet. They also found that, in the following weeks, the fisetin-treated mice had lower p16Ink4a expression levels when they did not receive more fisetin. Yousefzadeh et al. (2018) argue that this is consistent with the idea that fisetin can destroy senescent cells, but is not required to be continuously present to suppress senescence.<ref name=":0" />

=== Humans ===
In studies on humans, results have indicated that fisetin can be an effective supplement to combat aging. Studies have shown that it can improve lung fibroblast tissues, known as IMR90 cells.<ref name=":0" /> After two days following the fisetin treatment, they found that the enzyme only found in senescent cells called SA-β-gal, had decreased by 70 percent.

=== Other vertebrates ===
Fisetin has been found to extend lifespan by 55% in S. ''cerevisiae''<ref>Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., ... & Sinclair, D. A. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. ''Nature'', ''425''(6954), 191-196.</ref> and 23% in D. ''melanogaster.''<ref>Wood, J. G., Rogina, B., Lavu, S., Howitz, K., Helfand, S. L., Tatar, M., & Sinclair, D. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. ''Nature'', ''430''(7000), 686-689.</ref> <references />

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Metformin

2021-06-14T08:50:44Z

SV: Edited for American spelling and patient-centric language as per https://en.longevitywiki.org/wiki/Writing_tips_for_easy_reading

Metformin is an approved medication<ref name=":0">“Metformin: Medicine to Treat Type 2 Diabetes.” ''NHS'', 25 Feb. 2019, https://www.nhs.uk/medicines/metformin/.</ref> used to treat type 2 diabetes. It has been proposed as having longevity benefits based on data suggesting that it extends lifespan in people with diabetes more than in those without it. For this reason, it is currently being considered in the first large-scale human longevity trial - the TAME trial.<ref name=":1" />[[File:Metformin.svg.png|thumb|The chemical structure of Metformin]]

== Use in Medicine ==

Metformin is a common, inexpensive drug that has been used to treat and prevent type 2 diabetes for over 60 years. It is known to reduce the amount of sugar the liver releases into the blood and helps the body respond better to insulin.<ref>https://www.nhs.uk/medicines/metformin/#:~:text=Metformin%20works%20by%20reducing%20the,to%20reduce%20the%20side%20effects.</ref> Metformin is also used to treat metabolic syndrome, which is a combination of obesity, high blood pressure and diabetes, and is sometimes used for polycystic ovary syndrome (PCOS).<ref name=":0" />
== Life extension effects ==
=== Life extension in model organisms ===
In animal trials, metformin has been found to extend the lifespan of worms, mice, fruit flies and yeast from 5-50%.<ref>Lamming, Dudley W., et al. “Pharmacologic Means of Extending Lifespan.” ''Journal of Clinical & Experimental Pathology'', vol. Suppl 4, May 2012. ''PubMed Central'', doi:[https://www.omicsonline.org/pharmacologic-means-of-extending-lifespan-2161-0681.S4-002.php?aid=7327 10.4172/2161-0681.S4-002].</ref>

=== Life extension in humans ===
Research undertaken since metformin was approved by the FDA in 1994 has found that people who take metformin tend to be healthier than those who take another diabetes-related drug.<ref>Saraei, Pouya, et al. “The Beneficial Effects of Metformin on Cancer Prevention and Therapy: A Comprehensive Review of Recent Advances.” ''Cancer Management and Research'', vol. 11, Apr. 2019, pp. 3295–313. ''PubMed Central'', doi:[https://www.dovepress.com/the-beneficial-effects-of-metformin-on-cancer-prevention-and-therapy-a-peer-reviewed-fulltext-article-CMAR 10.2147/CMAR.S200059].</ref> They live longer, have fewer cardiovascular issues, get cancer less often, and tend to outlive other people with both diabetes and cancer on different medications.

In a retrospective observational study of 90,400 subjects with diabetes who took metformin, compared to those taking another diabetes drug, and a matched control group of subjects without diabetes, it was found that metformin patients not only outlived the other subjects with diabetes but also lived longer than the subjects in the control group.<ref>Bannister, C. A., et al. “Can People with Type 2 Diabetes Live Longer than Those without? A Comparison of Mortality in People Initiated with Metformin or Sulphonylurea Monotherapy and Matched, Non-Diabetic Controls.” ''Diabetes, Obesity and Metabolism'', vol. 16, no. 11, 2014, pp. 1165–73. ''Wiley Online Library'', doi:[https://dom-pubs.onlinelibrary.wiley.com/doi/abs/10.1111/dom.12354 https://doi.org/10.1111/dom.12354].</ref> While there are various criticisms of the methodology of this paper, this has led scientists at the forefront of longevity to consider metformin as a drug with the potential to extend healthy lifespans – which could help people to not just live longer, but live more healthily for longer.

== Mechanism ==
Metformin mimics the processes involved with dietary restriction without the person having to restrict their diet.<ref>Lee, Shin-Hae, and Kyung-Jin Min. “Caloric Restriction and Its Mimetics.” ''BMB Reports'', vol. 46, no. 4, Apr. 2013, pp. 181–87. ''PubMed Central'', doi:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133883/ 10.5483/BMBRep.2013.46.4.033].</ref> Pathways involved in longevity signaling in human cells are increased with metformin, which can help reduce the harmful effects of sugar and fat storage, and prevent hardening of the arteries.

Both type 1 and type 2 diabetes are regarded by aging biology researchers as diseases of accelerated aging. They lead to premature morbidity and mortality due to frailty, cancer, stroke, heart disease, dementia, kidney disease, diabetic retinopathy, peripheral neuropathy, and many other age-related diseases.

As metformin is known to inhibit complex I of the mitochondria to activate AMPK and reduce mTOR signaling, which are molecular pathways associated with aging, there is biological rationale for repurposing this diabetes drug as a potential drug for healthy aging in people without diabetes.<ref>Vial, Guillaume, et al. “Role of Mitochondria in the Mechanism(s) of Action of Metformin.” ''Frontiers in Endocrinology'', vol. 10, 2019. ''Frontiers'', doi:[https://www.frontiersin.org/articles/10.3389/fendo.2019.00294/full 10.3389/fendo.2019.00294].</ref>

== The TAME Trial ==
Studies have shown that metformin can delay the effects of aging in animals, and it seems fairly likely that these benefits may extend to humans as well. The Targeting Aging with Metformin (TAME) trials are a series of clinical trials at 14 leading research institutions in the United States. They are looking to study whether metformin can delay the development or progression of age-related diseases (such as dementia and cancer) in 3,000 65-to-79-year-olds over six years.<ref name=":1">“TAME - Targeting Aging with Metformin.” ''American Federation for Aging Research'', https://www.afar.org/tame-trial. </ref>

== Side effects ==
Common side effects (which affect 1 in 100 people) include feeling or being sick, stomach ache, loss of appetite and/or a metallic taste in the mouth.

Serious side effects are very rare and affect less than 1 in 10,000 people. These can include severe tiredness, a slow heart rate, liver problems, or a rash. It is also possible to have a serious allergic reaction (anaphylaxis) to metformin if one is allergic to its active ingredients.

== References ==

Metformin

2021-06-14T07:42:04Z

SV: I edited the article for grammar and sentence structure. I also aligned the references with longevitywiki standards.

Metformin is an approved medication<ref name=":0">“Metformin: Medicine to Treat Type 2 Diabetes.” ''NHS'', 25 Feb. 2019, https://www.nhs.uk/medicines/metformin/.</ref> used to treat type 2 diabetes. It has been proposed as having longevity benefits based on data suggesting it extends lifespan in diabetics more than that of non-diabetics. For this reason, it is currently being considered in the first large-scale human longevity trial - the TAME trial.<ref name=":1" />[[File:Metformin.svg.png|thumb|The chemical structure of Metformin]]

== Use in Medicine ==

Metformin is a common, inexpensive drug that has been used to treat and prevent type 2 diabetes for over 60 years. It is known to reduce the amount of sugar the liver releases into the blood and helps the body respond better to insulin.<ref>https://www.nhs.uk/medicines/metformin/#:~:text=Metformin%20works%20by%20reducing%20the,to%20reduce%20the%20side%20effects.</ref> Metformin is also used to treat metabolic syndrome, which is a combination of obesity, high blood pressure and diabetes, and is sometimes used for polycystic ovary syndrome (PCOS).<ref name=":0" />
== Life extension effects ==
=== Life extension in model organisms ===
In animal trials, metformin has been found to extend the lifespan of worms, mice, fruit flies and yeast from 5-50%.<ref>Lamming, Dudley W., et al. “Pharmacologic Means of Extending Lifespan.” ''Journal of Clinical & Experimental Pathology'', vol. Suppl 4, May 2012. ''PubMed Central'', doi:[https://www.omicsonline.org/pharmacologic-means-of-extending-lifespan-2161-0681.S4-002.php?aid=7327 10.4172/2161-0681.S4-002].</ref>

=== Life extension in humans ===
Research undertaken since metformin was approved by the FDA in 1994 has found that people who take metformin tend to be healthier than those who take another diabetes-related drug.<ref>Saraei, Pouya, et al. “The Beneficial Effects of Metformin on Cancer Prevention and Therapy: A Comprehensive Review of Recent Advances.” ''Cancer Management and Research'', vol. 11, Apr. 2019, pp. 3295–313. ''PubMed Central'', doi:[https://www.dovepress.com/the-beneficial-effects-of-metformin-on-cancer-prevention-and-therapy-a-peer-reviewed-fulltext-article-CMAR 10.2147/CMAR.S200059].</ref> They live longer, have fewer cardiovascular issues, get cancer less often, and tend to outlive other diabetics with cancer on different medications.

In a retrospective observational study of 90,400 diabetics who took metformin, compared to diabetics taking another diabetes drug and a matched control group of non-diabetics, it was found that metformin patients not only outlived the other diabetics but also lived longer than the non-diabetics in the control group.<ref>Bannister, C. A., et al. “Can People with Type 2 Diabetes Live Longer than Those without? A Comparison of Mortality in People Initiated with Metformin or Sulphonylurea Monotherapy and Matched, Non-Diabetic Controls.” ''Diabetes, Obesity and Metabolism'', vol. 16, no. 11, 2014, pp. 1165–73. ''Wiley Online Library'', doi:[https://dom-pubs.onlinelibrary.wiley.com/doi/abs/10.1111/dom.12354 https://doi.org/10.1111/dom.12354].</ref> While there are various criticisms of the methodology of this paper, this has led scientists at the forefront of longevity to consider metformin as a drug with the potential to extend healthy lifespans – which could help people to not just live longer, but live more healthily for longer.

== Mechanism ==
Metformin mimics the processes involved with dietary restriction without the person having to restrict their diet.<ref>Lee, Shin-Hae, and Kyung-Jin Min. “Caloric Restriction and Its Mimetics.” ''BMB Reports'', vol. 46, no. 4, Apr. 2013, pp. 181–87. ''PubMed Central'', doi:[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133883/ 10.5483/BMBRep.2013.46.4.033].</ref> Pathways involved in longevity signalling in human cells are increased with metformin, which can help reduce the harmful effects of sugar and fat storage, and prevent hardening of the arteries.

Both type 1 and type 2 diabetes are regarded by aging biology researchers as diseases of accelerated aging. They lead to premature morbidity and mortality due to frailty, cancer, stroke, heart disease, dementia, kidney disease, diabetic retinopathy, peripheral neuropathy, and many other age-related diseases.

As metformin is known to inhibit complex I of the mitochondria to activate AMPK and reduce mTOR signalling, which are molecular pathways associated with aging, there is biological rationale for repurposing this diabetic drug as a potential drug for healthy aging in non-diabetics.<ref>Vial, Guillaume, et al. “Role of Mitochondria in the Mechanism(s) of Action of Metformin.” ''Frontiers in Endocrinology'', vol. 10, 2019. ''Frontiers'', doi:[https://www.frontiersin.org/articles/10.3389/fendo.2019.00294/full 10.3389/fendo.2019.00294].</ref>

== The TAME Trial ==
Studies have shown that metformin can delay the effects of aging in animals, and it seems fairly likely that these benefits may extend to humans as well. The Targeting Aging with Metformin (TAME) trials are a series of clinical trials at 14 leading research institutions in the United States. They are looking to study whether metformin can delay the development or progression of age-related diseases (such as dementia and cancer) in 3,000 65-to-79-year-olds over six years.<ref name=":1">“TAME - Targeting Aging with Metformin.” ''American Federation for Aging Research'', https://www.afar.org/tame-trial. </ref>

== Side effects ==
Common side effects (which affect 1 in 100 people) include feeling or being sick, stomach ache, loss of appetite and/or a metallic taste in the mouth.

Serious side effects are very rare and affect less than 1 in 10,000 people. These can include severe tiredness, a slow heart rate, liver problems, or a rash. It is also possible to have a serious allergic reaction (anaphylaxis) to metformin if one is allergic to its active ingredients.

== References ==

COVID-19

2021-06-13T18:04:09Z

SV: I primarily edited for grammar and sentence structure, throughout the article. I also added citations where they had been referred in-text, especially for NCTs, and removed a duplicate citation. In some places, I added context where the cited study specified its importance. I removed some incomplete and uncited sentences, although I have left some up for query with the relevant writers.

[[File:Covid risk 1.png|alt=Age as a risk factor for COVID-19 mortality|thumb|462x462px|* Fold risk of COVID-19 mortality versus reference group aged 5-17 [https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html (US CDC statistics)]]]
Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

The novel coronavirus emerged in late 2019 and rapidly spread throughout the world, evolving into a human pandemic. The substantial suffering and mortality that followed ranks it as one of the greatest pandemics in human history.

While the precise molecular reasons for why COVID-19 disproportionately affects the elderly remain unanswered, what is apparent is that age is the largest - and by several orders of magnitude - risk factor for mortality.<ref name=":0">Mueller, A. L., McNamara, M. S., & Sinclair, D. A. (2020). Why does COVID-19 disproportionately affect older people?. ''Aging (Albany NY)'', ''12''(10), 9959.</ref>

== SARS-CoV-2 as a Disease of Aging: Epidemiology and Risk Factors ==
The salient feature of the COVID-19 pandemic was the extreme predisposition of the elderly to morbidity and mortality; therefore, understanding why and how this occurs should be a primary focus of therapeutic strategy.
For decades, scientists and doctors have known of the disproportionate susceptibility of older adults to respiratory infections.<ref name=":0" /> Similarly to COVID-19, respiratory infections such as pneumonia, influenza and other coronaviruses show similar mortality risk profiles in the elderly.

Influenza is a notable example of the age-related susceptibility to various pathogen-induced infections, which is historically linked to the annual deaths of 389,000 worldwide, 67% of which occur in people aged 65 or older.<ref>Paget, J., Spreeuwenberg, P., Charu, V., Taylor, R. J., Iuliano, A. D., Bresee, J., ... & Viboud, C. (2019). Global mortality associated with seasonal influenza epidemics: New burden estimates and predictors from the GLaMOR Project. ''Journal of global health'', ''9''(2).</ref> The posited explanations, from the perspective of broad biological mechanisms, are immunosenescence (immune aging) and inflammaging (age-related systemic inflammation).<ref name=":0" /><ref>Akbar, A. N., & Gilroy, D. W. (2020). Aging immunity may exacerbate COVID-19. ''Science'', ''369''(6501), 256-257.</ref><ref name=":2">[[Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. Aging and disease, 11(4), 725.|Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. ''Aging and disease'', ''11''(4), 725.]]</ref>

=== Aging, Comorbidities, and COVID-19 ===
Current epidemiological data provides limited support for the idea that ''single'' comorbidities (often age-related diseases such as type 2 diabetes or hypertension) are important in isolation as predictors (risk factors) for SARS-CoV-2 mortality.<ref name=":4" /> While COVID-19 can be comorbid with one other disease, the resulting increase in mortality risk is small; any single comorbidity as a risk factor for mortality remains on the order of single-digit magnitude.<ref>Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. ''Nature'', ''584''(7821), 430-436.</ref>

Multimorbidity, or having more than two comorbidities, appears to be more important in predicting COVID-19 mortality. In developed countries, the risk of having multimorbidity increases exponentially with age, with a prevalence of 20% before age 40, increasing to 75% at age 70.<ref name=":4" /><ref>Violan, C., Foguet-Boreu, Q., Flores-Mateo, G., Salisbury, C., Blom, J., Freitag, M., ... & Valderas, J. M. (2014). Prevalence, determinants and patterns of multimorbidity in primary care: a systematic review of observational studies. ''PloS one'', ''9''(7), e102149.</ref>

Analyses of the available epidemiological data for COVID-19 reveals that age uniquely confers the greatest risk for mortality, with no other putative risk factor approaching comparable magnitude.<ref name=":0" />'''<ref name=":1" />''' When [[wikipedia:Comorbidity|comorbidities]] are controlled for in correlational analyses, by separating apparently healthy older adults from those of similar age with chronic diseases, age still remains as the dominant risk factor for mortality.'''<ref name=":1" />'''

Similarly, when controlling for age, the predictive value of comorbidities on mortality to SARS-CoV-2 infections fades, indicating substantial confounding by age. Conversely, the residual predictive value of various comorbidities, such as hypertension and cardiovascular diseases, is consistent with the idea that comorbidities may act as partial indicators of biological age, reflecting differences in aging that cannot simply be captured by chronological age.<ref name=":4">Polidori, M. C., Sies, H., Ferrucci, L., & Benzing, T. (2021). COVID-19 mortality as a fingerprint of biological age. ''Ageing Research Reviews'', 101308.
</ref> Furthermore, most pre-existing conditions that are risk factors for COVID-19 mortality are age-related diseases, which adds to the idea that biological aging is fundamental to the ability of SARS-CoV-2 (age-dependent mortality) to induce mortality the elderly.

=== COVID-19 as a Disease of Aging ===
'''As detailed in the paper "[https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13230 COVID‐19 is an emergent disease of aging"],<ref name=":1">[[Santesmasses, D., Castro, J. P., Zenin, A. A., Shindyapina, A. V., Gerashchenko, M. V., Zhang, B., ... & Gladyshev, V. N. (2020). COVID‐19 is an emergent disease of aging. Aging cell, 19(10), e13230.|Santesmasses, D., Castro, J. P., Zenin, A. A., Shindyapina, A. V., Gerashchenko, M. V., Zhang, B., ... & Gladyshev, V. N. (2020). COVID‐19 is an emergent disease of aging. ''Aging cell'', ''19''(10), e13230.]]</ref> COVID-19 can be defined as an age-related disease due to the following epidemiological traits:<ref name=":2" /><ref>[[Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. The Journals of Gerontology: Series A, 75(9), e30-e33.|Promislow, D. E. (2020). A geroscience perspective on COVID-19 mortality. ''The Journals of Gerontology: Series A'', ''75''(9), e30-e33.]]</ref><ref>Alberts, S. C., Archie, E. A., Gesquiere, L. R., Altmann, J., Vaupel, J. W., & Christensen, K. (2014). The male-female health-survival paradox: a comparative perspective on sex differences in aging and mortality. In ''Sociality, hierarchy, health: comparative biodemography: a collection of papers''. National Academies Press (US).</ref><ref>[[Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. Journal of the American Geriatrics Society, 68(5), 951.|Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. ''Journal of the American Geriatrics Society'', ''68''(5), 951.]]</ref>'''

'''1) The doubling time for COVID-19 mortality approaches that of the doubling time of 8 years for all-cause mortality/morbidity (as observed for all age-related diseases), per the Gompertz law.'''

'''2) There is a greater mortality rate in men, consistent with known sex differences in rates of aging.'''

'''3) There is a greater mortality rate for those with age-related comorbidities, consistent with accelerated biological aging.'''

'''4) Age dwarfs all other putative [[wikipedia:Risk_factor|risk factors]] for mortality by several orders of magnitude.'''

''Risk factors are used medicine to assess individual and population risks for certain diseases, in order to guide diagnosis and clinical management. An example of a risk factor is smoking status, which increases the risk of lung cancer by approximately 7 fold.<ref>[[O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. BMJ open, 8(10), e021611.|O’Keeffe, L. M., Taylor, G., Huxley, R. R., Mitchell, P., Woodward, M., & Peters, S. A. (2018). Smoking as a risk factor for lung cancer in women and men: a systematic review and meta-analysis. ''BMJ open'', ''8''(10), e021611.]]</ref>''[[File:CDC stat table.jpg|center|thumb|883x883px|link=https://longevitywiki.org/wiki/File:CDC_stat_table.jpg]]When compared to a reference group of youths aged 5-14, the risk of death for COVID-19 patients over the age of 85 is 8700 times greater, according to data from the United States Centers for Disease Control and Prevention. Other common risk factors identified in COVID-19 scientific discourse are comparatively inconsequential; for example, a history of chronic lung disease confers only a 2 times greater risk of mortality.<ref>[[Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. Nature, 584(7821), 430-436.|Williamson, E. J., Walker, A. J., Bhaskaran, K., Bacon, S., Bates, C., Morton, C. E., ... & Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. ''Nature'', ''584''(7821), 430-436.]]</ref> COVID-19 results in systemic involvement with neurologic, kidney, liver, heart, endocrine, and gut complications;<ref>Gupta, A., Madhavan, M. V., Sehgal, K., Nair, N., Mahajan, S., Sehrawat, T. S., ... & Landry, D. W. (2020). Extrapulmonary manifestations of COVID-19. ''Nature medicine'', ''26''(7), 1017-1032.</ref> therefore, geroprotectors that treat systemic aging may be valuable for increasing the resilience of multiple aged and vulnerable organ systems.<ref>[[Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. Journal of the American Geriatrics Society, 68(5), 951.|Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. ''Journal of the American Geriatrics Society'', ''68''(5), 951.]]</ref><ref>[[Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. Aging and disease, 11(4), 725.|Barzilai, N., Appleby, J. C., Austad, S. N., Cuervo, A. M., Kaeberlein, M., Gonzalez-Billault, C., ... & Sierra, F. (2020). Geroscience in the Age of COVID-19. ''Aging and disease'', ''11''(4), 725.]]</ref>

As the underlying reason for susceptibility is due to age-related increases in vulnerability, targeting aging biology mechanisms might allow for the treatment of multiple age-related disease simultaneously. Therapies that address the fundamental biological processes, shared by future communicable diseases of pandemic potential, could substantially mitigate the impact of pandemics in which age-related immune dysfunction is central to mortality and morbidity.

When considering the systemic consequences of SARS-CoV-2, in addition to the magnitude of the risks conferred by age, it has been suggested that an emphasis on the specific organ system of respiration (or the virus itself) rather than the aging host, may be a short-sighted therapeutic strategy.<ref>[https://agsjournals.onlinelibrary.wiley.com/doi/full/10.1111/jgs.16489 Sierra, F. (2020). Geroscience and the Coronavirus Pandemic: The Whack‐a‐Mole Approach is not Enough. ''Journal of the American Geriatrics Society'', ''68''(5), 951.]</ref>

=== Aging and COVID-19 Infection Fatality Rate (IFR) ===
In the research field of [[wikipedia:Epidemiology|epidemiology]], the infection fatality rate (IFR) – the ratio of fatalities to total infections – is an important metric for determining the virulence of an infectious disease.<ref>Levin, A. T., Hanage, W. P., Owusu-Boaitey, N., Cochran, K. B., Walsh, S. P., & Meyerowitz-Katz, G. (2020). Assessing the age specificity of infection fatality rates for COVID-19: systematic review, meta-analysis, and public policy implications. ''European journal of epidemiology'', 1-16.</ref> In the early stages of the pandemic, determining the IFR of COVID-19 was subject to significant uncertainty due to lack of data.

One estimate found that the IFR of a given country's population was significantly dependent on the age structure.<ref name=":7">O’Driscoll, M., Dos Santos, G. R., Wang, L., Cummings, D. A., Azman, A. S., Paireau, J., ... & Salje, H. (2021). Age-specific mortality and immunity patterns of SARS-CoV-2. ''Nature'', ''590''(7844), 140-145.</ref> For example, Japan, which has a large proportion of elderly citizens, had the highest estimated IFR, at 1.09% (95% credible interval, 0.94–1.26%), whereas Kenya, which has a relatively young population base, had the lowest estimated IFR, at 0.09% (95% credible interval, 0.08–0.10%).<ref name=":7" /> Countries with minimal public health resources fared well during the pandemic from the perspective of COVID-19 mortality. Public health stakeholders in developing countries that failed to take age-specific IFRs into account may have caused unnecessary harm, such as with the cessation of vaccination for malaria in Africa?

=== Aging Immunity and Vulnerability to Infectious Disease ===
Both immunosenescence and inflammaging are well-known biological mechanisms that underlie age-related susceptibility to various infectious diseases, such as the common cold, influenza, and pneumonia.

Immunosenescence is characterised by the age-related decline in the host's ability to mount an appropriate immune response to an infectious agent.<ref name=":6">Furman, D., Campisi, J., Verdin, E., Carrera-Bastos, P., Targ, S., Franceschi, C., ... & Slavich, G. M. (2019). Chronic inflammation in the etiology of disease across the life span. ''Nature medicine'', ''25''(12), 1822-1832.</ref> A major reason for this decline is related to atrophy of the thymus (thymic involution), an important organ that is important for generating naive T cells. It is therefore central to the adaptive immune system, which is integral to providing long-term protection against old and new infectious pathogens.

Inflammaging describes the age-related systemic inflammation, which affects various systems across the body that leads to organ and tissue dysfunction.<ref name=":6" /> It is known that with aging, dysregulation of the innate immune system results in chronic hyperactivation, and becomes a key driver of multiple age-related diseases via chronic inflammation.<ref>Shaw, A. C., Goldstein, D. R., & Montgomery, R. R. (2013). Age-dependent dysregulation of innate immunity. ''Nature Reviews Immunology'', ''13''(12), 875-887.</ref>

== COVID-19 Clinical Trials Targeting Aging ==
The following drugs are currently being investigated in clinical trials for the treatment of COVID-19; they are not currently regarded as safe or effective for this indication.

=== RTB101 ===
<blockquote>RTB101 (dactolisib) is an FDA-approved drug used in oncology, with primary mechanism of action of ATP-competitive PI3K/mTOR dual kinase inhibition.

Inhibition of mTOR has been shown in human clinical studies to improve immune function in older adults.<ref>Mannick, J. B., Del Giudice, G., Lattanzi, M., Valiante, N. M., Praestgaard, J., Huang, B., ... & Klickstein, L. B. (2014). mTOR inhibition improves immune function in the elderly. ''Science translational medicine'', ''6''(268), 268ra179-268ra179.</ref><ref>Mannick, J. B., Morris, M., Hockey, H. U. P., Roma, G., Beibel, M., Kulmatycki, K., ... & Klickstein, L. B. (2018). TORC1 inhibition enhances immune function and reduces infections in the elderly. ''Science translational medicine'', ''10''(449).</ref> Phase 2 studies have shown that mTOR inhibitors can reduce viral infection severity and improve the effectiveness of vaccination, such as for influenza. This is in contrast to the known ability for rapamycin (and its analogues) to induce immunosuppression, which is related to its primary indication as an FDA-approved liver and lung transplant drug.

Following the success of two [https://clinicaltrials.gov/ct2/show/NCT03373903?term=restorbio&draw=2&rank=4 phase 2 clinical trials] investigating mTOR inhibition for targeting the aging immune system, RTB101 (dactolisib) is currently being pursued for the treatment of COVID-19 in a phase 2a placebo-controlled trial, exploring the potential for preventing severe disease in asymptomatic elderly adults who have been exposed to COVID-19.<ref>Restorbio Inc. ''A Randomized, Double-Blind, Placebo-Controlled Phase 2a Study of RTB101 as COVID-19 Post-Exposure Prophylaxis in Adults Age ≥65 Years''. Clinical trial registration, NCT04584710, clinicaltrials.gov, 5 Feb. 2021. ''clinicaltrials.gov'', https://clinicaltrials.gov/ct2/show/NCT04584710.</ref><ref>Restorbio Inc. ''Randomized Double Blind Placebo-Controlled Study to Determine If Prophylaxis With RTB101 Compared to Placebo Reduces Severity of Lab Confirmed COVID19 in Adults ≥65 Years in a Nursing Home in Which ≥1 Person(s) Have Lab Confirmed COVID19''. Clinical trial registration, NCT04409327, clinicaltrials.gov, 5 Feb. 2021. ''clinicaltrials.gov'', https://clinicaltrials.gov/ct2/show/NCT04409327.</ref>

This trial is being run by the biopharmaceutical company resTORbio and has obtained funding from the [https://www.nia.nih.gov/ National Institute on Aging].

The primary rationale for why RTB101 has potential to show benefit for the 2019 strain of coronavirus stems from phase 2b and phase 3 clinical trial data of RTB101, showing [https://www.globenewswire.com/NewsRoom/AttachmentNg/2efab205-5689-453e-b2c6-5bdb006d89d4 fewer laboratory-confirmed (non-COVID-19) coronavirus cases], and [https://www.globenewswire.com/NewsRoom/AttachmentNg/4e5cdc45-cc2b-4d9a-815f-4907690bb06f reduced severity of coronavirus infection] in elderly adults aged ≥ 65. The phase 3 randomised, double-blind, placebo-controlled clinical trial for RTB101 was withdrawn in November 2019, following failure to meet its primary endpoint of reducing symptoms of respiratory tract infections (RTIs) in adults aged ≥ 65, with or without laboratory-confirmed viral illness.

Considering the promising clinical data from the phase 2 trials, which involved investigations of both rapamycin and RTB101, some regard this failure as unsurprising due to the decision to move ahead with only RTB101 in the phase 3 trial.<ref name=":5">Kaeberlein, M. (2020). RTB101 and immune function in the elderly: Interpreting an unsuccessful clinical trial. ''Translational Medicine of Aging'', ''4'', 32-34.
</ref> This is because only rapamycin, an allosteric inhibitor of mTOR, has demonstrated the extension of healthspan and lifespan in various animal models, with a rejuvenation of immune function; while RTB101, an ATP-competitive PI3K/mTOR dual kinase inhibitor of differing mechanism of action to rapamycin, has not yet demonstrated these effects in animal models.<ref name=":5" /> The decision to omit the use of rapamycin and continue with RTB101 in the phase 3 trial is speculated to be related to the off-patent status; it would be prohibitive for a publicly-traded company with fiduciary responsibility to shareholders to advance a drug with no commercial potential into late-stage clinical trials.<ref name=":5" />

Joan Mannick, the Chief Medical Officer of resTORbio, has since justified the trial's failure at several [https://www.youtube.com/watch?v=BVQci0V8uPk medical conferences] with the belief that it was related to a change in the primary endpoint, as requested by the [[wikipedia:Food_and_Drug_Administration|US FDA]], when the trial advanced from phase 2 to 3. In the prior successful phase 2 trial, the primary endpoint had been RTI symptoms ''with'' laboratory confirmation of a causative virus, but this endpoint was changed to RTI symptoms ''with or without'' laboratory-confirmed viral illness in the [https://clinicaltrials.gov/ct2/show/NCT04139915?cond=rtb101&draw=2&rank=1 failed phase 3 trial]. This is a problem for interpreting the clinical trial because it was not the original endpoint for which the drug had showed benefits, and is also introduced as older adults inherently experience respiratory tract symptoms at greater rates, even ''without'' laboratory-confirmation of viral presence. </blockquote>

=== Fisetin ===
Fisetin is a [[Senolytics|senolytic]] that is being investigated in two phase 2 clinical trials at the Mayo Clinic<ref>Kirkland, James L. ''COVID-FISETIN: A Phase 2 Placebo-Controlled Pilot Study in SARS-CoV-2 of Fisetin to Alleviate Dysfunction and Excessive Inflammatory Response in Hospitalized Adults''. Clinical trial registration, NCT04476953, clinicaltrials.gov, 16 Feb. 2021. ''clinicaltrials.gov'', <nowiki>https://clinicaltrials.gov/ct2/show/NCT04476953</nowiki>.</ref>, with the second trial being funded by the National Institute on Aging of the [[wikipedia:National_Institutes_of_Health|US NIH]]<ref>PhD, James L. Kirkland, MD. ''COVID-FIS: A Phase 2 Placebo-Controlled Pilot Study in COVID-19 of Fisetin to Alleviate Dysfunction and Excessive Inflammatory Response in Older Adults in Nursing Homes''. Clinical trial registration, NCT04537299, clinicaltrials.gov, 1 June 2021. ''clinicaltrials.gov'', <nowiki>https://clinicaltrials.gov/ct2/show/NCT04537299</nowiki>.</ref>.

For SARS-CoV-2, fibrosis of the lung tissue is a well-known serious complication following acute respiratory distress syndrome (ARDS). Senolytic drugs are capable of slowing and/or reversing age-related lung fibrosis in mice, as well as promoting health in multiple tissues/organs, and so may provide benefit for both acute and chronic manifestations of COVID-19.<ref name=":3" /> The pro-inflammatory secretions of senescent cells have been identified as key drivers of tissue and organ dysfunction with aging, which have been linked to the cytokine storm associated with COVID-19 ARDS.<ref name=":3" /> It is hypothesised that senolytics may alleviate the age-associated decline in lung function, in addition to improving immune function such as via the clearance of senescent T cells.<ref name=":3">Nehme, J., Borghesan, M., Mackedenski, S., Bird, T. G., & Demaria, M. (2020). Cellular senescence as a potential mediator of COVID‐19 severity in the elderly. ''Aging Cell'', ''19''(10), e13237</ref><ref>Akbar, A. N., & Gilroy, D. W. (2020). Aging immunity may exacerbate COVID-19. ''Science'', ''369''(6501), 256-257.</ref>

=== BGE-175 ===
BGE-175 is an investigational new drug for COVID-19 that was previously studied in phase 1 to 3 trials for allergic rhinitis involving 2400 study participants. It is an oral inhibitor of prostaglandin D2 (PGD2) DP1 signaling.<ref>https://www.businesswire.com/news/home/20210322005146/en/BioAge-Initiates-Phase-2-Trial-of-BGE-175-to-Treat-COVID-19-by-Reversing-Immune-Aging-a-Key-Cause-of-Morbidity-and-Mortality-in-Older-Patients</ref> It is being advanced in clinical trials by BioAge, a privately-held biotechnology company that aims to treat aging and aging-related diseases.

While BGE-175 has not been shown to extend healthspan and/or lifespan in published animal models, the company claims that the rationale for its consideration as an aging drug is based on targeting the apelin pathway that is associated with healthspan and lifespan in humans.<ref>https://www.fiercebiotech.com/biotech/bioage-picks-up-muscle-aging-program-from-amgen-bringing-pipeline-count-to-3</ref><ref>Zhou, Q., Chen, L., Tang, M., Guo, Y., & Li, L. (2018). Apelin/APJ system: A novel promising target for anti-aging intervention. ''Clinica Chimica Acta'', ''487'', 233-240.</ref>

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