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Gompertz-Makeham law of mortality

2022-08-15T19:25:16Z

Volunteer Longevity Writer 007: Expanded on "Gompertz Law as an Intrinsic Principle of Aging" section, and "Usage" section.

[[File:Gompertz-Makeham Law of Mortality.jpg|thumb|143x143px|Gompertz-Makeham Law of Mortality, where ''μ(x)'' indicates mortality rate, ''α'' and ''β'' are constants, and ''γ'' represents factors unrelated to age which contribute to mortality.]]
The Gompertz-Makeham Law of Mortality is an equation which shows the increase in mortality rates for organisms as they age.<ref name=":0">''Gompertz-Makeham_law_of_mortality''. (n.d.). Retrieved August 7, 2022, from <nowiki>https://www.bionity.com/en/encyclopedia/Gompertz-Makeham_law_of_mortality.html</nowiki></ref><gallery>
</gallery>

== History ==
The law's predecessor, Gompertz's law (written as μ(x)=α''e''βx), was formulated by an actuary named Benjamin Gompertz, and published in an 1825 paper. He wished to help others in his profession calculate the most profitable rates at which to sell annuities to purchasers of various ages. He had observed that mortality rate appeared to increase exponentially over the adult human lifespan. As his model fit reasonably well with observed data, it was quickly adopted by actuaries and demographers for their own work.<ref name=":1">Kirkwood, T. B. L. (2015). Deciphering death: A commentary on Gompertz (1825) ‘On the nature of the function expressive of the law of human mortality, and on a new mode of determining the value of life contingencies.’ ''Philosophical Transactions of the Royal Society B: Biological Sciences, 370''(1666), 20140379. <nowiki>https://doi.org/10.1098/rstb.2014.0379</nowiki></ref> The law in its modern form appeared with a modification to Gompertz’s law (generally attributed to William Makeham)<ref name=":1" /><ref name=":2">Stephanie. (2021, November 15). ''Gompertz-Makeham Distribution''. Statistics How To. <nowiki>https://www.statisticshowto.com/gompertz-makeham-distribution/</nowiki></ref> to account for age-independent factors affecting mortality rate (which Makeham himself had speculated might improve its accuracy).<ref name=":1" />

== Description ==
When solved for mortality rate, the law can be written as μ(x)=α''e''βx+γ, where "μ(x)" represents mortality rate at age x, "α" and "β" are arbitrary constants, and "γ" is a constant representing age-independent mortality.<ref name=":1" /> The term "α''e''βx" is known as the "Gompertz function" while "γ" is known as the "Makeham term" of the equation.<ref name=":0" /><ref name=":2" />

== Usage ==
The Gompertz-Makeham Law of Mortality is used even in modern times by insurance companies to model expected adult lifetimes, as it gives fairly accurate death rates for human populations between the ages of 30 and 80.<ref name=":0" /><ref name=":2" /> It should be noted, however, that at more advanced ages human death rates cease to increase as quickly as it predicts.<ref name=":0" /> It can also be used to predict death rates for species besides humans, though there are species to which it does not apply, and it does not necessarily describe mortality for child, infant, or extremely elderly individuals in those species for which it applies.<ref name=":1" /> In addition, several studies have found incidence curves of certain cancers to be nearly parallel to the Gompertz function, suggesting that they, and perhaps some other pathologies, depend on intrinsic aging processes. Researchers working with the University of Groningen have suggested using such similarities to distinguish between mainly intrinsically aging-associated and extrinsically caused mortality.<ref name=":3">Sas, A. A., Snieder, H., & Korf, J. (2012). Gompertz’ survivorship law as an intrinsic principle of aging. ''Medical Hypotheses'', ''78''(5), 659–663. <nowiki>https://doi.org/10.1016/j.mehy.2012.02.004</nowiki></ref>

== The Gompertz Law as an Intrinsic Principle of Aging ==
The neatness and simplicity of the Gompertz law (the original, simpler version of the Gompertz-Makeham Law of Mortality) has prompted some researchers to speculate that it is a fundamental law of nature, akin to some of the laws of physics.<ref name=":1" /> For example, when it is written as mt = Stkc''e''kt, where mt is the mortality rate, St is the proportion of survivors of the original population, and k and c are free parameters, researchers working with the University of Groningen have suggested that k and c may represent biological characteristics. They suggest that the parameter "k" might represent the accumulation of random damage or perturbations, while "c" might represent the vitality of an organism.<ref name=":3" />

== References ==
<references />
[[Category:Drafts]]
[[Category:Longevity]]

Gompertz-Makeham law of mortality

2022-08-15T00:53:36Z

Volunteer Longevity Writer 007: Added a few words to "Gompertz Law as an Intrinsic Principle of Aging" section.

[[File:Gompertz-Makeham Law of Mortality.jpg|thumb|143x143px|Gompertz-Makeham Law of Mortality, where ''μ(x)'' indicates mortality rate, ''α'' and ''β'' are constants, and ''γ'' represents factors unrelated to age which contribute to mortality.]]
The Gompertz-Makeham Law of Mortality is an equation which shows the increase in mortality rates for organisms as they age.<ref name=":0">''Gompertz-Makeham_law_of_mortality''. (n.d.). Retrieved August 7, 2022, from <nowiki>https://www.bionity.com/en/encyclopedia/Gompertz-Makeham_law_of_mortality.html</nowiki></ref><gallery>
</gallery>

== History ==
The law's predecessor, Gompertz's law (written as μ(x)=α''e''βx), was formulated by an actuary named Benjamin Gompertz, and published in an 1825 paper. He wished to help others in his profession calculate the most profitable rates at which to sell annuities to purchasers of various ages. He had observed that mortality rate appeared to increase exponentially over the adult human lifespan. As his model fit reasonably well with observed data, it was quickly adopted by actuaries and demographers for their own work.<ref name=":1">Kirkwood, T. B. L. (2015). Deciphering death: A commentary on Gompertz (1825) ‘On the nature of the function expressive of the law of human mortality, and on a new mode of determining the value of life contingencies.’ ''Philosophical Transactions of the Royal Society B: Biological Sciences, 370''(1666), 20140379. <nowiki>https://doi.org/10.1098/rstb.2014.0379</nowiki></ref> The law in its modern form appeared with a modification to Gompertz’s law (generally attributed to William Makeham)<ref name=":1" /><ref name=":2">Stephanie. (2021, November 15). ''Gompertz-Makeham Distribution''. Statistics How To. <nowiki>https://www.statisticshowto.com/gompertz-makeham-distribution/</nowiki></ref> to account for age-independent factors affecting mortality rate (which Makeham himself had speculated might improve its accuracy).<ref name=":1" />

== Description ==
When solved for mortality rate, the law can be written as μ(x)=α''e''βx+γ, where "μ(x)" represents mortality rate at age x, "α" and "β" are arbitrary constants, and "γ" is a constant representing age-independent mortality.<ref name=":1" /> The term "α''e''βx" is known as the "Gompertz function" while "γ" is known as the "Makeham term" of the equation.<ref name=":0" /><ref name=":2" />

== Usage ==
The Gompertz-Makeham Law of Mortality is used even in modern times by insurance companies to model expected adult lifetimes, as it gives fairly accurate death rates for human populations between the ages of 30 and 80.<ref name=":0" /><ref name=":2" /> It should be noted, however, that at more advanced ages human death rates cease to increase as quickly as it predicts.<ref name=":0" /> It can also be used to predict death rates for species besides humans, though there are species to which it does not apply, and it does not necessarily describe mortality for child, infant, or extremely elderly individuals in those species for which it applies.<ref name=":1" />

== The Gompertz Law as an Intrinsic Principle of Aging ==
The neatness and simplicity of the Gompertz Law (the original, simpler version of the Gompertz-Makeham Law of Mortality) has prompted some researchers to speculate that it is a fundamental law of nature, akin to some of the laws of physics.<ref name=":1" /> For example, when it is written as mt = Stkc''e''kt,

== References ==
<references />
[[Category:Drafts]]
[[Category:Longevity]]

Gompertz-Makeham law of mortality

2022-08-15T00:41:13Z

Volunteer Longevity Writer 007: Added to "Gompertz Law as an Intrinsic Principal of Aging" section.

[[File:Gompertz-Makeham Law of Mortality.jpg|thumb|143x143px|Gompertz-Makeham Law of Mortality, where ''μ(x)'' indicates mortality rate, ''α'' and ''β'' are constants, and ''γ'' represents factors unrelated to age which contribute to mortality.]]
The Gompertz-Makeham Law of Mortality is an equation which shows the increase in mortality rates for organisms as they age.<ref name=":0">''Gompertz-Makeham_law_of_mortality''. (n.d.). Retrieved August 7, 2022, from <nowiki>https://www.bionity.com/en/encyclopedia/Gompertz-Makeham_law_of_mortality.html</nowiki></ref><gallery>
</gallery>

== History ==
The law's predecessor, Gompertz's law (written as μ(x)=α''e''βx), was formulated by an actuary named Benjamin Gompertz, and published in an 1825 paper. He wished to help others in his profession calculate the most profitable rates at which to sell annuities to purchasers of various ages. He had observed that mortality rate appeared to increase exponentially over the adult human lifespan. As his model fit reasonably well with observed data, it was quickly adopted by actuaries and demographers for their own work.<ref name=":1">Kirkwood, T. B. L. (2015). Deciphering death: A commentary on Gompertz (1825) ‘On the nature of the function expressive of the law of human mortality, and on a new mode of determining the value of life contingencies.’ ''Philosophical Transactions of the Royal Society B: Biological Sciences, 370''(1666), 20140379. <nowiki>https://doi.org/10.1098/rstb.2014.0379</nowiki></ref> The law in its modern form appeared with a modification to Gompertz’s law (generally attributed to William Makeham)<ref name=":1" /><ref name=":2">Stephanie. (2021, November 15). ''Gompertz-Makeham Distribution''. Statistics How To. <nowiki>https://www.statisticshowto.com/gompertz-makeham-distribution/</nowiki></ref> to account for age-independent factors affecting mortality rate (which Makeham himself had speculated might improve its accuracy).<ref name=":1" />

== Description ==
When solved for mortality rate, the law can be written as μ(x)=α''e''βx+γ, where "μ(x)" represents mortality rate at age x, "α" and "β" are arbitrary constants, and "γ" is a constant representing age-independent mortality.<ref name=":1" /> The term "α''e''βx" is known as the "Gompertz function" while "γ" is known as the "Makeham term" of the equation.<ref name=":0" /><ref name=":2" />

== Usage ==
The Gompertz-Makeham Law of Mortality is used even in modern times by insurance companies to model expected adult lifetimes, as it gives fairly accurate death rates for human populations between the ages of 30 and 80.<ref name=":0" /><ref name=":2" /> It should be noted, however, that at more advanced ages human death rates cease to increase as quickly as it predicts.<ref name=":0" /> It can also be used to predict death rates for species besides humans, though there are species to which it does not apply, and it does not necessarily describe mortality for child, infant, or extremely elderly individuals in those species for which it applies.<ref name=":1" />

== The Gompertz Law as an Intrinsic Principle of Aging ==
The neatness and simplicity of the Gompertz Law (the original, simpler version of the Gompertz-Makeham Law of Mortality) has prompted some researchers to speculate that it is a fundamental law of nature, akin to some of the laws of physics.<ref name=":1" />

== References ==
<references />
[[Category:Drafts]]
[[Category:Longevity]]

Gompertz-Makeham law of mortality

2022-08-11T22:54:12Z

Volunteer Longevity Writer 007: Began new section of article.

Gompertz-Makeham law of mortality

2022-08-08T20:43:51Z

Volunteer Longevity Writer 007: Finished "History" section, added "Description" and "Usage" sections, and added one reference.

Gompertz-Makeham law of mortality

2022-08-08T01:02:32Z

Volunteer Longevity Writer 007: Added "History" section and citations list.

Gompertz-Makeham law of mortality

2022-08-07T21:04:02Z

Volunteer Longevity Writer 007: Created page and added summary.

The Gompertz-Makeham Law of Mortality is an equation which expresses mortality as a function of an organism's age.<gallery>
</gallery>
[[Category:Drafts]]

File:Gompertz-Makeham Law of Mortality.jpg

2022-08-07T20:36:03Z

Volunteer Longevity Writer 007:

One formulation of the Gompertz-Makeham Law of Mortality. Image credit: Thomas B. L. Kirkwood. (April 19, 2015). [Formulation of the Gompertz-Makeham Law of Mortality]. Retrieved August 8, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360127/#!po=6.36364

Mitochondrial dysfunction

2021-12-23T21:27:06Z

Volunteer Longevity Writer 007: Added images to osteoporosis and free radical theory of aging sections, and moved diagram of mitochondrion.

<gallery widths="1000">
</gallery>Mitochondrial dysfunction is a state of inefficient energy production resulting from damage to energy-producing structures called mitochondria.<ref name=":17">Cui, H., Kong, Y., & Zhang, H. (2012). Oxidative stress, mitochondrial dysfunction, and aging. ''Journal of signal transduction'', ''2012''.</ref>

== Introduction ==
Mitochondria are responsible for creating adenosine triphosphate (ATP), a chemical which provides the energy for many processes within a cell.<ref name=":1">''A link between mitochondrial damage and osteoporosis.'' (2019, May 9). ScienceDaily. <nowiki>https://www.sciencedaily.com/releases/2019/05/190509153425.htm</nowiki></ref> This process also creates byproducts, such as reactive oxygen species (ROS).<ref name=":17" /> Over time, the accumulation of ROS damages cells and mitochondria, contributing to the decline in health associated with old age, according to the free radical theory of aging.<ref name=":17" /><ref name=":1" />

Mitochondrial dysfunction is considered one of the hallmarks of aging due to multiple lines of evidence linking it to aging and its associated diseases, such as osteoporosis and Parkinson's disease.<ref name=":2">Age-related mitochondrial dysfunction as a key factor in COVID-19 disease. (2020). ''Experimental Gerontology, 142'', 111147. <nowiki>https://doi.org/10.1016/j.exger.2020.111147</nowiki></ref><ref name=":3">Chen, C., Turnbull, D. M., & Reeve, A. K. (2019). Mitochondrial dysfunction in Parkinson’s disease—Cause or consequence? ''Biology, 8''(2). <nowiki>https://doi.org/10.3390/biology8020038</nowiki></ref><ref name=":4">López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. ''Cell, 153''(6), 1194–1217. <nowiki>https://doi.org/10.1016/j.cell.2013.05.039</nowiki></ref> It should be noted that the free radical theory of aging is not supported by more recent research. Some evidence in multiple animal models suggests that mild mitochondrial dysfunction actually lengthens lifespan, with resultant damage from ROS leading to increased long-term stress resistance.<ref name=":18">Ristow, M., & Zarse, K. (2010). How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis). ''Experimental gerontology'', ''45''(6), 410-418.
</ref>

== Basics of mitochondria ==
<gallery widths="1000">
File:A basic diagram of a mitochondrion.jpg|Diagram of a mitochondrion. [Diagram of mitochondrion]. (n.d.). https://www.medicalnewstoday.com/articles/320875
</gallery>Mitochondria are structures found in almost all eukaryotic cells (cells with clearly defined nuclei).<ref name=":5">''Mitochondrion | definition, function, structure, & facts.'' (n.d.). Encyclopedia Britannica. Retrieved May 11, 2021, from <nowiki>https://www.britannica.com/science/mitochondrion</nowiki></ref> Scientists believe that they began as independent organisms which were engulfed by host cells with which they formed a symbiotic relationship, eventually becoming part of the host cells.<ref name=":6">''Osteoporosis overview | NIH Osteoporosis and Related Bone Diseases National Resource Center.'' (n.d.). Retrieved May 27, 2021, from <nowiki>https://www.bones.nih.gov/health-info/bone/osteoporosis/overview</nowiki></ref> They possess their own DNA, separate from that of the organisms they inhabit, called mitochondrial DNA (mtDNA).<ref name=":7">Wang, W., Zhao, F., Ma, X., Perry, G., & Zhu, X. (2020). Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: Recent advances. ''Molecular Neurodegeneration, 15''(1), 30. <nowiki>https://doi.org/10.1186/s13024-020-00376-6</nowiki></ref><ref name=":1" /><ref name=":6" /> A mitochondrion (the singular of mitochondria) possesses two membranes; one enveloping the other.<ref name=":8">Buneeva, O., Fedchenko, V., Kopylov, A., & Medvedev, A. (2020). Mitochondrial dysfunction in Parkinson’s disease: Focus on mitochondrial DNA. ''Biomedicines, 8''(12), 591. <nowiki>https://doi.org/10.3390/biomedicines8120591</nowiki></ref> Within the matrix (the region within the inner membrane), a series of reactions known as the Krebs cycle produces a chemical called NADH.<ref name=":6" /> A structure called complex 1, on the inner membrane, then uses the NADH in a process which pumps protons from the region within the inner membrane to the area between the membranes. Structures known as complex 3 and complex 4 (the latter of which requires oxygen to fill its role) are necessary components, also located on the inner membrane.<ref name=":8" /> The result is the formation of a membrane potential used by another structure, complex 5, to generate ATP, which provides energy for cells.<ref name=":8" /><ref name=":5" /> This process by which mitochondria create ATP is known as oxidative phosphorylation.<ref name=":6" />

== Free radical theory of aging ==
<gallery widths="1000" heights="220">
File:Free radicals oxidative stress image.jpg|Free radicals damaging a cell. [Diagram of the effect of free radicals on a cell]. (n.d.). https://nouvelleresearch.com/index.php/articles/368-horse-dog-health-impact-free-radicals-oxidative-stress
</gallery>Reactive oxygen species, also known as free radicals, are unstable molecules containing oxygen, which easily react with other molecules in a cell.<ref>[NciAppModulePage]. (2011, February 2). <nowiki>https://www.cancer.gov/publications/dictionaries/cancer-terms/def/reactive-oxygen-species</nowiki></ref> The process of respiration via oxidative phosphorylation produces ROS as a byproduct. The mitochondrial free radical theory of aging proposes that over time, increasing ROS production triggers mitochondrial dysfunction, which causes further increases in ROS production and cellular deterioration.<ref name=":17" /><ref name=":9">Bárcena, C., Mayoral, P., & Quirós, P. M. (2018). Mitohormesis, an antiaging paradigm. In ''International Review of Cell and Molecular Biology'' (Vol. 340, pp. 35–77). Elsevier. <nowiki>https://doi.org/10.1016/bs.ircmb.2018.05.002</nowiki></ref> Specifically, free radicals trigger mitochondrial dysfunction by damaging the DNA of the mitochondria by causing its atoms to lose electrons, although some studies suggest that this damage is done indirectly.<ref name=":9" /><ref name=":1" /> This does not usually harm the cell, as quality-control mechanisms destroy the damaged mitochondria, but those mechanisms become less effective as people age.<ref name=":1" /> Over time, this damage to the mitochondria leaves cells less efficient at producing energy. In addition to harming the mitochondria, ROS contribute to the health declines of old age by causing muscle weakness, bone frailty, immune suppression, and even cancer, among other conditions.<ref name=":1" />

The free radical theory of aging is no longer widely accepted among biogerontology researchers for various reasons. Importantly, preclinical and clinical research has shown that reducing ROS with antioxidants not only fails to increase healthy lifespan, but may also cause harm. For example, the Beta-Carotene and Retinol Efficacy Trial investigated two supplements in thousands of older adults previously exposed to asbestos, finding increased lung cancer in smokers relative to placebo.<ref name=":19">Omenn, G. S., Goodman, G. E., Thornquist, M. D., Balmes, J., Cullen, M. R., Glass, A., ... & Hammar, S. (1996). Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. ''New England journal of medicine'', ''334''(18), 1150-1155.</ref> Beta carotene was an antioxidant, and retinol is also known as vitamin A. The study not only found lack of benefit for multiple endpoints, including risk of cancer, heart disease, and mortality, but also found increased risk of death in the treatment group.<ref name=":19" />

Additionally, there is evidence that mild mitochondrial dysfunction may increase lifespan. Relatively low level damage from ROS has been shown to increase long-term stress resistance.<ref name=":18" /> This has been linked to hormesis, a well-known process in biology where low levels of stress can lead to compensatory responses that result in benefit.<ref name=":18" />

== Mitohormesis ==
Mitohormesis is a response of mitochondria to stressors or toxins which so thoroughly repairs their damage that the cell is healthier after the damage than before.<ref name=":17" /><ref name=":9" /><ref name=":10">Bell, S. M., Barnes, K., De Marco, M., Shaw, P. J., Ferraiuolo, L., Blackburn, D. J., Venneri, A., & Mortiboys, H. (2021). Mitochondrial dysfunction in alzheimer’s disease: A biomarker of the future? ''Biomedicines, 9''(1). <nowiki>https://doi.org/10.3390/biomedicines9010063</nowiki></ref> It is a form of hormesis, which is described above.<ref>Zhu, X., Wei, Y., Yang, B., Yin, X., & Guo, X. (2020). The mitohormetic response as part of the cytoprotection mechanism of berberine. ''Molecular Medicine, 26''(1), 10. <nowiki>https://doi.org/10.1186/s10020-020-0136-8</nowiki></ref> In fact, such damage may trigger a mitochondrial defensive response not only in the tissues containing the defective mitochondria, but also distant tissues. Evidence exists which shows that mitohormesis may be able to extend lifespan in mammals, but there is no consensus on this view.<ref name=":4" /> For mitohormesis to occur, mitochondria must communicate with the cell's nucleus.<ref name=":10" /> They appear to use ROS, among other things, as signals for this communication.<ref name=":9" /><ref name=":10" /> This productive role for ROS may explain why increased ROS sometimes appears to slow aging, rather than aggravate it. Some scientists have suggested that a certain amount of ROS is beneficial, but any greater amounts are harmful.<ref name=":9" />

== Inflammation ==
Mitochondrial dysfunction can contribute to a chronic background level of inflammation some call "inflammaging".<ref name=":1" /> As the name suggests, this problem occurs with aging. Inflammaging has been associated with increased morbidity and mortality, but some researchers have found high levels of pro-inflammatory markers in people over 100 years old. This casts some doubt on whether inflammaging truly harms the elderly.<ref name=":7" /> Mitochondrial dysfunction contributes to inflammaging by increasing the cell's ROS levels.<ref name=":1" /> Increased ROS modulate the expression and activity of a substance called NF-κB, which leads to inflammation.<ref name=":7" /> Mitochondrial dysfunction may also contribute to inflammaging through mtDNA; that is, it may cause mitochondria to release mtDNA, which causes an inflammatory response when the immune system mistakes the mtDNA for pathogens.<ref name=":11">Dobson, P. F., Dennis, E. P., Hipps, D., Reeve, A., Laude, A., Bradshaw, C., Stamp, C., Smith, A., Deehan, D. J., Turnbull, D. M., & Greaves, L. C. (2020). Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss. ''Scientific Reports, 10.'' <nowiki>https://doi.org/10.1038/s41598-020-68566-2</nowiki></ref><ref name=":7" /> Scientists believe this occurs due to mitochondria's bacterial origins.<ref name=":7" />

== Mitochondrial dysfunction in disease ==
Mitochondrial dysfunction contributes to a number of aging-related ailments.

=== Alzheimer's disease ===
Alzheimer’s disease (AD) occurs almost exclusively in older adults, resulting in deterioration of cognition and memory due to progressive and selective loss of neurons in the forebrain and other brain areas.<ref name=":12">Sterling, J. (2019, October 18). Metabolic mitochondria dysfunction may be primary cause of alzheimer’s. ''GEN - Genetic Engineering and Biotechnology News.'' <nowiki>https://www.genengnews.com/news/metabolic-mitochondria-dysfunction-may-be-primary-cause-of-alzheimers/</nowiki></ref><ref name=":7" /> Historically, there have been two mainstream hypotheses within the research community on its cause. The first is that it results primarily from the accumulation of amyloid-beta proteins in the brain; the second is the accumulation of neurofibrillary tangles called tau.<ref>Ittner, L. M., & Götz, J. (2011). Amyloid-β and tau—a toxic pas de deux in Alzheimer's disease. ''Nature Reviews Neuroscience'', ''12''(2), 67-72.</ref>

Mitochondrial dysfunction is a posited contributor to AD, leading to destruction of neurons and causing AD.<ref>Wang, X., Wang, W., Li, L., Perry, G., Lee, H. G., & Zhu, X. (2014). Oxidative stress and mitochondrial dysfunction in Alzheimer's disease. ''Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease'', ''1842''(8), 1240-1247.

</ref> Researchers have found impaired energy metabolism in AD patients, as well as mitochondrial abnormalities in their brains, which gives support to this hypothesis.<ref name=":7" /> A clear role for mitochondrial dysfunction in AD has not been determined. Clinical trials targeting mechanisms related to mitochondrial dysfunction in this disease will be required to provide evidence of a causative role in AD.

=== Parkinson's disease ===
Parkinson’s disease (PD) is a movement disorder resulting from degenerative loss of certain brain cells involved with the chemical dopamine, in the brain region called the substantia nigra.<ref name=":3" /><ref name=":11" /> Its main symptoms are: tremor in the hands, arms, legs, trunk, and/or head; stiffness of the limbs and trunk; slow movement; and impaired balance and coordination. Other symptoms may include depression and other emotional changes; difficulty walking, swallowing, chewing, or speaking; urinary problems and constipation; skin problems; and sleep disruption. Symptoms usually begin gradually and get worse over time, and PD is by far most common in the elderly.<ref name=":12" /> Evidence suggests that PD is at least partly caused by mitochondrial dysfunction, though it is not conclusive.<ref name=":0">''The hallmarks of aging, in plain English | Geroscience.'' (n.d.). Retrieved May 2, 2021, from <nowiki>http://geroscience.com/hallmarks-aging/</nowiki></ref> Scientists speculate that mitochondrial dysfunction harms ATP production and a process called "calcium buffering" (another function of mitochondria), as well as exacerbating oxidative stress (an imbalance between oxidants and antioxidants).<ref name=":13">Dingman, M. (2014, November 15). ''Know your brain: Substantia nigra.'' Neuroscientifically Challenged. <nowiki>https://www.neuroscientificallychallenged.com/blog/know-your-brain-substantia-nigra</nowiki></ref><ref>Picca, A., Lezza, A. M. S., Leeuwenburgh, C., Pesce, V., Calvani, R., Landi, F., Bernabei, R., & Marzetti, E. (2017). Fueling inflamm-aging through mitochondrial dysfunction: Mechanisms and molecular targets. ''International Journal of Molecular Sciences, 18''(5), 933. <nowiki>https://doi.org/10.3390/ijms18050933</nowiki></ref> These processes are theorized to cause PD by killing brain cells in the substantia nigra. Recent evidence also suggests that certain processes controlling the distribution and structure of mitochondria are linked with PD.<ref name=":13" />

=== Osteoporosis ===
[[File:Osteoporosis Diagram.jpg|thumb|340x340px|[Diagram showing some conditions associated with osteoporosis]. (n.d.). https://www.endocrineweb.com/conditions/osteoporosis/osteoporosis-overview]]
Osteoporosis is a bone disease that develops following bone mass and mineral density decrease, or when the quality or structure of bone changes. This can reduce its strength, which can increase the risk of breaking. The risk of osteoporosis dramatically increases with increasing age.<ref>''Parkinson’s Disease.'' (n.d.). National Institute on Aging. Retrieved May 27, 2021, from <nowiki>http://www.nia.nih.gov/health/parkinsons-disease</nowiki></ref>

Some evidence suggests that mitochondrial dysfunction in osteoblasts (cells which produce bone) and osteoclasts (cells which break down bone) contributes to osteoporosis, by mutating the body's mtDNA.<ref name=":2" /><ref name=":14">''Hallmarks of aging: Mitochondrial dysfunction'' ''| Lifespan. Io.'' (n.d.). Retrieved May 2, 2021, from <nowiki>https://www.lifespan.io/news/hallmarks-of-aging-mitochondrial-dysfunction/</nowiki></ref> One study found that mice experiencing an accelerated accumulation of mtDNA mutations lost bone at a faster rate than normal mice. The investigators also showed a reduced bone formation rate, reduced osteoblast population densities, and increased osteoclast population densities, among other differences. Researchers involved in the study argued that similar processes could contribute to human osteoporosis.<ref name=":14" />

=== COVID-19 ===
Note: Information below describes the relationship between COVID-19 and mitochondrial dysfunction. For details on the relationship between COVID-19 and the aging process in general, see [[COVID-19]].

COVID-19 is an infectious disease caused by a virus known as SARS-CoV-2. COVID-19 disproportionately affects the elderly, resulting in severe symptoms and substantially increased mortality risk. Yet, youth infected with SARS-CoV-2 tend to have mild symptoms or are asymptomatic. Mitochondrial dysfunction is associated with some risk factors for COVID-19, and there is some evidence that it contributes to COVID-19 severity.<ref>Shenoy, S. (2020). Coronavirus (Covid-19) sepsis: revisiting mitochondrial dysfunction in pathogenesis, aging, inflammation, and mortality. ''Inflammation Research'', 1-9.</ref><ref name=":15">Ayala, D. J. M. F., Navas, P., & López-Lluch, G. (2020). Age-related mitochondrial dysfunction as a key factor in COVID-19 disease. ''Experimental gerontology'', 111147.</ref><ref name=":16">Gibellini, L., De Biasi, S., Paolini, A., Borella, R., Boraldi, F., Mattioli, M., ... & Cossarizza, A. (2020). Altered bioenergetics and mitochondrial dysfunction of monocytes in patients with COVID‐19 pneumonia. ''EMBO molecular medicine'', ''12''(12), e13001.</ref>

Some researchers have suggested that the downstream effects of mitochondrial dysfunction is partly responsible for the severe pneumonia, multi-organ failure, and death which accompanies COVID-19.<ref name=":15" /> However, as SARS-CoV-2 was discovered relatively recently, there is generally a lack of direct evidence linking mitochondrial dysfunction to COVID-19.

In patients suffering from COVID-19 induced pneumonia, it has been shown that mitochondrial function is dysregulated in monocytes.<ref name=":16" /> Monocytes are cells that are part of the innate immune system, and may contribute to an exaggerated immune response that drives poor outcomes following infection.<ref name=":16" />

== Citations ==
<references />
[[Category:Longevity]]

File:Osteoporosis Diagram.jpg

2021-12-23T21:21:05Z

Volunteer Longevity Writer 007:

Diagram showing some conditions associated with osteoporosis.

Mitochondrial dysfunction

2021-12-23T21:04:07Z

Volunteer Longevity Writer 007: Added image of mitochondrion.

<gallery widths="1000">
File:A basic diagram of a mitochondrion.jpg|Diagram of a mitochondrion. [Diagram of mitochondrion]. (n.d.). https://www.medicalnewstoday.com/articles/320875
</gallery>Mitochondrial dysfunction is a state of inefficient energy production resulting from damage to energy-producing structures called mitochondria.<ref name=":17">Cui, H., Kong, Y., & Zhang, H. (2012). Oxidative stress, mitochondrial dysfunction, and aging. ''Journal of signal transduction'', ''2012''.</ref>

== Introduction ==
Mitochondria are responsible for creating adenosine triphosphate (ATP), a chemical which provides the energy for many processes within a cell.<ref name=":1">''A link between mitochondrial damage and osteoporosis.'' (2019, May 9). ScienceDaily. <nowiki>https://www.sciencedaily.com/releases/2019/05/190509153425.htm</nowiki></ref> This process also creates byproducts, such as reactive oxygen species (ROS).<ref name=":17" /> Over time, the accumulation of ROS damages cells and mitochondria, contributing to the decline in health associated with old age, according to the free radical theory of aging.<ref name=":17" /><ref name=":1" />

Mitochondrial dysfunction is considered one of the hallmarks of aging due to multiple lines of evidence linking it to aging and its associated diseases, such as osteoporosis and Parkinson's disease.<ref name=":2">Age-related mitochondrial dysfunction as a key factor in COVID-19 disease. (2020). ''Experimental Gerontology, 142'', 111147. <nowiki>https://doi.org/10.1016/j.exger.2020.111147</nowiki></ref><ref name=":3">Chen, C., Turnbull, D. M., & Reeve, A. K. (2019). Mitochondrial dysfunction in Parkinson’s disease—Cause or consequence? ''Biology, 8''(2). <nowiki>https://doi.org/10.3390/biology8020038</nowiki></ref><ref name=":4">López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. ''Cell, 153''(6), 1194–1217. <nowiki>https://doi.org/10.1016/j.cell.2013.05.039</nowiki></ref> It should be noted that the free radical theory of aging is not supported by more recent research. Some evidence in multiple animal models suggests that mild mitochondrial dysfunction actually lengthens lifespan, with resultant damage from ROS leading to increased long-term stress resistance.<ref name=":18">Ristow, M., & Zarse, K. (2010). How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis). ''Experimental gerontology'', ''45''(6), 410-418.
</ref>

== Basics of mitochondria ==
Mitochondria are structures found in almost all eukaryotic cells (cells with clearly defined nuclei).<ref name=":5">''Mitochondrion | definition, function, structure, & facts.'' (n.d.). Encyclopedia Britannica. Retrieved May 11, 2021, from <nowiki>https://www.britannica.com/science/mitochondrion</nowiki></ref> Scientists believe that they began as independent organisms which were engulfed by host cells with which they formed a symbiotic relationship, eventually becoming part of the host cells.<ref name=":6">''Osteoporosis overview | NIH Osteoporosis and Related Bone Diseases National Resource Center.'' (n.d.). Retrieved May 27, 2021, from <nowiki>https://www.bones.nih.gov/health-info/bone/osteoporosis/overview</nowiki></ref> They possess their own DNA, separate from that of the organisms they inhabit, called mitochondrial DNA (mtDNA).<ref name=":7">Wang, W., Zhao, F., Ma, X., Perry, G., & Zhu, X. (2020). Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: Recent advances. ''Molecular Neurodegeneration, 15''(1), 30. <nowiki>https://doi.org/10.1186/s13024-020-00376-6</nowiki></ref><ref name=":1" /><ref name=":6" /> A mitochondrion (the singular of mitochondria) possesses two membranes; one enveloping the other.<ref name=":8">Buneeva, O., Fedchenko, V., Kopylov, A., & Medvedev, A. (2020). Mitochondrial dysfunction in Parkinson’s disease: Focus on mitochondrial DNA. ''Biomedicines, 8''(12), 591. <nowiki>https://doi.org/10.3390/biomedicines8120591</nowiki></ref> Within the matrix (the region within the inner membrane), a series of reactions known as the Krebs cycle produces a chemical called NADH.<ref name=":6" /> A structure called complex 1, on the inner membrane, then uses the NADH in a process which pumps protons from the region within the inner membrane to the area between the membranes. Structures known as complex 3 and complex 4 (the latter of which requires oxygen to fill its role) are necessary components, also located on the inner membrane.<ref name=":8" /> The result is the formation of a membrane potential used by another structure, complex 5, to generate ATP, which provides energy for cells.<ref name=":8" /><ref name=":5" /> This process by which mitochondria create ATP is known as oxidative phosphorylation.<ref name=":6" />

== Free radical theory of aging ==
Reactive oxygen species, also known as free radicals, are unstable molecules containing oxygen, which easily react with other molecules in a cell.<ref>[NciAppModulePage]. (2011, February 2). <nowiki>https://www.cancer.gov/publications/dictionaries/cancer-terms/def/reactive-oxygen-species</nowiki></ref> The process of respiration via oxidative phosphorylation produces ROS as a byproduct. The mitochondrial free radical theory of aging proposes that over time, increasing ROS production triggers mitochondrial dysfunction, which causes further increases in ROS production and cellular deterioration.<ref name=":17" /><ref name=":9">Bárcena, C., Mayoral, P., & Quirós, P. M. (2018). Mitohormesis, an antiaging paradigm. In ''International Review of Cell and Molecular Biology'' (Vol. 340, pp. 35–77). Elsevier. <nowiki>https://doi.org/10.1016/bs.ircmb.2018.05.002</nowiki></ref> Specifically, free radicals trigger mitochondrial dysfunction by damaging the DNA of the mitochondria by causing its atoms to lose electrons, although some studies suggest that this damage is done indirectly.<ref name=":9" /><ref name=":1" /> This does not usually harm the cell, as quality-control mechanisms destroy the damaged mitochondria, but those mechanisms become less effective as people age.<ref name=":1" /> Over time, this damage to the mitochondria leaves cells less efficient at producing energy. In addition to harming the mitochondria, ROS contribute to the health declines of old age by causing muscle weakness, bone frailty, immune suppression, and even cancer, among other conditions.<ref name=":1" />

The free radical theory of aging is no longer widely accepted among biogerontology researchers for various reasons. Importantly, preclinical and clinical research has shown that reducing ROS with antioxidants not only fails to increase healthy lifespan, but may also cause harm. For example, the Beta-Carotene and Retinol Efficacy Trial investigated two supplements in thousands of older adults previously exposed to asbestos, finding increased lung cancer in smokers relative to placebo.<ref name=":19">Omenn, G. S., Goodman, G. E., Thornquist, M. D., Balmes, J., Cullen, M. R., Glass, A., ... & Hammar, S. (1996). Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. ''New England journal of medicine'', ''334''(18), 1150-1155.</ref> Beta carotene was an antioxidant, and retinol is also known as vitamin A. The study not only found lack of benefit for multiple endpoints, including risk of cancer, heart disease, and mortality, but also found increased risk of death in the treatment group.<ref name=":19" />

Additionally, there is evidence that mild mitochondrial dysfunction may increase lifespan. Relatively low level damage from ROS has been shown to increase long-term stress resistance.<ref name=":18" /> This has been linked to hormesis, a well-known process in biology where low levels of stress can lead to compensatory responses that result in benefit.<ref name=":18" />

== Mitohormesis ==
Mitohormesis is a response of mitochondria to stressors or toxins which so thoroughly repairs their damage that the cell is healthier after the damage than before.<ref name=":17" /><ref name=":9" /><ref name=":10">Bell, S. M., Barnes, K., De Marco, M., Shaw, P. J., Ferraiuolo, L., Blackburn, D. J., Venneri, A., & Mortiboys, H. (2021). Mitochondrial dysfunction in alzheimer’s disease: A biomarker of the future? ''Biomedicines, 9''(1). <nowiki>https://doi.org/10.3390/biomedicines9010063</nowiki></ref> It is a form of hormesis, which is described above.<ref>Zhu, X., Wei, Y., Yang, B., Yin, X., & Guo, X. (2020). The mitohormetic response as part of the cytoprotection mechanism of berberine. ''Molecular Medicine, 26''(1), 10. <nowiki>https://doi.org/10.1186/s10020-020-0136-8</nowiki></ref> In fact, such damage may trigger a mitochondrial defensive response not only in the tissues containing the defective mitochondria, but also distant tissues. Evidence exists which shows that mitohormesis may be able to extend lifespan in mammals, but there is no consensus on this view.<ref name=":4" /> For mitohormesis to occur, mitochondria must communicate with the cell's nucleus.<ref name=":10" /> They appear to use ROS, among other things, as signals for this communication.<ref name=":9" /><ref name=":10" /> This productive role for ROS may explain why increased ROS sometimes appears to slow aging, rather than aggravate it. Some scientists have suggested that a certain amount of ROS is beneficial, but any greater amounts are harmful.<ref name=":9" />

== Inflammation ==
Mitochondrial dysfunction can contribute to a chronic background level of inflammation some call "inflammaging".<ref name=":1" /> As the name suggests, this problem occurs with aging. Inflammaging has been associated with increased morbidity and mortality, but some researchers have found high levels of pro-inflammatory markers in people over 100 years old. This casts some doubt on whether inflammaging truly harms the elderly.<ref name=":7" /> Mitochondrial dysfunction contributes to inflammaging by increasing the cell's ROS levels.<ref name=":1" /> Increased ROS modulate the expression and activity of a substance called NF-κB, which leads to inflammation.<ref name=":7" /> Mitochondrial dysfunction may also contribute to inflammaging through mtDNA; that is, it may cause mitochondria to release mtDNA, which causes an inflammatory response when the immune system mistakes the mtDNA for pathogens.<ref name=":11">Dobson, P. F., Dennis, E. P., Hipps, D., Reeve, A., Laude, A., Bradshaw, C., Stamp, C., Smith, A., Deehan, D. J., Turnbull, D. M., & Greaves, L. C. (2020). Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss. ''Scientific Reports, 10.'' <nowiki>https://doi.org/10.1038/s41598-020-68566-2</nowiki></ref><ref name=":7" /> Scientists believe this occurs due to mitochondria's bacterial origins.<ref name=":7" />

== Mitochondrial dysfunction in disease ==
Mitochondrial dysfunction contributes to a number of aging-related ailments.

=== Alzheimer's disease ===
Alzheimer’s disease (AD) occurs almost exclusively in older adults, resulting in deterioration of cognition and memory due to progressive and selective loss of neurons in the forebrain and other brain areas.<ref name=":12">Sterling, J. (2019, October 18). Metabolic mitochondria dysfunction may be primary cause of alzheimer’s. ''GEN - Genetic Engineering and Biotechnology News.'' <nowiki>https://www.genengnews.com/news/metabolic-mitochondria-dysfunction-may-be-primary-cause-of-alzheimers/</nowiki></ref><ref name=":7" /> Historically, there have been two mainstream hypotheses within the research community on its cause. The first is that it results primarily from the accumulation of amyloid-beta proteins in the brain; the second is the accumulation of neurofibrillary tangles called tau.<ref>Ittner, L. M., & Götz, J. (2011). Amyloid-β and tau—a toxic pas de deux in Alzheimer's disease. ''Nature Reviews Neuroscience'', ''12''(2), 67-72.</ref>

Mitochondrial dysfunction is a posited contributor to AD, leading to destruction of neurons and causing AD.<ref>Wang, X., Wang, W., Li, L., Perry, G., Lee, H. G., & Zhu, X. (2014). Oxidative stress and mitochondrial dysfunction in Alzheimer's disease. ''Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease'', ''1842''(8), 1240-1247.

</ref> Researchers have found impaired energy metabolism in AD patients, as well as mitochondrial abnormalities in their brains, which gives support to this hypothesis.<ref name=":7" /> A clear role for mitochondrial dysfunction in AD has not been determined. Clinical trials targeting mechanisms related to mitochondrial dysfunction in this disease will be required to provide evidence of a causative role in AD.

=== Parkinson's disease ===
Parkinson’s disease (PD) is a movement disorder resulting from degenerative loss of certain brain cells involved with the chemical dopamine, in the brain region called the substantia nigra.<ref name=":3" /><ref name=":11" /> Its main symptoms are: tremor in the hands, arms, legs, trunk, and/or head; stiffness of the limbs and trunk; slow movement; and impaired balance and coordination. Other symptoms may include depression and other emotional changes; difficulty walking, swallowing, chewing, or speaking; urinary problems and constipation; skin problems; and sleep disruption. Symptoms usually begin gradually and get worse over time, and PD is by far most common in the elderly.<ref name=":12" /> Evidence suggests that PD is at least partly caused by mitochondrial dysfunction, though it is not conclusive.<ref name=":0">''The hallmarks of aging, in plain English | Geroscience.'' (n.d.). Retrieved May 2, 2021, from <nowiki>http://geroscience.com/hallmarks-aging/</nowiki></ref> Scientists speculate that mitochondrial dysfunction harms ATP production and a process called "calcium buffering" (another function of mitochondria), as well as exacerbating oxidative stress (an imbalance between oxidants and antioxidants).<ref name=":13">Dingman, M. (2014, November 15). ''Know your brain: Substantia nigra.'' Neuroscientifically Challenged. <nowiki>https://www.neuroscientificallychallenged.com/blog/know-your-brain-substantia-nigra</nowiki></ref><ref>Picca, A., Lezza, A. M. S., Leeuwenburgh, C., Pesce, V., Calvani, R., Landi, F., Bernabei, R., & Marzetti, E. (2017). Fueling inflamm-aging through mitochondrial dysfunction: Mechanisms and molecular targets. ''International Journal of Molecular Sciences, 18''(5), 933. <nowiki>https://doi.org/10.3390/ijms18050933</nowiki></ref> These processes are theorized to cause PD by killing brain cells in the substantia nigra. Recent evidence also suggests that certain processes controlling the distribution and structure of mitochondria are linked with PD.<ref name=":13" />

=== Osteoporosis ===
Osteoporosis is a bone disease that develops following bone mass and mineral density decrease, or when the quality or structure of bone changes. This can reduce its strength, which can increase the risk of breaking. The risk of osteoporosis dramatically increases with increasing age.<ref>''Parkinson’s Disease.'' (n.d.). National Institute on Aging. Retrieved May 27, 2021, from <nowiki>http://www.nia.nih.gov/health/parkinsons-disease</nowiki></ref>

Some evidence suggests that mitochondrial dysfunction in osteoblasts (cells which produce bone) and osteoclasts (cells which break down bone) contributes to osteoporosis, by mutating the body's mtDNA.<ref name=":2" /><ref name=":14">''Hallmarks of aging: Mitochondrial dysfunction'' ''| Lifespan. Io.'' (n.d.). Retrieved May 2, 2021, from <nowiki>https://www.lifespan.io/news/hallmarks-of-aging-mitochondrial-dysfunction/</nowiki></ref> One study found that mice experiencing an accelerated accumulation of mtDNA mutations lost bone at a faster rate than normal mice. The investigators also showed a reduced bone formation rate, reduced osteoblast population densities, and increased osteoclast population densities, among other differences. Researchers involved in the study argued that similar processes could contribute to human osteoporosis.<ref name=":14" />

=== COVID-19 ===
Note: Information below describes the relationship between COVID-19 and mitochondrial dysfunction. For details on the relationship between COVID-19 and the aging process in general, see [[COVID-19]].

COVID-19 is an infectious disease caused by a virus known as SARS-CoV-2. COVID-19 disproportionately affects the elderly, resulting in severe symptoms and substantially increased mortality risk. Yet, youth infected with SARS-CoV-2 tend to have mild symptoms or are asymptomatic. Mitochondrial dysfunction is associated with some risk factors for COVID-19, and there is some evidence that it contributes to COVID-19 severity.<ref>Shenoy, S. (2020). Coronavirus (Covid-19) sepsis: revisiting mitochondrial dysfunction in pathogenesis, aging, inflammation, and mortality. ''Inflammation Research'', 1-9.</ref><ref name=":15">Ayala, D. J. M. F., Navas, P., & López-Lluch, G. (2020). Age-related mitochondrial dysfunction as a key factor in COVID-19 disease. ''Experimental gerontology'', 111147.</ref><ref name=":16">Gibellini, L., De Biasi, S., Paolini, A., Borella, R., Boraldi, F., Mattioli, M., ... & Cossarizza, A. (2020). Altered bioenergetics and mitochondrial dysfunction of monocytes in patients with COVID‐19 pneumonia. ''EMBO molecular medicine'', ''12''(12), e13001.</ref>

Some researchers have suggested that the downstream effects of mitochondrial dysfunction is partly responsible for the severe pneumonia, multi-organ failure, and death which accompanies COVID-19.<ref name=":15" /> However, as SARS-CoV-2 was discovered relatively recently, there is generally a lack of direct evidence linking mitochondrial dysfunction to COVID-19.

In patients suffering from COVID-19 induced pneumonia, it has been shown that mitochondrial function is dysregulated in monocytes.<ref name=":16" /> Monocytes are cells that are part of the innate immune system, and may contribute to an exaggerated immune response that drives poor outcomes following infection.<ref name=":16" />

== Citations ==
<references />
[[Category:Longevity]]

File:Free radicals oxidative stress image.jpg

2021-12-22T22:19:33Z

Volunteer Longevity Writer 007:

Diagram of the effect of free radicals on cells.

[Diagram of free radicals' effect on cells]. (n.d.). https://www.lifespan.io/topic/mitochondrial-dysfunction/

File:A basic diagram of a mitochondrion.jpg

2021-12-22T21:41:13Z

Volunteer Longevity Writer 007:

A basic diagram of a mitochondrion.

Mitochondrial dysfunction

2021-10-07T16:56:06Z

Volunteer Longevity Writer 007: Gave citations section its own heading.

Mitochondrial dysfunction is a state of inefficient energy production in cells resulting from damage to structures called mitochondria.<ref name=":0">''The hallmarks of aging, in plain English | Geroscience.'' (n.d.). Retrieved May 2, 2021, from <nowiki>http://geroscience.com/hallmarks-aging/</nowiki></ref>

== Introduction ==
Mitochondria are responsible for creating adenosine triphosphate (ATP), a chemical which provides the energy for many cellular processes.<ref name=":1">''A link between mitochondrial damage and osteoporosis.'' (2019, May 9). ScienceDaily. <nowiki>https://www.sciencedaily.com/releases/2019/05/190509153425.htm</nowiki></ref> This process also creates molecules called reactive oxygen species (ROS) as a byproduct. Over time, the accumulation of ROS damages cells and mitochondria, contributing to the decline in health associated with old age, according to the free radical theory of aging.<ref name=":0" /><ref name=":1" /> Researchers have linked mitochondrial dysfunction to a number of aging-related diseases, including osteoporosis<ref name=":2">Age-related mitochondrial dysfunction as a key factor in COVID-19 disease. (2020). ''Experimental Gerontology, 142'', 111147. <nowiki>https://doi.org/10.1016/j.exger.2020.111147</nowiki></ref> and Parkinson's disease.<ref name=":3">Chen, C., Turnbull, D. M., & Reeve, A. K. (2019). Mitochondrial dysfunction in Parkinson’s disease—Cause or consequence? ''Biology, 8''(2). <nowiki>https://doi.org/10.3390/biology8020038</nowiki></ref> It is thus considered one of the hallmarks of aging.<ref name=":0" /> However, it should be noted that some evidence suggests that mild mitochondrial dysfunction actually lengthens lifespan, possibly by inducing hormesis (in which mild toxic treatments trigger compensatory responses that actually leave cells healthier than before the toxic treatment).<ref name=":4">López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. ''Cell, 153''(6), 1194–1217. <nowiki>https://doi.org/10.1016/j.cell.2013.05.039</nowiki></ref>

== Basics of Mitochondria ==
Mitochondria are structures found in almost all eukaryotic cells (cells with clearly defined nuclei).<ref name=":5">''Mitochondrion | definition, function, structure, & facts.'' (n.d.). Encyclopedia Britannica. Retrieved May 11, 2021, from <nowiki>https://www.britannica.com/science/mitochondrion</nowiki></ref> Scientists believe that they began as independent organisms which were engulfed by host cells with which they formed a symbiotic relationship, eventually becoming part of the host cells.<ref name=":6">''Osteoporosis overview | NIH Osteoporosis and Related Bone Diseases National Resource Center.'' (n.d.). Retrieved May 27, 2021, from <nowiki>https://www.bones.nih.gov/health-info/bone/osteoporosis/overview</nowiki></ref> They possess their own DNA, separate from that of the organisms they inhabit, called mitochondrial DNA (mtDNA).<ref name=":7">Wang, W., Zhao, F., Ma, X., Perry, G., & Zhu, X. (2020). Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: Recent advances. ''Molecular Neurodegeneration, 15''(1), 30. <nowiki>https://doi.org/10.1186/s13024-020-00376-6</nowiki></ref><ref name=":1" /><ref name=":6" /> A mitochondrion (the singular of mitochondria) possesses two membranes; one enveloping the other.<ref name=":8">Buneeva, O., Fedchenko, V., Kopylov, A., & Medvedev, A. (2020). Mitochondrial dysfunction in Parkinson’s disease: Focus on mitochondrial DNA. ''Biomedicines, 8''(12), 591. <nowiki>https://doi.org/10.3390/biomedicines8120591</nowiki></ref> Within the matrix (the region within the inner membrane), a series of reactions known as the Krebs cycle produces a chemical called NADH.<ref name=":6" /> A structure called complex 1, on the inner membrane, then uses the NADH in a process which pumps protons from the region within the inner membrane to the area between the membranes. This process also utilizes structures known as complex 3 and complex 4 (the latter of which requires oxygen to fill its role), also located on the inner membrane.<ref name=":8" /> This process creates a membrane potential used by another structure, complex 5, to generate ATP, which provides energy for cells.<ref name=":8" /><ref name=":5" /> This process, by which mitochondria create ATP, is known as oxidative phosphorylation.<ref name=":6" />

== Reactive Oxygen Species ==
Reactive oxygen species, also known as free radicals, are unstable molecules containing oxygen, which easily react with other molecules in a cell.<ref>[NciAppModulePage]. (2011, February 2). <nowiki>https://www.cancer.gov/publications/dictionaries/cancer-terms/def/reactive-oxygen-species</nowiki></ref> Oxidative phosphorylation produces them as a byproduct. The mitochondrial free radical theory of aging proposes that over time, increasing ROS production triggers mitochondrial dysfunction, which causes further increases in ROS production and cellular deterioration.<ref name=":9">Bárcena, C., Mayoral, P., & Quirós, P. M. (2018). Mitohormesis, an antiaging paradigm. In ''International Review of Cell and Molecular Biology'' (Vol. 340, pp. 35–77). Elsevier. <nowiki>https://doi.org/10.1016/bs.ircmb.2018.05.002</nowiki></ref><ref name=":0" /> Specifically, free radicals trigger mitochondrial dysfunction by damaging the DNA of the mitochondria by causing its atoms to lose electrons (although some studies suggest that this damage is done indirectly, and it should also be noted that the mitochondrial free radical theory of aging is not universally accepted among researchers).<ref name=":9" /><ref name=":1" /> Usually, this doesn't harm the cell, as quality-control mechanisms destroy the damaged mitochondria, but those mechanisms become less effective as people age.<ref name=":1" /> Over time, this damage to the mitochondria leaves cells less efficient at producing energy.<ref name=":0" /> In addition to harming the mitochondria, ROS contribute to the health declines of old age by causing muscle weakness, bone frailty, immune suppression, and even cancer, among other conditions.<ref name=":1" />

== Mitohormesis ==
Mitohormesis is a response of mitochondria to stressors or toxins which so thoroughly repairs their damage that the cell is healthier after the damage than before.<ref name=":9" /><ref name=":10">Bell, S. M., Barnes, K., De Marco, M., Shaw, P. J., Ferraiuolo, L., Blackburn, D. J., Venneri, A., & Mortiboys, H. (2021). Mitochondrial dysfunction in alzheimer’s disease: A biomarker of the future? ''Biomedicines, 9''(1). <nowiki>https://doi.org/10.3390/biomedicines9010063</nowiki></ref> It is a form of hormesis, which is described above.<ref>Zhu, X., Wei, Y., Yang, B., Yin, X., & Guo, X. (2020). The mitohormetic response as part of the cytoprotection mechanism of berberine. ''Molecular Medicine, 26''(1), 10. <nowiki>https://doi.org/10.1186/s10020-020-0136-8</nowiki></ref> In fact, such damage may trigger a mitochondrial defensive response not only in the tissues containing the defective mitochondria, but also distant tissues. Evidence exists which shows that mitohormesis may be able to extend lifespan in mammals, but there is no consensus on this view.<ref name=":4" /> For mitohormesis to occur, mitochondria must communicate with the cell's nucleus.<ref name=":10" /> They appear to use ROS, among other things, as signals for this communication.<ref name=":9" /><ref name=":10" /> This productive role for ROS may explain why increased ROS sometimes appears to slow aging, rather than aggravate it. Some scientists have suggested that a certain amount of ROS is beneficial, but any greater amounts are harmful.<ref name=":9" />

== Inflammation ==
Mitochondrial dysfunction can contribute to a chronic background level of inflammation some call "inflammaging".<ref name=":1" /> As the name suggests, this problem occurs with aging. Inflammaging has been associated with increased morbidity and mortality, but some researchers have found high levels of pro-inflammatory markers in people over 100 years old. This casts some doubt on whether inflammaging truly harms the elderly.<ref name=":7" /> Mitochondrial dysfunction contributes to inflammaging by increasing the cell's ROS levels.<ref name=":1" /> Increased ROS modulate the expression and activity of a substance called NF-κB, which leads to inflammation.<ref name=":7" /> Mitochondrial dysfunction may also contribute to inflammaging through mtDNA; that is, it may cause mitochondria to release mtDNA, which causes an inflammatory response when the immune system mistakes the mtDNA for pathogens.<ref name=":11">Dobson, P. F., Dennis, E. P., Hipps, D., Reeve, A., Laude, A., Bradshaw, C., Stamp, C., Smith, A., Deehan, D. J., Turnbull, D. M., & Greaves, L. C. (2020). Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss. ''Scientific Reports, 10.'' <nowiki>https://doi.org/10.1038/s41598-020-68566-2</nowiki></ref><ref name=":7" /> Scientists believe this occurs due to mitochondria's bacterial origins.<ref name=":7" />

== Mitochondrial Dysfunction in Disease ==
Mitochondrial dysfunction contributes to a number of aging-related health problems.<ref name=":0" /> Several examples are described below.

=== Alzheimer's disease ===
Alzheimer’s disease (AD) is a disease, more common in the elderly, causing deterioration of cognition and memory due to the progressive and selective loss of neurons in the forebrain and other brain areas.<ref name=":12">Sterling, J. (2019, October 18). Metabolic mitochondria dysfunction may be primary cause of alzheimer’s. ''GEN - Genetic Engineering and Biotechnology News.'' <nowiki>https://www.genengnews.com/news/metabolic-mitochondria-dysfunction-may-be-primary-cause-of-alzheimers/</nowiki></ref><ref name=":7" /> There are two competing hypotheses as to its cause. The first is that it results primarily from the accumulation of amyloid-beta proteins in the brain; the second is that it results from mitochondrial dysfunction. On the latter view, mitochondrial dysfunction leaves mitochondria incapable of the functions for which they are necessary, destroying neurons and causing AD. Researchers have found impaired energy metabolism in AD patients, as well as mitochondrial abnormalities in their brains, which gives support to this hypothesis. However, it is not fully accepted as a consensus, and the correlation of these conditions with AD does not prove they are its causes.<ref name=":7" />

=== Parkinson's disease ===
Parkinson’s disease (PD) is a movement disorder resulting from degenerative loss of certain brain cells involved with the chemical dopamine, in the brain region called the substantia nigra.<ref name=":3" /><ref name=":11" /> Its main symptoms are: tremor (trembling) in the hands, arms, legs, trunk, and/or head; stiffness of the limbs and trunk; slow movement; and impaired balance and coordination. Besides these main symptoms, other symptoms may include depression and other emotional changes; difficulty walking, swallowing, chewing, or speaking; urinary problems and constipation; skin problems; and sleep disruptions. Symptoms usually begin gradually and get worse over time, and PD is by far most common in the elderly.<ref name=":12" /> Evidence exists which suggests that PD is at least partly caused by mitochondrial dysfunction, though it is not conclusive.<ref name=":0" /> Scientists speculate that mitochondrial dysfunction harms ATP production and a process called "calcium buffering" (another function of mitochondria), as well as exacerbating oxidative stress (an imbalance between oxidants and antioxidants).<ref name=":13">Dingman, M. (2014, November 15). ''Know your brain: Substantia nigra.'' Neuroscientifically Challenged. <nowiki>https://www.neuroscientificallychallenged.com/blog/know-your-brain-substantia-nigra</nowiki></ref><ref>Picca, A., Lezza, A. M. S., Leeuwenburgh, C., Pesce, V., Calvani, R., Landi, F., Bernabei, R., & Marzetti, E. (2017). Fueling inflamm-aging through mitochondrial dysfunction: Mechanisms and molecular targets. ''International Journal of Molecular Sciences, 18''(5), 933. <nowiki>https://doi.org/10.3390/ijms18050933</nowiki></ref> These processes cause PD by killing brain cells in the substantia nigra, in theory. Recent evidence also suggests that certain processes controlling the distribution and structure of mitochondria are linked with PD.<ref name=":13" />

=== Osteoporosis ===
Osteoporosis is a bone disease that develops when bone mineral density and bone mass decrease, or when the quality or structure of bone changes. This can reduce bones' strength, which can increase their risk of breaking. Osteoporosis can strike at any age, but the risk increases with increasing age.<ref>''Parkinson’s Disease.'' (n.d.). National Institute on Aging. Retrieved May 27, 2021, from <nowiki>http://www.nia.nih.gov/health/parkinsons-disease</nowiki></ref> Evidence exists which suggests that mitochondrial dysfunction in osteoblasts (cells which produce bone) and osteoclasts (cells which break down bone) contributes to osteoporosis, by mutating the body's mtDNA.<ref name=":2" /><ref name=":14">''Hallmarks of aging: Mitochondrial dysfunction'' ''| Lifespan. Io.'' (n.d.). Retrieved May 2, 2021, from <nowiki>https://www.lifespan.io/news/hallmarks-of-aging-mitochondrial-dysfunction/</nowiki></ref> Specifically, a study of mice found that mice with biological abnormalities causing them to accumulate mtDNA mutations more quickly lost bone at a faster rate than normal mice. They also showed a reduced bone formation rate, reduced osteoblast population densities, and increased osteoclast population densities, among other differences. Researchers involved in the study argued that similar processes could contribute to human osteoporosis.<ref name=":14" />

=== COVID-19 ===
Note: the below information is on the relationship between COVID-19 and mitochondrial dysfunction. For information on the relationship between COVID-19 and the aging process in general, see [[COVID-19]].

COVID-19 is a severe form of pneumonia caused by a virus known as SARS-CoV-2. COVID-19 mainly affects the elderly and is responsible for a global pandemic. Many patients infected with the SARS-CoV-2 virus are asymptomatic or show low intensity symptoms, but around 20% of its victims, mainly elderly people, manifest severe symptoms and a high mortality ratio. Mitochondrial dysfunction is associated with some risk factors for COVID-19, and there is some evidence that it contributes to the disease. Some researchers, for example, have suggested that the chronic inflammation caused by mitochondrial dysfunction is responsible for the severe pneumonia, multi-organ failure, and death which accompany COVID-19.<ref>Aunan, J. R., Watson, M. M., Hagland, H. R., & Søreide, K. (2016). Molecular and biological hallmarks of ageing. ''British Journal of Surgery, 103''(2), e29–e46. <nowiki>https://doi.org/10.1002/bjs.10053</nowiki></ref> However, as SARS-CoV-2 was discovered relatively recently, and the COVID-19 pandemic is a rapidly changing situation, readers should be cautious about drawing conclusions from current data.

== Citations ==
<references />
[[Category:Longevity]]

Mitochondrial dysfunction

2021-10-07T14:27:56Z

Volunteer Longevity Writer 007: Corrected headings' format.

Mitochondrial dysfunction is a state of inefficient energy production in cells resulting from damage to structures called mitochondria.<ref name=":0">''The hallmarks of aging, in plain English | Geroscience.'' (n.d.). Retrieved May 2, 2021, from <nowiki>http://geroscience.com/hallmarks-aging/</nowiki></ref>

== Introduction ==
Mitochondria are responsible for creating adenosine triphosphate (ATP), a chemical which provides the energy for many cellular processes.<ref name=":1">''A link between mitochondrial damage and osteoporosis.'' (2019, May 9). ScienceDaily. <nowiki>https://www.sciencedaily.com/releases/2019/05/190509153425.htm</nowiki></ref> This process also creates molecules called reactive oxygen species (ROS) as a byproduct. Over time, the accumulation of ROS damages cells and mitochondria, contributing to the decline in health associated with old age, according to the free radical theory of aging.<ref name=":0" /><ref name=":1" /> Researchers have linked mitochondrial dysfunction to a number of aging-related diseases, including osteoporosis<ref name=":2">Age-related mitochondrial dysfunction as a key factor in COVID-19 disease. (2020). ''Experimental Gerontology, 142'', 111147. <nowiki>https://doi.org/10.1016/j.exger.2020.111147</nowiki></ref> and Parkinson's disease.<ref name=":3">Chen, C., Turnbull, D. M., & Reeve, A. K. (2019). Mitochondrial dysfunction in Parkinson’s disease—Cause or consequence? ''Biology, 8''(2). <nowiki>https://doi.org/10.3390/biology8020038</nowiki></ref> It is thus considered one of the hallmarks of aging.<ref name=":0" /> However, it should be noted that some evidence suggests that mild mitochondrial dysfunction actually lengthens lifespan, possibly by inducing hormesis (in which mild toxic treatments trigger compensatory responses that actually leave cells healthier than before the toxic treatment).<ref name=":4">López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. ''Cell, 153''(6), 1194–1217. <nowiki>https://doi.org/10.1016/j.cell.2013.05.039</nowiki></ref>

== Basics of Mitochondria ==
Mitochondria are structures found in almost all eukaryotic cells (cells with clearly defined nuclei).<ref name=":5">''Mitochondrion | definition, function, structure, & facts.'' (n.d.). Encyclopedia Britannica. Retrieved May 11, 2021, from <nowiki>https://www.britannica.com/science/mitochondrion</nowiki></ref> Scientists believe that they began as independent organisms which were engulfed by host cells with which they formed a symbiotic relationship, eventually becoming part of the host cells.<ref name=":6">''Osteoporosis overview | NIH Osteoporosis and Related Bone Diseases National Resource Center.'' (n.d.). Retrieved May 27, 2021, from <nowiki>https://www.bones.nih.gov/health-info/bone/osteoporosis/overview</nowiki></ref> They possess their own DNA, separate from that of the organisms they inhabit, called mitochondrial DNA (mtDNA).<ref name=":7">Wang, W., Zhao, F., Ma, X., Perry, G., & Zhu, X. (2020). Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: Recent advances. ''Molecular Neurodegeneration, 15''(1), 30. <nowiki>https://doi.org/10.1186/s13024-020-00376-6</nowiki></ref><ref name=":1" /><ref name=":6" /> A mitochondrion (the singular of mitochondria) possesses two membranes; one enveloping the other.<ref name=":8">Buneeva, O., Fedchenko, V., Kopylov, A., & Medvedev, A. (2020). Mitochondrial dysfunction in Parkinson’s disease: Focus on mitochondrial DNA. ''Biomedicines, 8''(12), 591. <nowiki>https://doi.org/10.3390/biomedicines8120591</nowiki></ref> Within the matrix (the region within the inner membrane), a series of reactions known as the Krebs cycle produces a chemical called NADH.<ref name=":6" /> A structure called complex 1, on the inner membrane, then uses the NADH in a process which pumps protons from the region within the inner membrane to the area between the membranes. This process also utilizes structures known as complex 3 and complex 4 (the latter of which requires oxygen to fill its role), also located on the inner membrane.<ref name=":8" /> This process creates a membrane potential used by another structure, complex 5, to generate ATP, which provides energy for cells.<ref name=":8" /><ref name=":5" /> This process, by which mitochondria create ATP, is known as oxidative phosphorylation.<ref name=":6" />

== Reactive Oxygen Species ==
Reactive oxygen species, also known as free radicals, are unstable molecules containing oxygen, which easily react with other molecules in a cell.<ref>[NciAppModulePage]. (2011, February 2). <nowiki>https://www.cancer.gov/publications/dictionaries/cancer-terms/def/reactive-oxygen-species</nowiki></ref> Oxidative phosphorylation produces them as a byproduct. The mitochondrial free radical theory of aging proposes that over time, increasing ROS production triggers mitochondrial dysfunction, which causes further increases in ROS production and cellular deterioration.<ref name=":9">Bárcena, C., Mayoral, P., & Quirós, P. M. (2018). Mitohormesis, an antiaging paradigm. In ''International Review of Cell and Molecular Biology'' (Vol. 340, pp. 35–77). Elsevier. <nowiki>https://doi.org/10.1016/bs.ircmb.2018.05.002</nowiki></ref><ref name=":0" /> Specifically, free radicals trigger mitochondrial dysfunction by damaging the DNA of the mitochondria by causing its atoms to lose electrons (although some studies suggest that this damage is done indirectly, and it should also be noted that the mitochondrial free radical theory of aging is not universally accepted among researchers).<ref name=":9" /><ref name=":1" /> Usually, this doesn't harm the cell, as quality-control mechanisms destroy the damaged mitochondria, but those mechanisms become less effective as people age.<ref name=":1" /> Over time, this damage to the mitochondria leaves cells less efficient at producing energy.<ref name=":0" /> In addition to harming the mitochondria, ROS contribute to the health declines of old age by causing muscle weakness, bone frailty, immune suppression, and even cancer, among other conditions.<ref name=":1" />

== Mitohormesis ==
Mitohormesis is a response of mitochondria to stressors or toxins which so thoroughly repairs their damage that the cell is healthier after the damage than before.<ref name=":9" /><ref name=":10">Bell, S. M., Barnes, K., De Marco, M., Shaw, P. J., Ferraiuolo, L., Blackburn, D. J., Venneri, A., & Mortiboys, H. (2021). Mitochondrial dysfunction in alzheimer’s disease: A biomarker of the future? ''Biomedicines, 9''(1). <nowiki>https://doi.org/10.3390/biomedicines9010063</nowiki></ref> It is a form of hormesis, which is described above.<ref>Zhu, X., Wei, Y., Yang, B., Yin, X., & Guo, X. (2020). The mitohormetic response as part of the cytoprotection mechanism of berberine. ''Molecular Medicine, 26''(1), 10. <nowiki>https://doi.org/10.1186/s10020-020-0136-8</nowiki></ref> In fact, such damage may trigger a mitochondrial defensive response not only in the tissues containing the defective mitochondria, but also distant tissues. Evidence exists which shows that mitohormesis may be able to extend lifespan in mammals, but there is no consensus on this view.<ref name=":4" /> For mitohormesis to occur, mitochondria must communicate with the cell's nucleus.<ref name=":10" /> They appear to use ROS, among other things, as signals for this communication.<ref name=":9" /><ref name=":10" /> This productive role for ROS may explain why increased ROS sometimes appears to slow aging, rather than aggravate it. Some scientists have suggested that a certain amount of ROS is beneficial, but any greater amounts are harmful.<ref name=":9" />

== Inflammation ==
Mitochondrial dysfunction can contribute to a chronic background level of inflammation some call "inflammaging".<ref name=":1" /> As the name suggests, this problem occurs with aging. Inflammaging has been associated with increased morbidity and mortality, but some researchers have found high levels of pro-inflammatory markers in people over 100 years old. This casts some doubt on whether inflammaging truly harms the elderly.<ref name=":7" /> Mitochondrial dysfunction contributes to inflammaging by increasing the cell's ROS levels.<ref name=":1" /> Increased ROS modulate the expression and activity of a substance called NF-κB, which leads to inflammation.<ref name=":7" /> Mitochondrial dysfunction may also contribute to inflammaging through mtDNA; that is, it may cause mitochondria to release mtDNA, which causes an inflammatory response when the immune system mistakes the mtDNA for pathogens.<ref name=":11">Dobson, P. F., Dennis, E. P., Hipps, D., Reeve, A., Laude, A., Bradshaw, C., Stamp, C., Smith, A., Deehan, D. J., Turnbull, D. M., & Greaves, L. C. (2020). Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss. ''Scientific Reports, 10.'' <nowiki>https://doi.org/10.1038/s41598-020-68566-2</nowiki></ref><ref name=":7" /> Scientists believe this occurs due to mitochondria's bacterial origins.<ref name=":7" />

== Mitochondrial Dysfunction in Disease ==
Mitochondrial dysfunction contributes to a number of aging-related health problems.<ref name=":0" /> Several examples are described below.

=== Alzheimer's disease ===
Alzheimer’s disease (AD) is a disease, more common in the elderly, causing deterioration of cognition and memory due to the progressive and selective loss of neurons in the forebrain and other brain areas.<ref name=":12">Sterling, J. (2019, October 18). Metabolic mitochondria dysfunction may be primary cause of alzheimer’s. ''GEN - Genetic Engineering and Biotechnology News.'' <nowiki>https://www.genengnews.com/news/metabolic-mitochondria-dysfunction-may-be-primary-cause-of-alzheimers/</nowiki></ref><ref name=":7" /> There are two competing hypotheses as to its cause. The first is that it results primarily from the accumulation of amyloid-beta proteins in the brain; the second is that it results from mitochondrial dysfunction. On the latter view, mitochondrial dysfunction leaves mitochondria incapable of the functions for which they are necessary, destroying neurons and causing AD. Researchers have found impaired energy metabolism in AD patients, as well as mitochondrial abnormalities in their brains, which gives support to this hypothesis. However, it is not fully accepted as a consensus, and the correlation of these conditions with AD does not prove they are its causes.<ref name=":7" />

=== Parkinson's disease ===
Parkinson’s disease (PD) is a movement disorder resulting from degenerative loss of certain brain cells involved with the chemical dopamine, in the brain region called the substantia nigra.<ref name=":3" /><ref name=":11" /> Its main symptoms are: tremor (trembling) in the hands, arms, legs, trunk, and/or head; stiffness of the limbs and trunk; slow movement; and impaired balance and coordination. Besides these main symptoms, other symptoms may include depression and other emotional changes; difficulty walking, swallowing, chewing, or speaking; urinary problems and constipation; skin problems; and sleep disruptions. Symptoms usually begin gradually and get worse over time, and PD is by far most common in the elderly.<ref name=":12" /> Evidence exists which suggests that PD is at least partly caused by mitochondrial dysfunction, though it is not conclusive.<ref name=":0" /> Scientists speculate that mitochondrial dysfunction harms ATP production and a process called "calcium buffering" (another function of mitochondria), as well as exacerbating oxidative stress (an imbalance between oxidants and antioxidants).<ref name=":13">Dingman, M. (2014, November 15). ''Know your brain: Substantia nigra.'' Neuroscientifically Challenged. <nowiki>https://www.neuroscientificallychallenged.com/blog/know-your-brain-substantia-nigra</nowiki></ref><ref>Picca, A., Lezza, A. M. S., Leeuwenburgh, C., Pesce, V., Calvani, R., Landi, F., Bernabei, R., & Marzetti, E. (2017). Fueling inflamm-aging through mitochondrial dysfunction: Mechanisms and molecular targets. ''International Journal of Molecular Sciences, 18''(5), 933. <nowiki>https://doi.org/10.3390/ijms18050933</nowiki></ref> These processes cause PD by killing brain cells in the substantia nigra, in theory. Recent evidence also suggests that certain processes controlling the distribution and structure of mitochondria are linked with PD.<ref name=":13" />

=== Osteoporosis ===
Osteoporosis is a bone disease that develops when bone mineral density and bone mass decrease, or when the quality or structure of bone changes. This can reduce bones' strength, which can increase their risk of breaking. Osteoporosis can strike at any age, but the risk increases with increasing age.<ref>''Parkinson’s Disease.'' (n.d.). National Institute on Aging. Retrieved May 27, 2021, from <nowiki>http://www.nia.nih.gov/health/parkinsons-disease</nowiki></ref> Evidence exists which suggests that mitochondrial dysfunction in osteoblasts (cells which produce bone) and osteoclasts (cells which break down bone) contributes to osteoporosis, by mutating the body's mtDNA.<ref name=":2" /><ref name=":14">''Hallmarks of aging: Mitochondrial dysfunction'' ''| Lifespan. Io.'' (n.d.). Retrieved May 2, 2021, from <nowiki>https://www.lifespan.io/news/hallmarks-of-aging-mitochondrial-dysfunction/</nowiki></ref> Specifically, a study of mice found that mice with biological abnormalities causing them to accumulate mtDNA mutations more quickly lost bone at a faster rate than normal mice. They also showed a reduced bone formation rate, reduced osteoblast population densities, and increased osteoclast population densities, among other differences. Researchers involved in the study argued that similar processes could contribute to human osteoporosis.<ref name=":14" />

=== COVID-19 ===
Note: the below information is on the relationship between COVID-19 and mitochondrial dysfunction. For information on the relationship between COVID-19 and the aging process in general, see [[COVID-19]].

COVID-19 is a severe form of pneumonia caused by a virus known as SARS-CoV-2. COVID-19 mainly affects the elderly and is responsible for a global pandemic. Many patients infected with the SARS-CoV-2 virus are asymptomatic or show low intensity symptoms, but around 20% of its victims, mainly elderly people, manifest severe symptoms and a high mortality ratio. Mitochondrial dysfunction is associated with some risk factors for COVID-19, and there is some evidence that it contributes to the disease. Some researchers, for example, have suggested that the chronic inflammation caused by mitochondrial dysfunction is responsible for the severe pneumonia, multi-organ failure, and death which accompany COVID-19.<ref>Aunan, J. R., Watson, M. M., Hagland, H. R., & Søreide, K. (2016). Molecular and biological hallmarks of ageing. ''British Journal of Surgery, 103''(2), e29–e46. <nowiki>https://doi.org/10.1002/bjs.10053</nowiki></ref> However, as SARS-CoV-2 was discovered relatively recently, and the COVID-19 pandemic is a rapidly changing situation, readers should be cautious about drawing conclusions from current data.

=== Citations ===
<references />
[[Category:Longevity]]

Mitochondrial dysfunction

2021-10-06T16:09:17Z

Volunteer Longevity Writer 007: Put article in "Longevity" category.

Mitochondrial dysfunction is a state of inefficient energy production in cells resulting from damage to structures called mitochondria.<ref name=":0">''The hallmarks of aging, in plain English | Geroscience.'' (n.d.). Retrieved May 2, 2021, from <nowiki>http://geroscience.com/hallmarks-aging/</nowiki></ref>

Introduction

Mitochondria are responsible for creating adenosine triphosphate (ATP), a chemical which provides the energy for many cellular processes.<ref name=":1">''A link between mitochondrial damage and osteoporosis.'' (2019, May 9). ScienceDaily. <nowiki>https://www.sciencedaily.com/releases/2019/05/190509153425.htm</nowiki></ref> This process also creates molecules called reactive oxygen species (ROS) as a byproduct. Over time, the accumulation of ROS damages cells and mitochondria, contributing to the decline in health associated with old age, according to the free radical theory of aging.<ref name=":0" /><ref name=":1" /> Researchers have linked mitochondrial dysfunction to a number of aging-related diseases, including osteoporosis<ref name=":2">Age-related mitochondrial dysfunction as a key factor in COVID-19 disease. (2020). ''Experimental Gerontology, 142'', 111147. <nowiki>https://doi.org/10.1016/j.exger.2020.111147</nowiki></ref> and Parkinson's disease.<ref name=":3">Chen, C., Turnbull, D. M., & Reeve, A. K. (2019). Mitochondrial dysfunction in Parkinson’s disease—Cause or consequence? ''Biology, 8''(2). <nowiki>https://doi.org/10.3390/biology8020038</nowiki></ref> It is thus considered one of the hallmarks of aging.<ref name=":0" /> However, it should be noted that some evidence suggests that mild mitochondrial dysfunction actually lengthens lifespan, possibly by inducing hormesis (in which mild toxic treatments trigger compensatory responses that actually leave cells healthier than before the toxic treatment).<ref name=":4">López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. ''Cell, 153''(6), 1194–1217. <nowiki>https://doi.org/10.1016/j.cell.2013.05.039</nowiki></ref>

Basics of Mitochondria

Mitochondria are structures found in almost all eukaryotic cells (cells with clearly defined nuclei).<ref name=":5">''Mitochondrion | definition, function, structure, & facts.'' (n.d.). Encyclopedia Britannica. Retrieved May 11, 2021, from <nowiki>https://www.britannica.com/science/mitochondrion</nowiki></ref> Scientists believe that they began as independent organisms which were engulfed by host cells with which they formed a symbiotic relationship, eventually becoming part of the host cells.<ref name=":6">''Osteoporosis overview | NIH Osteoporosis and Related Bone Diseases National Resource Center.'' (n.d.). Retrieved May 27, 2021, from <nowiki>https://www.bones.nih.gov/health-info/bone/osteoporosis/overview</nowiki></ref> They possess their own DNA, separate from that of the organisms they inhabit, called mitochondrial DNA (mtDNA).<ref name=":7">Wang, W., Zhao, F., Ma, X., Perry, G., & Zhu, X. (2020). Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: Recent advances. ''Molecular Neurodegeneration, 15''(1), 30. <nowiki>https://doi.org/10.1186/s13024-020-00376-6</nowiki></ref><ref name=":1" /><ref name=":6" /> A mitochondrion (the singular of mitochondria) possesses two membranes; one enveloping the other.<ref name=":8">Buneeva, O., Fedchenko, V., Kopylov, A., & Medvedev, A. (2020). Mitochondrial dysfunction in Parkinson’s disease: Focus on mitochondrial DNA. ''Biomedicines, 8''(12), 591. <nowiki>https://doi.org/10.3390/biomedicines8120591</nowiki></ref> Within the matrix (the region within the inner membrane), a series of reactions known as the Krebs cycle produces a chemical called NADH.<ref name=":6" /> A structure called complex 1, on the inner membrane, then uses the NADH in a process which pumps protons from the region within the inner membrane to the area between the membranes. This process also utilizes structures known as complex 3 and complex 4 (the latter of which requires oxygen to fill its role), also located on the inner membrane.<ref name=":8" /> This process creates a membrane potential used by another structure, complex 5, to generate ATP, which provides energy for cells.<ref name=":8" /><ref name=":5" /> This process, by which mitochondria create ATP, is known as oxidative phosphorylation.<ref name=":6" />

Reactive Oxygen Species

Reactive oxygen species, also known as free radicals, are unstable molecules containing oxygen, which easily react with other molecules in a cell.<ref>[NciAppModulePage]. (2011, February 2). <nowiki>https://www.cancer.gov/publications/dictionaries/cancer-terms/def/reactive-oxygen-species</nowiki></ref> Oxidative phosphorylation produces them as a byproduct. The mitochondrial free radical theory of aging proposes that over time, increasing ROS production triggers mitochondrial dysfunction, which causes further increases in ROS production and cellular deterioration.<ref name=":9">Bárcena, C., Mayoral, P., & Quirós, P. M. (2018). Mitohormesis, an antiaging paradigm. In ''International Review of Cell and Molecular Biology'' (Vol. 340, pp. 35–77). Elsevier. <nowiki>https://doi.org/10.1016/bs.ircmb.2018.05.002</nowiki></ref><ref name=":0" /> Specifically, free radicals trigger mitochondrial dysfunction by damaging the DNA of the mitochondria by causing its atoms to lose electrons (although some studies suggest that this damage is done indirectly, and it should also be noted that the mitochondrial free radical theory of aging is not universally accepted among researchers).<ref name=":9" /><ref name=":1" /> Usually, this doesn't harm the cell, as quality-control mechanisms destroy the damaged mitochondria, but those mechanisms become less effective as people age.<ref name=":1" /> Over time, this damage to the mitochondria leaves cells less efficient at producing energy.<ref name=":0" /> In addition to harming the mitochondria, ROS contribute to the health declines of old age by causing muscle weakness, bone frailty, immune suppression, and even cancer, among other conditions.<ref name=":1" />

Mitohormesis

Mitohormesis is a response of mitochondria to stressors or toxins which so thoroughly repairs their damage that the cell is healthier after the damage than before.<ref name=":9" /><ref name=":10">Bell, S. M., Barnes, K., De Marco, M., Shaw, P. J., Ferraiuolo, L., Blackburn, D. J., Venneri, A., & Mortiboys, H. (2021). Mitochondrial dysfunction in alzheimer’s disease: A biomarker of the future? ''Biomedicines, 9''(1). <nowiki>https://doi.org/10.3390/biomedicines9010063</nowiki></ref> It is a form of hormesis, which is described above.<ref>Zhu, X., Wei, Y., Yang, B., Yin, X., & Guo, X. (2020). The mitohormetic response as part of the cytoprotection mechanism of berberine. ''Molecular Medicine, 26''(1), 10. <nowiki>https://doi.org/10.1186/s10020-020-0136-8</nowiki></ref> In fact, such damage may trigger a mitochondrial defensive response not only in the tissues containing the defective mitochondria, but also distant tissues. Evidence exists which shows that mitohormesis may be able to extend lifespan in mammals, but there is no consensus on this view.<ref name=":4" /> For mitohormesis to occur, mitochondria must communicate with the cell's nucleus.<ref name=":10" /> They appear to use ROS, among other things, as signals for this communication.<ref name=":9" /><ref name=":10" /> This productive role for ROS may explain why increased ROS sometimes appears to slow aging, rather than aggravate it. Some scientists have suggested that a certain amount of ROS is beneficial, but any greater amounts are harmful.<ref name=":9" />

Inflammation

Mitochondrial dysfunction can contribute to a chronic background level of inflammation some call "inflammaging".<ref name=":1" /> As the name suggests, this problem occurs with aging. Inflammaging has been associated with increased morbidity and mortality, but some researchers have found high levels of pro-inflammatory markers in people over 100 years old. This casts some doubt on whether inflammaging truly harms the elderly.<ref name=":7" /> Mitochondrial dysfunction contributes to inflammaging by increasing the cell's ROS levels.<ref name=":1" /> Increased ROS modulate the expression and activity of a substance called NF-κB, which leads to inflammation.<ref name=":7" /> Mitochondrial dysfunction may also contribute to inflammaging through mtDNA; that is, it may cause mitochondria to release mtDNA, which causes an inflammatory response when the immune system mistakes the mtDNA for pathogens.<ref name=":11">Dobson, P. F., Dennis, E. P., Hipps, D., Reeve, A., Laude, A., Bradshaw, C., Stamp, C., Smith, A., Deehan, D. J., Turnbull, D. M., & Greaves, L. C. (2020). Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss. ''Scientific Reports, 10.'' <nowiki>https://doi.org/10.1038/s41598-020-68566-2</nowiki></ref><ref name=":7" /> Scientists believe this occurs due to mitochondria's bacterial origins.<ref name=":7" />

Mitochondrial dysfunction in disease

Mitochondrial dysfunction contributes to a number of aging-related health problems.<ref name=":0" /> Several examples are described below.

Alzheimer's disease

Alzheimer’s disease (AD) is a disease, more common in the elderly, causing deterioration of cognition and memory due to the progressive and selective loss of neurons in the forebrain and other brain areas.<ref name=":12">Sterling, J. (2019, October 18). Metabolic mitochondria dysfunction may be primary cause of alzheimer’s. ''GEN - Genetic Engineering and Biotechnology News.'' <nowiki>https://www.genengnews.com/news/metabolic-mitochondria-dysfunction-may-be-primary-cause-of-alzheimers/</nowiki></ref><ref name=":7" /> There are two competing hypotheses as to its cause. The first is that it results primarily from the accumulation of amyloid-beta proteins in the brain; the second is that it results from mitochondrial dysfunction. On the latter view, mitochondrial dysfunction leaves mitochondria incapable of the functions for which they are necessary, destroying neurons and causing AD. Researchers have found impaired energy metabolism in AD patients, as well as mitochondrial abnormalities in their brains, which gives support to this hypothesis. However, it is not fully accepted as a consensus, and the correlation of these conditions with AD does not prove they are its causes.<ref name=":7" />

Parkinson's disease

Parkinson’s disease (PD) is a movement disorder resulting from degenerative loss of certain brain cells involved with the chemical dopamine, in the brain region called the substantia nigra.<ref name=":3" /><ref name=":11" /> Its main symptoms are: tremor (trembling) in the hands, arms, legs, trunk, and/or head; stiffness of the limbs and trunk; slow movement; and impaired balance and coordination. Besides these main symptoms, other symptoms may include depression and other emotional changes; difficulty walking, swallowing, chewing, or speaking; urinary problems and constipation; skin problems; and sleep disruptions. Symptoms usually begin gradually and get worse over time, and PD is by far most common in the elderly.<ref name=":12" /> Evidence exists which suggests that PD is at least partly caused by mitochondrial dysfunction, though it is not conclusive.<ref name=":0" /> Scientists speculate that mitochondrial dysfunction harms ATP production and a process called "calcium buffering" (another function of mitochondria), as well as exacerbating oxidative stress (an imbalance between oxidants and antioxidants).<ref name=":13">Dingman, M. (2014, November 15). ''Know your brain: Substantia nigra.'' Neuroscientifically Challenged. <nowiki>https://www.neuroscientificallychallenged.com/blog/know-your-brain-substantia-nigra</nowiki></ref><ref>Picca, A., Lezza, A. M. S., Leeuwenburgh, C., Pesce, V., Calvani, R., Landi, F., Bernabei, R., & Marzetti, E. (2017). Fueling inflamm-aging through mitochondrial dysfunction: Mechanisms and molecular targets. ''International Journal of Molecular Sciences, 18''(5), 933. <nowiki>https://doi.org/10.3390/ijms18050933</nowiki></ref> These processes cause PD by killing brain cells in the substantia nigra, in theory. Recent evidence also suggests that certain processes controlling the distribution and structure of mitochondria are linked with PD.<ref name=":13" />

Osteoporosis

Osteoporosis is a bone disease that develops when bone mineral density and bone mass decrease, or when the quality or structure of bone changes. This can reduce bones' strength, which can increase their risk of breaking. Osteoporosis can strike at any age, but the risk increases with increasing age.<ref>''Parkinson’s Disease.'' (n.d.). National Institute on Aging. Retrieved May 27, 2021, from <nowiki>http://www.nia.nih.gov/health/parkinsons-disease</nowiki></ref> Evidence exists which suggests that mitochondrial dysfunction in osteoblasts (cells which produce bone) and osteoclasts (cells which break down bone) contributes to osteoporosis, by mutating the body's mtDNA.<ref name=":2" /><ref name=":14">''Hallmarks of aging: Mitochondrial dysfunction'' ''| Lifespan. Io.'' (n.d.). Retrieved May 2, 2021, from <nowiki>https://www.lifespan.io/news/hallmarks-of-aging-mitochondrial-dysfunction/</nowiki></ref> Specifically, a study of mice found that mice with biological abnormalities causing them to accumulate mtDNA mutations more quickly lost bone at a faster rate than normal mice. They also showed a reduced bone formation rate, reduced osteoblast population densities, and increased osteoclast population densities, among other differences. Researchers involved in the study argued that similar processes could contribute to human osteoporosis.<ref name=":14" />

COVID-19

Note: the below information is on the relationship between COVID-19 and mitochondrial dysfunction. For information on the relationship between COVID-19 and the aging process in general, see [[COVID-19]].

COVID-19 is a severe form of pneumonia caused by a virus known as SARS-CoV-2. COVID-19 mainly affects the elderly and is responsible for a global pandemic. Many patients infected with the SARS-CoV-2 virus are asymptomatic or show low intensity symptoms, but around 20% of its victims, mainly elderly people, manifest severe symptoms and a high mortality ratio. Mitochondrial dysfunction is associated with some risk factors for COVID-19, and there is some evidence that it contributes to the disease. Some researchers, for example, have suggested that the chronic inflammation caused by mitochondrial dysfunction is responsible for the severe pneumonia, multi-organ failure, and death which accompany COVID-19.<ref>Aunan, J. R., Watson, M. M., Hagland, H. R., & Søreide, K. (2016). Molecular and biological hallmarks of ageing. ''British Journal of Surgery, 103''(2), e29–e46. <nowiki>https://doi.org/10.1002/bjs.10053</nowiki></ref> However, as SARS-CoV-2 was discovered relatively recently, and the COVID-19 pandemic is a rapidly changing situation, readers should be cautious about drawing conclusions from current data.

=== Citations ===
<references />
[[Category:Longevity]]

Gotu Kola

2021-10-04T00:52:55Z

Volunteer Longevity Writer 007: Copied and pasted text of initial article from draft I wrote in a Google doc during the early days of Longevity Wiki, after it had been reviewed by other volunteers.

Gotu kola (also known by its scientific name ''Centella asiatica'') is an herb in the parsley family used in traditional Chinese and Ayurvedic medicine (two forms of complementary and alternative medicine).<ref name=":0">Gohil, K., Patel, J., & Gajjar, A. (2010). Pharmacological review on Centella asiatica: A potential herbal cure-all. ''Indian Journal of Pharmaceutical Sciences, 72''(5), 546. <nowiki>https://doi.org/10.4103/0250-474X.78519</nowiki></ref><ref name=":1">''Gotu kola: Overview, uses, side effects, precautions, interactions, dosing and reviews.'' (n.d.). Retrieved June 8, 2021, from <nowiki>https://www.webmd.com/vitamins/ai/ingredientmono-753/gotu-kola</nowiki></ref><ref>''What is Ayurveda?'' (n.d.). WebMD. Retrieved June 8, 2021, from <nowiki>https://www.webmd.com/balance/guide/ayurvedic-treatments</nowiki></ref><ref>''What is traditional Chinese medicine?'' (n.d.). WebMD. Retrieved June 8, 2021, from <nowiki>https://www.webmd.com/balance/guide/what-is-traditional-chinese-medicine</nowiki></ref>

Gotu kola is native to tropical and subtropical parts of Asia, and it should not be confused with kola nut, as it does not contain caffeine and has not been shown to have stimulant properties.<ref name=":0" /><ref name=":2">''Gotu kola: Health benefits and side effects.'' (2020, March 10). <nowiki>https://www.medicalnewstoday.com/articles/gotu-kola-benefits</nowiki></ref> It is used to treat burns, poor circulation, schistosomiasis, atherosclerosis, and many other conditions.<ref name=":1" /><ref name=":2" /> Some also claim that gotu kola can benefit the brain and nervous system, increasing attention span and concentration, and improving memory.<ref name=":0" /><ref name=":2" /> However, scientists have not yet performed sufficient research to justify these uses of gotu kola, with the exceptions of second-degree burns, varicose veins, and venous insufficiency.

Gotu kola does appear to accelerate the healing process when applied to second-degree burns, and taking gotu kola (or Centellase, an extract of it) by mouth seems to improve blood circulation and reduce swelling in people with poor blood circulation in the legs. Its effect on blood circulation and swelling lets it serve as a treatment for varicose veins (a vein condition causing itchy skin, swelling, and aching in the legs, which becomes more likely as patients age) and venous insufficiency (in which veins have problems moving blood from the legs to the heart).<ref name=":1" /><ref>''The basics of varicose veins.'' (n.d.). WebMD. Retrieved June 12, 2021, from <nowiki>https://www.webmd.com/skin-problems-and-treatments/understanding-varicose-veins-basics</nowiki></ref><ref>''Venous insufficiency: Medlineplus medical encyclopedia.'' (n.d.). Retrieved June 12, 2021, from <nowiki>https://medlineplus.gov/ency/article/000203.htm</nowiki></ref>

It should be noted that science has not found evidence ''against'' gotu kola's effectiveness against other conditions; it simply has not found evidence ''for'' gotu kola's effectiveness. An exception is radiation dermatitis (a type of skin damage), as some research has shown that a cream containing gotu kola extract does not reduce the severity of radiation dermatitis from breast cancer treatments.<ref name=":1" />

== Citations ==
<references />

Mitochondrial dysfunction

2021-10-03T23:02:39Z

Volunteer Longevity Writer 007: Added link to COVID-19 article.

Mitochondrial dysfunction is a state of inefficient energy production in cells resulting from damage to structures called mitochondria.[21]

Introduction

Mitochondria are responsible for creating adenosine triphosphate (ATP), a chemical which provides the energy for many cellular processes.[10] This process also creates molecules called reactive oxygen species (ROS) as a byproduct. Over time, the accumulation of ROS damages cells and mitochondria, contributing to the decline in health associated with old age, according to the free radical theory of aging.[10][21] Researchers have linked mitochondrial dysfunction to a number of aging-related diseases, including osteoporosis [1] and Parkinson's disease.[6] It is thus considered one of the hallmarks of aging.[21] However, it should be noted that some evidence suggests that mild mitochondrial dysfunction actually lengthens lifespan, possibly by inducing hormesis (in which mild toxic treatments trigger compensatory responses that actually leave cells healthier than before the toxic treatment).[11]

Basics of Mitochondria

Mitochondria are structures found in almost all eukaryotic cells (cells with clearly defined nuclei).[12] Scientists believe that they began as independent organisms which were engulfed by host cells with which they formed a symbiotic relationship, eventually becoming part of the host cells.[15] They possess their own DNA, separate from that of the organisms they inhabit, called mitochondrial DNA (mtDNA).[22][10][15] A mitochondrion (the singular of mitochondria) possesses two membranes; one enveloping the other.[5] Within the matrix (the region within the inner membrane), a series of reactions known as the Krebs cycle produces a chemical called NADH.[15] A structure called complex 1, on the inner membrane, then uses the NADH in a process which pumps protons from the region within the inner membrane to the area between the membranes. This process also utilizes structures known as complex 3 and complex 4 (the latter of which requires oxygen to fill its role), also located on the inner membrane.[5] This process creates a membrane potential used by another structure, complex 5, to generate ATP, which provides energy for cells.[5][12] This process, by which mitochondria create ATP, is known as oxidative phosphorylation.[15]

Reactive Oxygen Species

Reactive oxygen species, also known as free radicals, are unstable molecules containing oxygen, which easily react with other molecules in a cell.[14] Oxidative phosphorylation produces them as a byproduct. The mitochondrial free radical theory of aging proposes that over time, increasing ROS production triggers mitochondrial dysfunction, which causes further increases in ROS production and cellular deterioration.[3][21] Specifically, free radicals trigger mitochondrial dysfunction by damaging the DNA of the mitochondria by causing its atoms to lose electrons (although some studies suggest that this damage is done indirectly, and it should also be noted that the mitochondrial free radical theory of aging is not universally accepted among researchers).[3][10] Usually, this doesn't harm the cell, as quality-control mechanisms destroy the damaged mitochondria, but those mechanisms become less effective as people age.[10] Over time, this damage to the mitochondria leaves cells less efficient at producing energy.[21] In addition to harming the mitochondria, ROS contribute to the health declines of old age by causing muscle weakness, bone frailty, immune suppression, and even cancer, among other conditions.[10]

Mitohormesis

Mitohormesis is a response of mitochondria to stressors or toxins which so thoroughly repairs their damage that the cell is healthier after the damage than before.[3][4] It is a form of hormesis, which is described above.[23] In fact, such damage may trigger a mitochondrial defensive response not only in the tissues containing the defective mitochondria, but also distant tissues. Evidence exists which shows that mitohormesis may be able to extend lifespan in mammals, but there is no consensus on this view.[11] For mitohormesis to occur, mitochondria must communicate with the cell's nucleus.[4] They appear to use ROS, among other things, as signals for this communication.[3][4] This productive role for ROS may explain why increased ROS sometimes appears to slow aging, rather than aggravate it. Some scientists have suggested that a certain amount of ROS is beneficial, but any greater amounts are harmful.[3]

Inflammation

Mitochondrial dysfunction can contribute to a chronic background level of inflammation some call "inflammaging".[10] As the name suggests, this problem occurs with aging. Inflammaging has been associated with increased morbidity and mortality, but some researchers have found high levels of pro-inflammatory markers in people over 100 years old. This casts some doubt on whether inflammaging truly harms the elderly.[22] Mitochondrial dysfunction contributes to inflammaging by increasing the cell's ROS levels.[10] Increased ROS modulate the expression and activity of a substance called NF-κB, which leads to inflammation.[22] Mitochondrial dysfunction may also contribute to inflammaging through mtDNA; that is, it may cause mitochondria to release mtDNA, which causes an inflammatory response when the immune system mistakes the mtDNA for pathogens.[8][22] Scientists believe this occurs due to mitochondria's bacterial origins.[22]

Mitochondrial dysfunction in disease

Mitochondrial dysfunction contributes to a number of aging-related health problems.[21] Several examples are described below.

Alzheimer's disease

Alzheimer’s disease (AD) is a disease, more common in the elderly, causing deterioration of cognition and memory due to the progressive and selective loss of neurons in the forebrain and other brain areas.[20][22] There are two competing hypotheses as to its cause. The first is that it results primarily from the accumulation of amyloid-beta proteins in the brain; the second is that it results from mitochondrial dysfunction. On the latter view, mitochondrial dysfunction leaves mitochondria incapable of the functions for which they are necessary, destroying neurons and causing AD. Researchers have found impaired energy metabolism in AD patients, as well as mitochondrial abnormalities in their brains, which gives support to this hypothesis. However, it is not fully accepted as a consensus, and the correlation of these conditions with AD does not prove they are its causes.[22]

Parkinson's disease

Parkinson’s disease (PD) is a movement disorder resulting from degenerative loss of certain brain cells involved with the chemical dopamine, in the brain region called the substantia nigra.[6][8] Its main symptoms are: tremor (trembling) in the hands, arms, legs, trunk, and/or head; stiffness of the limbs and trunk; slow movement; and impaired balance and coordination. Besides these main symptoms, other symptoms may include depression and other emotional changes; difficulty walking, swallowing, chewing, or speaking; urinary problems and constipation; skin problems; and sleep disruptions. Symptoms usually begin gradually and get worse over time, and PD is by far most common in the elderly.[20] Evidence exists which suggests that PD is at least partly caused by mitochondrial dysfunction, though it is not conclusive.[21] Scientists speculate that mitochondrial dysfunction harms ATP production and a process called "calcium buffering" (another function of mitochondria), as well as exacerbating oxidative stress (an imbalance between oxidants and antioxidants).[7][19] These processes cause PD by killing brain cells in the substantia nigra, in theory. Recent evidence also suggests that certain processes controlling the distribution and structure of mitochondria are linked with PD.[7]

Osteoporosis

Osteoporosis is a bone disease that develops when bone mineral density and bone mass decrease, or when the quality or structure of bone changes. This can reduce bones' strength, which can increase their risk of breaking. Osteoporosis can strike at any age, but the risk increases with increasing age.[18] Evidence exists which suggests that mitochondrial dysfunction in osteoblasts (cells which produce bone) and osteoclasts (cells which break down bone) contributes to osteoporosis, by mutating the body's mtDNA.[1][9] Specifically, a study of mice found that mice with biological abnormalities causing them to accumulate mtDNA mutations more quickly lost bone at a faster rate than normal mice. They also showed a reduced bone formation rate, reduced osteoblast population densities, and increased osteoclast population densities, among other differences. Researchers involved in the study argued that similar processes could contribute to human osteoporosis.[9]

COVID-19

Note: the below information is on the relationship between COVID-19 and mitochondrial dysfunction. For information on the relationship between COVID-19 and the aging process in general, see [[COVID-19]].

COVID-19 is a severe form of pneumonia caused by a virus known as SARS-CoV-2. COVID-19 mainly affects the elderly and is responsible for a global pandemic. Many patients infected with the SARS-CoV-2 virus are asymptomatic or show low intensity symptoms, but around 20% of its victims, mainly elderly people, manifest severe symptoms and a high mortality ratio. Mitochondrial dysfunction is associated with some risk factors for COVID-19, and there is some evidence that it contributes to the disease. Some researchers, for example, have suggested that the chronic inflammation caused by mitochondrial dysfunction is responsible for the severe pneumonia, multi-organ failure, and death which accompany COVID-19.[2] However, as SARS-CoV-2 was discovered relatively recently, and the COVID-19 pandemic is a rapidly changing situation, readers should be cautious about drawing conclusions from current data.

References

# Age-related mitochondrial dysfunction as a key factor in COVID-19 disease. (2020). ''Experimental Gerontology, 142'', 111147. <nowiki>https://doi.org/10.1016/j.exger.2020.111147</nowiki>
# Aunan, J. R., Watson, M. M., Hagland, H. R., & Søreide, K. (2016). Molecular and biological hallmarks of ageing. ''British Journal of Surgery, 103''(2), e29–e46. <nowiki>https://doi.org/10.1002/bjs.10053</nowiki>
# Bárcena, C., Mayoral, P., & Quirós, P. M. (2018). Mitohormesis, an antiaging paradigm. In ''International Review of Cell and Molecular Biology'' (Vol. 340, pp. 35–77). Elsevier. <nowiki>https://doi.org/10.1016/bs.ircmb.2018.05.002</nowiki>
# Bell, S. M., Barnes, K., De Marco, M., Shaw, P. J., Ferraiuolo, L., Blackburn, D. J., Venneri, A., & Mortiboys, H. (2021). Mitochondrial dysfunction in alzheimer’s disease: A biomarker of the future? ''Biomedicines, 9''(1). <nowiki>https://doi.org/10.3390/biomedicines9010063</nowiki>
# Buneeva, O., Fedchenko, V., Kopylov, A., & Medvedev, A. (2020). Mitochondrial dysfunction in Parkinson’s disease: Focus on mitochondrial DNA. ''Biomedicines, 8''(12), 591. <nowiki>https://doi.org/10.3390/biomedicines8120591</nowiki>
# Chen, C., Turnbull, D. M., & Reeve, A. K. (2019). Mitochondrial dysfunction in Parkinson’s disease—Cause or consequence? ''Biology, 8''(2). <nowiki>https://doi.org/10.3390/biology8020038</nowiki>
# Dingman, M. (2014, November 15). ''Know your brain: Substantia nigra.'' Neuroscientifically Challenged. <nowiki>https://www.neuroscientificallychallenged.com/blog/know-your-brain-substantia-nigra</nowiki>
# Dobson, P. F., Dennis, E. P., Hipps, D., Reeve, A., Laude, A., Bradshaw, C., Stamp, C., Smith, A., Deehan, D. J., Turnbull, D. M., & Greaves, L. C. (2020). Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss. ''Scientific Reports, 10.'' <nowiki>https://doi.org/10.1038/s41598-020-68566-2</nowiki>
# ''Hallmarks of aging: Mitochondrial dysfunction'' ''| Lifespan. Io.'' (n.d.). Retrieved May 2, 2021, from <nowiki>https://www.lifespan.io/news/hallmarks-of-aging-mitochondrial-dysfunction/</nowiki>
# ''A link between mitochondrial damage and osteoporosis.'' (2019, May 9). ScienceDaily. <nowiki>https://www.sciencedaily.com/releases/2019/05/190509153425.htm</nowiki>
# López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. ''Cell, 153''(6), 1194–1217. <nowiki>https://doi.org/10.1016/j.cell.2013.05.039</nowiki>
# ''Mitochondrion | definition, function, structure, & facts.'' (n.d.). Encyclopedia Britannica. Retrieved May 11, 2021, from <nowiki>https://www.britannica.com/science/mitochondrion</nowiki>
# ''Mitochondrion – much more than an energy converter | British Society for Cell Biology.'' (n.d.). Retrieved May 13, 2021, from <nowiki>https://bscb.org/learning-resources/softcell-e-learning/mitochondrion-much-more-than-an-energy-converter/</nowiki>
# [NciAppModulePage]. (2011, February 2). <nowiki>https://www.cancer.gov/publications/dictionaries/cancer-terms/def/reactive-oxygen-species</nowiki>
# ''Osteoporosis overview | NIH Osteoporosis and Related Bone Diseases National Resource Center.'' (n.d.). Retrieved May 27, 2021, from <nowiki>https://www.bones.nih.gov/health-info/bone/osteoporosis/overview</nowiki>
# ''Oxidative stress—An overview | ScienceDirect topics.'' (n.d.). Retrieved May 25, 2021, from <nowiki>https://www.sciencedirect.com/topics/medicine-and-dentistry/oxidative-stress</nowiki>
# Park, J.-S., Davis, R. L., & Sue, C. M. (2018). Mitochondrial dysfunction in Parkinson’s disease: New mechanistic insights and therapeutic perspectives. ''Current Neurology and Neuroscience Reports, 18''(5). <nowiki>https://doi.org/10.1007/s11910-018-0829-3</nowiki>
# ''Parkinson’s Disease.'' (n.d.). National Institute on Aging. Retrieved May 27, 2021, from <nowiki>http://www.nia.nih.gov/health/parkinsons-disease</nowiki>
# Picca, A., Lezza, A. M. S., Leeuwenburgh, C., Pesce, V., Calvani, R., Landi, F., Bernabei, R., & Marzetti, E. (2017). Fueling inflamm-aging through mitochondrial dysfunction: Mechanisms and molecular targets. ''International Journal of Molecular Sciences, 18''(5), 933. <nowiki>https://doi.org/10.3390/ijms18050933</nowiki>
# Sterling, J. (2019, October 18). Metabolic mitochondria dysfunction may be primary cause of alzheimer’s. ''GEN - Genetic Engineering and Biotechnology News.'' <nowiki>https://www.genengnews.com/news/metabolic-mitochondria-dysfunction-may-be-primary-cause-of-alzheimers/</nowiki>
# ''The hallmarks of aging, in plain English | Geroscience.'' (n.d.). Retrieved May 2, 2021, from <nowiki>http://geroscience.com/hallmarks-aging/</nowiki>
# Wang, W., Zhao, F., Ma, X., Perry, G., & Zhu, X. (2020). Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: Recent advances. ''Molecular Neurodegeneration, 15''(1), 30. <nowiki>https://doi.org/10.1186/s13024-020-00376-6</nowiki>
# Zhu, X., Wei, Y., Yang, B., Yin, X., & Guo, X. (2020). The mitohormetic response as part of the cytoprotection mechanism of berberine. ''Molecular Medicine, 26''(1), 10. <nowiki>https://doi.org/10.1186/s10020-020-0136-8</nowiki>

Mitochondrial dysfunction

2021-10-03T22:54:30Z

Volunteer Longevity Writer 007: Corrected format of several citations.

Mitochondrial dysfunction is a state of inefficient energy production in cells resulting from damage to structures called mitochondria.[21]

Introduction

Mitochondria are responsible for creating adenosine triphosphate (ATP), a chemical which provides the energy for many cellular processes.[10] This process also creates molecules called reactive oxygen species (ROS) as a byproduct. Over time, the accumulation of ROS damages cells and mitochondria, contributing to the decline in health associated with old age, according to the free radical theory of aging.[10][21] Researchers have linked mitochondrial dysfunction to a number of aging-related diseases, including osteoporosis [1] and Parkinson's disease.[6] It is thus considered one of the hallmarks of aging.[21] However, it should be noted that some evidence suggests that mild mitochondrial dysfunction actually lengthens lifespan, possibly by inducing hormesis (in which mild toxic treatments trigger compensatory responses that actually leave cells healthier than before the toxic treatment).[11]

Basics of Mitochondria

Mitochondria are structures found in almost all eukaryotic cells (cells with clearly defined nuclei).[12] Scientists believe that they began as independent organisms which were engulfed by host cells with which they formed a symbiotic relationship, eventually becoming part of the host cells.[15] They possess their own DNA, separate from that of the organisms they inhabit, called mitochondrial DNA (mtDNA).[22][10][15] A mitochondrion (the singular of mitochondria) possesses two membranes; one enveloping the other.[5] Within the matrix (the region within the inner membrane), a series of reactions known as the Krebs cycle produces a chemical called NADH.[15] A structure called complex 1, on the inner membrane, then uses the NADH in a process which pumps protons from the region within the inner membrane to the area between the membranes. This process also utilizes structures known as complex 3 and complex 4 (the latter of which requires oxygen to fill its role), also located on the inner membrane.[5] This process creates a membrane potential used by another structure, complex 5, to generate ATP, which provides energy for cells.[5][12] This process, by which mitochondria create ATP, is known as oxidative phosphorylation.[15]

Reactive Oxygen Species

Reactive oxygen species, also known as free radicals, are unstable molecules containing oxygen, which easily react with other molecules in a cell.[14] Oxidative phosphorylation produces them as a byproduct. The mitochondrial free radical theory of aging proposes that over time, increasing ROS production triggers mitochondrial dysfunction, which causes further increases in ROS production and cellular deterioration.[3][21] Specifically, free radicals trigger mitochondrial dysfunction by damaging the DNA of the mitochondria by causing its atoms to lose electrons (although some studies suggest that this damage is done indirectly, and it should also be noted that the mitochondrial free radical theory of aging is not universally accepted among researchers).[3][10] Usually, this doesn't harm the cell, as quality-control mechanisms destroy the damaged mitochondria, but those mechanisms become less effective as people age.[10] Over time, this damage to the mitochondria leaves cells less efficient at producing energy.[21] In addition to harming the mitochondria, ROS contribute to the health declines of old age by causing muscle weakness, bone frailty, immune suppression, and even cancer, among other conditions.[10]

Mitohormesis

Mitohormesis is a response of mitochondria to stressors or toxins which so thoroughly repairs their damage that the cell is healthier after the damage than before.[3][4] It is a form of hormesis, which is described above.[23] In fact, such damage may trigger a mitochondrial defensive response not only in the tissues containing the defective mitochondria, but also distant tissues. Evidence exists which shows that mitohormesis may be able to extend lifespan in mammals, but there is no consensus on this view.[11] For mitohormesis to occur, mitochondria must communicate with the cell's nucleus.[4] They appear to use ROS, among other things, as signals for this communication.[3][4] This productive role for ROS may explain why increased ROS sometimes appears to slow aging, rather than aggravate it. Some scientists have suggested that a certain amount of ROS is beneficial, but any greater amounts are harmful.[3]

Inflammation

Mitochondrial dysfunction can contribute to a chronic background level of inflammation some call "inflammaging".[10] As the name suggests, this problem occurs with aging. Inflammaging has been associated with increased morbidity and mortality, but some researchers have found high levels of pro-inflammatory markers in people over 100 years old. This casts some doubt on whether inflammaging truly harms the elderly.[22] Mitochondrial dysfunction contributes to inflammaging by increasing the cell's ROS levels.[10] Increased ROS modulate the expression and activity of a substance called NF-κB, which leads to inflammation.[22] Mitochondrial dysfunction may also contribute to inflammaging through mtDNA; that is, it may cause mitochondria to release mtDNA, which causes an inflammatory response when the immune system mistakes the mtDNA for pathogens.[8][22] Scientists believe this occurs due to mitochondria's bacterial origins.[22]

Mitochondrial dysfunction in disease

Mitochondrial dysfunction contributes to a number of aging-related health problems.[21] Several examples are described below.

Alzheimer's disease

Alzheimer’s disease (AD) is a disease, more common in the elderly, causing deterioration of cognition and memory due to the progressive and selective loss of neurons in the forebrain and other brain areas.[20][22] There are two competing hypotheses as to its cause. The first is that it results primarily from the accumulation of amyloid-beta proteins in the brain; the second is that it results from mitochondrial dysfunction. On the latter view, mitochondrial dysfunction leaves mitochondria incapable of the functions for which they are necessary, destroying neurons and causing AD. Researchers have found impaired energy metabolism in AD patients, as well as mitochondrial abnormalities in their brains, which gives support to this hypothesis. However, it is not fully accepted as a consensus, and the correlation of these conditions with AD does not prove they are its causes.[22]

Parkinson's disease

Parkinson’s disease (PD) is a movement disorder resulting from degenerative loss of certain brain cells involved with the chemical dopamine, in the brain region called the substantia nigra.[6][8] Its main symptoms are: tremor (trembling) in the hands, arms, legs, trunk, and/or head; stiffness of the limbs and trunk; slow movement; and impaired balance and coordination. Besides these main symptoms, other symptoms may include depression and other emotional changes; difficulty walking, swallowing, chewing, or speaking; urinary problems and constipation; skin problems; and sleep disruptions. Symptoms usually begin gradually and get worse over time, and PD is by far most common in the elderly.[20] Evidence exists which suggests that PD is at least partly caused by mitochondrial dysfunction, though it is not conclusive.[21] Scientists speculate that mitochondrial dysfunction harms ATP production and a process called "calcium buffering" (another function of mitochondria), as well as exacerbating oxidative stress (an imbalance between oxidants and antioxidants).[7][19] These processes cause PD by killing brain cells in the substantia nigra, in theory. Recent evidence also suggests that certain processes controlling the distribution and structure of mitochondria are linked with PD.[7]

Osteoporosis

Osteoporosis is a bone disease that develops when bone mineral density and bone mass decrease, or when the quality or structure of bone changes. This can reduce bones' strength, which can increase their risk of breaking. Osteoporosis can strike at any age, but the risk increases with increasing age.[18] Evidence exists which suggests that mitochondrial dysfunction in osteoblasts (cells which produce bone) and osteoclasts (cells which break down bone) contributes to osteoporosis, by mutating the body's mtDNA.[1][9] Specifically, a study of mice found that mice with biological abnormalities causing them to accumulate mtDNA mutations more quickly lost bone at a faster rate than normal mice. They also showed a reduced bone formation rate, reduced osteoblast population densities, and increased osteoclast population densities, among other differences. Researchers involved in the study argued that similar processes could contribute to human osteoporosis.[9]

COVID-19

Note: the below information is on the relationship between COVID-19 and mitochondrial dysfunction. For information on the relationship between COVID-19 and the aging process in general, see [insert link to COVID-19 Longevity Wiki article here].

COVID-19 is a severe form of pneumonia caused by a virus known as SARS-CoV-2. COVID-19 mainly affects the elderly and is responsible for a global pandemic. Many patients infected with the SARS-CoV-2 virus are asymptomatic or show low intensity symptoms, but around 20% of its victims, mainly elderly people, manifest severe symptoms and a high mortality ratio. Mitochondrial dysfunction is associated with some risk factors for COVID-19, and there is some evidence that it contributes to the disease. Some researchers, for example, have suggested that the chronic inflammation caused by mitochondrial dysfunction is responsible for the severe pneumonia, multi-organ failure, and death which accompany COVID-19.[2] However, as SARS-CoV-2 was discovered relatively recently, and the COVID-19 pandemic is a rapidly changing situation, readers should be cautious about drawing conclusions from current data.

References

# Age-related mitochondrial dysfunction as a key factor in COVID-19 disease. (2020). ''Experimental Gerontology, 142'', 111147. <nowiki>https://doi.org/10.1016/j.exger.2020.111147</nowiki>
# Aunan, J. R., Watson, M. M., Hagland, H. R., & Søreide, K. (2016). Molecular and biological hallmarks of ageing. ''British Journal of Surgery, 103''(2), e29–e46. <nowiki>https://doi.org/10.1002/bjs.10053</nowiki>
# Bárcena, C., Mayoral, P., & Quirós, P. M. (2018). Mitohormesis, an antiaging paradigm. In ''International Review of Cell and Molecular Biology'' (Vol. 340, pp. 35–77). Elsevier. <nowiki>https://doi.org/10.1016/bs.ircmb.2018.05.002</nowiki>
# Bell, S. M., Barnes, K., De Marco, M., Shaw, P. J., Ferraiuolo, L., Blackburn, D. J., Venneri, A., & Mortiboys, H. (2021). Mitochondrial dysfunction in alzheimer’s disease: A biomarker of the future? ''Biomedicines, 9''(1). <nowiki>https://doi.org/10.3390/biomedicines9010063</nowiki>
# Buneeva, O., Fedchenko, V., Kopylov, A., & Medvedev, A. (2020). Mitochondrial dysfunction in Parkinson’s disease: Focus on mitochondrial DNA. ''Biomedicines, 8''(12), 591. <nowiki>https://doi.org/10.3390/biomedicines8120591</nowiki>
# Chen, C., Turnbull, D. M., & Reeve, A. K. (2019). Mitochondrial dysfunction in Parkinson’s disease—Cause or consequence? ''Biology, 8''(2). <nowiki>https://doi.org/10.3390/biology8020038</nowiki>
# Dingman, M. (2014, November 15). ''Know your brain: Substantia nigra.'' Neuroscientifically Challenged. <nowiki>https://www.neuroscientificallychallenged.com/blog/know-your-brain-substantia-nigra</nowiki>
# Dobson, P. F., Dennis, E. P., Hipps, D., Reeve, A., Laude, A., Bradshaw, C., Stamp, C., Smith, A., Deehan, D. J., Turnbull, D. M., & Greaves, L. C. (2020). Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss. ''Scientific Reports, 10.'' <nowiki>https://doi.org/10.1038/s41598-020-68566-2</nowiki>
# ''Hallmarks of aging: Mitochondrial dysfunction'' ''| Lifespan. Io.'' (n.d.). Retrieved May 2, 2021, from <nowiki>https://www.lifespan.io/news/hallmarks-of-aging-mitochondrial-dysfunction/</nowiki>
# ''A link between mitochondrial damage and osteoporosis.'' (2019, May 9). ScienceDaily. <nowiki>https://www.sciencedaily.com/releases/2019/05/190509153425.htm</nowiki>
# López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. ''Cell, 153''(6), 1194–1217. <nowiki>https://doi.org/10.1016/j.cell.2013.05.039</nowiki>
# ''Mitochondrion | definition, function, structure, & facts.'' (n.d.). Encyclopedia Britannica. Retrieved May 11, 2021, from <nowiki>https://www.britannica.com/science/mitochondrion</nowiki>
# ''Mitochondrion – much more than an energy converter | British Society for Cell Biology.'' (n.d.). Retrieved May 13, 2021, from <nowiki>https://bscb.org/learning-resources/softcell-e-learning/mitochondrion-much-more-than-an-energy-converter/</nowiki>
# [NciAppModulePage]. (2011, February 2). <nowiki>https://www.cancer.gov/publications/dictionaries/cancer-terms/def/reactive-oxygen-species</nowiki>
# ''Osteoporosis overview | NIH Osteoporosis and Related Bone Diseases National Resource Center.'' (n.d.). Retrieved May 27, 2021, from <nowiki>https://www.bones.nih.gov/health-info/bone/osteoporosis/overview</nowiki>
# ''Oxidative stress—An overview | ScienceDirect topics.'' (n.d.). Retrieved May 25, 2021, from <nowiki>https://www.sciencedirect.com/topics/medicine-and-dentistry/oxidative-stress</nowiki>
# Park, J.-S., Davis, R. L., & Sue, C. M. (2018). Mitochondrial dysfunction in Parkinson’s disease: New mechanistic insights and therapeutic perspectives. ''Current Neurology and Neuroscience Reports, 18''(5). <nowiki>https://doi.org/10.1007/s11910-018-0829-3</nowiki>
# ''Parkinson’s Disease.'' (n.d.). National Institute on Aging. Retrieved May 27, 2021, from <nowiki>http://www.nia.nih.gov/health/parkinsons-disease</nowiki>
# Picca, A., Lezza, A. M. S., Leeuwenburgh, C., Pesce, V., Calvani, R., Landi, F., Bernabei, R., & Marzetti, E. (2017). Fueling inflamm-aging through mitochondrial dysfunction: Mechanisms and molecular targets. ''International Journal of Molecular Sciences, 18''(5), 933. <nowiki>https://doi.org/10.3390/ijms18050933</nowiki>
# Sterling, J. (2019, October 18). Metabolic mitochondria dysfunction may be primary cause of alzheimer’s. ''GEN - Genetic Engineering and Biotechnology News.'' <nowiki>https://www.genengnews.com/news/metabolic-mitochondria-dysfunction-may-be-primary-cause-of-alzheimers/</nowiki>
# ''The hallmarks of aging, in plain English | Geroscience.'' (n.d.). Retrieved May 2, 2021, from <nowiki>http://geroscience.com/hallmarks-aging/</nowiki>
# Wang, W., Zhao, F., Ma, X., Perry, G., & Zhu, X. (2020). Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: Recent advances. ''Molecular Neurodegeneration, 15''(1), 30. <nowiki>https://doi.org/10.1186/s13024-020-00376-6</nowiki>
# Zhu, X., Wei, Y., Yang, B., Yin, X., & Guo, X. (2020). The mitohormetic response as part of the cytoprotection mechanism of berberine. ''Molecular Medicine, 26''(1), 10. <nowiki>https://doi.org/10.1186/s10020-020-0136-8</nowiki>

Mitochondrial dysfunction

2021-10-03T21:59:35Z

Volunteer Longevity Writer 007:

Mitochondrial dysfunction is a state of inefficient energy production in cells resulting from damage to structures called mitochondria.[21]

Introduction

Mitochondria are responsible for creating adenosine triphosphate (ATP), a chemical which provides the energy for many cellular processes.[10] This process also creates molecules called reactive oxygen species (ROS) as a byproduct. Over time, the accumulation of ROS damages cells and mitochondria, contributing to the decline in health associated with old age, according to the free radical theory of aging.[10][21] Researchers have linked mitochondrial dysfunction to a number of aging-related diseases, including osteoporosis [1] and Parkinson's disease.[6] It is thus considered one of the hallmarks of aging.[21] However, it should be noted that some evidence suggests that mild mitochondrial dysfunction actually lengthens lifespan, possibly by inducing hormesis (in which mild toxic treatments trigger compensatory responses that actually leave cells healthier than before the toxic treatment).[11]

Basics of Mitochondria

Mitochondria are structures found in almost all eukaryotic cells (cells with clearly defined nuclei).[12] Scientists believe that they began as independent organisms which were engulfed by host cells with which they formed a symbiotic relationship, eventually becoming part of the host cells.[15] They possess their own DNA, separate from that of the organisms they inhabit, called mitochondrial DNA (mtDNA).[22][10][15] A mitochondrion (the singular of mitochondria) possesses two membranes; one enveloping the other.[5] Within the matrix (the region within the inner membrane), a series of reactions known as the Krebs cycle produces a chemical called NADH.[15] A structure called complex 1, on the inner membrane, then uses the NADH in a process which pumps protons from the region within the inner membrane to the area between the membranes. This process also utilizes structures known as complex 3 and complex 4 (the latter of which requires oxygen to fill its role), also located on the inner membrane.[5] This process creates a membrane potential used by another structure, complex 5, to generate ATP, which provides energy for cells.[5][12] This process, by which mitochondria create ATP, is known as oxidative phosphorylation.[15]

Reactive Oxygen Species

Reactive oxygen species, also known as free radicals, are unstable molecules containing oxygen, which easily react with other molecules in a cell.[14] Oxidative phosphorylation produces them as a byproduct. The mitochondrial free radical theory of aging proposes that over time, increasing ROS production triggers mitochondrial dysfunction, which causes further increases in ROS production and cellular deterioration.[3][21] Specifically, free radicals trigger mitochondrial dysfunction by damaging the DNA of the mitochondria by causing its atoms to lose electrons (although some studies suggest that this damage is done indirectly, and it should also be noted that the mitochondrial free radical theory of aging is not universally accepted among researchers).[3][10] Usually, this doesn't harm the cell, as quality-control mechanisms destroy the damaged mitochondria, but those mechanisms become less effective as people age.[10] Over time, this damage to the mitochondria leaves cells less efficient at producing energy.[21] In addition to harming the mitochondria, ROS contribute to the health declines of old age by causing muscle weakness, bone frailty, immune suppression, and even cancer, among other conditions.[10]

Mitohormesis

Mitohormesis is a response of mitochondria to stressors or toxins which so thoroughly repairs their damage that the cell is healthier after the damage than before.[3][4] It is a form of hormesis, which is described above.[23] In fact, such damage may trigger a mitochondrial defensive response not only in the tissues containing the defective mitochondria, but also distant tissues. Evidence exists which shows that mitohormesis may be able to extend lifespan in mammals, but there is no consensus on this view.[11] For mitohormesis to occur, mitochondria must communicate with the cell's nucleus.[4] They appear to use ROS, among other things, as signals for this communication.[3][4] This productive role for ROS may explain why increased ROS sometimes appears to slow aging, rather than aggravate it. Some scientists have suggested that a certain amount of ROS is beneficial, but any greater amounts are harmful.[3]

Inflammation

Mitochondrial dysfunction can contribute to a chronic background level of inflammation some call "inflammaging".[10] As the name suggests, this problem occurs with aging. Inflammaging has been associated with increased morbidity and mortality, but some researchers have found high levels of pro-inflammatory markers in people over 100 years old. This casts some doubt on whether inflammaging truly harms the elderly.[22] Mitochondrial dysfunction contributes to inflammaging by increasing the cell's ROS levels.[10] Increased ROS modulate the expression and activity of a substance called NF-κB, which leads to inflammation.[22] Mitochondrial dysfunction may also contribute to inflammaging through mtDNA; that is, it may cause mitochondria to release mtDNA, which causes an inflammatory response when the immune system mistakes the mtDNA for pathogens.[8][22] Scientists believe this occurs due to mitochondria's bacterial origins.[22]

Mitochondrial dysfunction in disease

Mitochondrial dysfunction contributes to a number of aging-related health problems.[21] Several examples are described below.

Alzheimer's disease

Alzheimer’s disease (AD) is a disease, more common in the elderly, causing deterioration of cognition and memory due to the progressive and selective loss of neurons in the forebrain and other brain areas.[20][22] There are two competing hypotheses as to its cause. The first is that it results primarily from the accumulation of amyloid-beta proteins in the brain; the second is that it results from mitochondrial dysfunction. On the latter view, mitochondrial dysfunction leaves mitochondria incapable of the functions for which they are necessary, destroying neurons and causing AD. Researchers have found impaired energy metabolism in AD patients, as well as mitochondrial abnormalities in their brains, which gives support to this hypothesis. However, it is not fully accepted as a consensus, and the correlation of these conditions with AD does not prove they are its causes.[22]

Parkinson's disease

Parkinson’s disease (PD) is a movement disorder resulting from degenerative loss of certain brain cells involved with the chemical dopamine, in the brain region called the substantia nigra.[6][8] Its main symptoms are: tremor (trembling) in the hands, arms, legs, trunk, and/or head; stiffness of the limbs and trunk; slow movement; and impaired balance and coordination. Besides these main symptoms, other symptoms may include depression and other emotional changes; difficulty walking, swallowing, chewing, or speaking; urinary problems and constipation; skin problems; and sleep disruptions. Symptoms usually begin gradually and get worse over time, and PD is by far most common in the elderly.[20] Evidence exists which suggests that PD is at least partly caused by mitochondrial dysfunction, though it is not conclusive.[21] Scientists speculate that mitochondrial dysfunction harms ATP production and a process called "calcium buffering" (another function of mitochondria), as well as exacerbating oxidative stress (an imbalance between oxidants and antioxidants).[7][19] These processes cause PD by killing brain cells in the substantia nigra, in theory. Recent evidence also suggests that certain processes controlling the distribution and structure of mitochondria are linked with PD.[7]

Osteoporosis

Osteoporosis is a bone disease that develops when bone mineral density and bone mass decrease, or when the quality or structure of bone changes. This can reduce bones' strength, which can increase their risk of breaking. Osteoporosis can strike at any age, but the risk increases with increasing age.[18] Evidence exists which suggests that mitochondrial dysfunction in osteoblasts (cells which produce bone) and osteoclasts (cells which break down bone) contributes to osteoporosis, by mutating the body's mtDNA.[1][9] Specifically, a study of mice found that mice with biological abnormalities causing them to accumulate mtDNA mutations more quickly lost bone at a faster rate than normal mice. They also showed a reduced bone formation rate, reduced osteoblast population densities, and increased osteoclast population densities, among other differences. Researchers involved in the study argued that similar processes could contribute to human osteoporosis.[9]

COVID-19

Note: the below information is on the relationship between COVID-19 and mitochondrial dysfunction. For information on the relationship between COVID-19 and the aging process in general, see [insert link to COVID-19 Longevity Wiki article here].

COVID-19 is a severe form of pneumonia caused by a virus known as SARS-CoV-2. COVID-19 mainly affects the elderly and is responsible for a global pandemic. Many patients infected with the SARS-CoV-2 virus are asymptomatic or show low intensity symptoms, but around 20% of its victims, mainly elderly people, manifest severe symptoms and a high mortality ratio. Mitochondrial dysfunction is associated with some risk factors for COVID-19, and there is some evidence that it contributes to the disease. Some researchers, for example, have suggested that the chronic inflammation caused by mitochondrial dysfunction is responsible for the severe pneumonia, multi-organ failure, and death which accompany COVID-19.[2] However, as SARS-CoV-2 was discovered relatively recently, and the COVID-19 pandemic is a rapidly changing situation, readers should be cautious about drawing conclusions from current data.

References

# Age-related mitochondrial dysfunction as a key factor in COVID-19 disease. (2020). ''Experimental Gerontology, 142'', 111147. <nowiki>https://doi.org/10.1016/j.exger.2020.111147</nowiki>
# Aunan, J. R., Watson, M. M., Hagland, H. R., & Søreide, K. (2016). Molecular and biological hallmarks of ageing. ''British Journal of Surgery, 103''(2), e29–e46. <nowiki>https://doi.org/10.1002/bjs.10053</nowiki>
# Bárcena, C., Mayoral, P., & Quirós, P. M. (2018). Mitohormesis, an antiaging paradigm. In ''International Review of Cell and Molecular Biology'' (Vol. 340, pp. 35–77). Elsevier. <nowiki>https://doi.org/10.1016/bs.ircmb.2018.05.002</nowiki>
# Bell, S. M., Barnes, K., De Marco, M., Shaw, P. J., Ferraiuolo, L., Blackburn, D. J., Venneri, A., & Mortiboys, H. (2021). Mitochondrial dysfunction in alzheimer’s disease: A biomarker of the future? ''Biomedicines, 9''(1). <nowiki>https://doi.org/10.3390/biomedicines9010063</nowiki>
# Buneeva, O., Fedchenko, V., Kopylov, A., & Medvedev, A. (2020). Mitochondrial dysfunction in Parkinson’s disease: Focus on mitochondrial DNA. ''Biomedicines, 8''(12), 591. <nowiki>https://doi.org/10.3390/biomedicines8120591</nowiki>
# Chen, C., Turnbull, D. M., & Reeve, A. K. (2019). Mitochondrial dysfunction in Parkinson’s disease—Cause or consequence? Biology, 8(2). <nowiki>https://doi.org/10.3390/biology8020038</nowiki>
# Dingman, M. (2014, November 15). Know your brain: Substantia nigra. Neuroscientifically Challenged. <nowiki>https://www.neuroscientificallychallenged.com/blog/know-your-brain-substantia-nigra</nowiki>
# Dobson, P. F., Dennis, E. P., Hipps, D., Reeve, A., Laude, A., Bradshaw, C., Stamp, C., Smith, A., Deehan, D. J., Turnbull, D. M., & Greaves, L. C. (2020). Mitochondrial dysfunction impairs osteogenesis, increases osteoclast activity, and accelerates age related bone loss. Scientific Reports, 10. <nowiki>https://doi.org/10.1038/s41598-020-68566-2</nowiki>
# Hallmarks of aging: Mitochondrial dysfunction | Lifespan. Io. (n.d.). Retrieved May 2, 2021, from <nowiki>https://www.lifespan.io/news/hallmarks-of-aging-mitochondrial-dysfunction/</nowiki>
# A link between mitochondrial damage and osteoporosis. (2019, May 9). ScienceDaily. <nowiki>https://www.sciencedaily.com/releases/2019/05/190509153425.htm</nowiki>
# López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194–1217. <nowiki>https://doi.org/10.1016/j.cell.2013.05.039</nowiki>
# Mitochondrion | definition, function, structure, & facts. (n.d.). Encyclopedia Britannica. Retrieved May 11, 2021, from <nowiki>https://www.britannica.com/science/mitochondrion</nowiki>
# Mitochondrion – much more than an energy converter | British Society for Cell Biology. (n.d.). Retrieved May 13, 2021, from <nowiki>https://bscb.org/learning-resources/softcell-e-learning/mitochondrion-much-more-than-an-energy-converter/</nowiki>
# [NciAppModulePage]. (2011, February 2). <nowiki>https://www.cancer.gov/publications/dictionaries/cancer-terms/def/reactive-oxygen-species</nowiki>
# Osteoporosis overview | NIH Osteoporosis and Related Bone Diseases National Resource Center. (n.d.). Retrieved May 27, 2021, from <nowiki>https://www.bones.nih.gov/health-info/bone/osteoporosis/overview</nowiki>
# Oxidative stress—An overview | ScienceDirect topics. (n.d.). Retrieved May 25, 2021, from <nowiki>https://www.sciencedirect.com/topics/medicine-and-dentistry/oxidative-stress</nowiki>
# Park, J.-S., Davis, R. L., & Sue, C. M. (2018). Mitochondrial dysfunction in Parkinson’s disease: New mechanistic insights and therapeutic perspectives. Current Neurology and Neuroscience Reports, 18(5). <nowiki>https://doi.org/10.1007/s11910-018-0829-3</nowiki>
# Parkinson’s Disease. (n.d.). National Institute on Aging. Retrieved May 27, 2021, from <nowiki>http://www.nia.nih.gov/health/parkinsons-disease</nowiki>
# Picca, A., Lezza, A. M. S., Leeuwenburgh, C., Pesce, V., Calvani, R., Landi, F., Bernabei, R., & Marzetti, E. (2017). Fueling inflamm-aging through mitochondrial dysfunction: Mechanisms and molecular targets. International Journal of Molecular Sciences, 18(5), 933. <nowiki>https://doi.org/10.3390/ijms18050933</nowiki>
# Sterling, J. (2019, October 18). Metabolic mitochondria dysfunction may be primary cause of alzheimer’s. GEN - Genetic Engineering and Biotechnology News. <nowiki>https://www.genengnews.com/news/metabolic-mitochondria-dysfunction-may-be-primary-cause-of-alzheimers/</nowiki>
# The hallmarks of aging, in plain English | Geroscience. (n.d.). Retrieved May 2, 2021, from <nowiki>http://geroscience.com/hallmarks-aging/</nowiki>
# Wang, W., Zhao, F., Ma, X., Perry, G., & Zhu, X. (2020). Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: Recent advances. Molecular Neurodegeneration, 15(1), 30. <nowiki>https://doi.org/10.1186/s13024-020-00376-6</nowiki>
# Zhu, X., Wei, Y., Yang, B., Yin, X., & Guo, X. (2020). The mitohormetic response as part of the cytoprotection mechanism of berberine. Molecular Medicine, 26(1), 10. <nowiki>https://doi.org/10.1186/s10020-020-0136-8</nowiki>

Mitochondrial dysfunction

2021-10-03T21:56:31Z

Volunteer Longevity Writer 007: Copied and pasted text of initial article from draft I wrote in a Google doc during the early days of Longevity Wiki, after it had been reviewed by other volunteers. Also partially corrected minor mistakes in the format of the citations at the bottom, which arose from the manner in which I copied and pasted them.

Mitochondrial dysfunction is a state of inefficient energy production in cells resulting from damage to structures called mitochondria.[21]

Introduction

Mitochondria are responsible for creating adenosine triphosphate (ATP), a chemical which provides the energy for many cellular processes.[10] This process also creates molecules called reactive oxygen species (ROS) as a byproduct. Over time, the accumulation of ROS damages cells and mitochondria, contributing to the decline in health associated with old age, according to the free radical theory of aging.[10][21] Researchers have linked mitochondrial dysfunction to a number of aging-related diseases, including osteoporosis.[1] and Parkinson's disease.[6] It is thus considered one of the hallmarks of aging.[21] However, it should be noted that some evidence suggests that mild mitochondrial dysfunction actually lengthens lifespan, possibly by inducing hormesis (in which mild toxic treatments trigger compensatory responses that actually leave cells healthier than before the toxic treatment).[11]

Basics of Mitochondria

Mitochondria are structures found in almost all eukaryotic cells (cells with clearly defined nuclei).[12] Scientists believe that they began as independent organisms which were engulfed by host cells with which they formed a symbiotic relationship, eventually becoming part of the host cells.[15] They possess their own DNA, separate from that of the organisms they inhabit, called mitochondrial DNA (mtDNA).[22][10][15] A mitochondrion (the singular of mitochondria) possesses two membranes; one enveloping the other.[5] Within the matrix (the region within the inner membrane), a series of reactions known as the Krebs cycle produces a chemical called NADH.[15] A structure called complex 1, on the inner membrane, then uses the NADH in a process which pumps protons from the region within the inner membrane to the area between the membranes. This process also utilizes structures known as complex 3 and complex 4 (the latter of which requires oxygen to fill its role), also located on the inner membrane.[5] This process creates a membrane potential used by another structure, complex 5, to generate ATP, which provides energy for cells.[5][12] This process, by which mitochondria create ATP, is known as oxidative phosphorylation.[15]

Reactive Oxygen Species

Reactive oxygen species, also known as free radicals, are unstable molecules containing oxygen, which easily react with other molecules in a cell.[14] Oxidative phosphorylation produces them as a byproduct. The mitochondrial free radical theory of aging proposes that over time, increasing ROS production triggers mitochondrial dysfunction, which causes further increases in ROS production and cellular deterioration.[3][21] Specifically, free radicals trigger mitochondrial dysfunction by damaging the DNA of the mitochondria by causing its atoms to lose electrons (although some studies suggest that this damage is done indirectly, and it should also be noted that the mitochondrial free radical theory of aging is not universally accepted among researchers).[3][10] Usually, this doesn't harm the cell, as quality-control mechanisms destroy the damaged mitochondria, but those mechanisms become less effective as people age.[10] Over time, this damage to the mitochondria leaves cells less efficient at producing energy.[21] In addition to harming the mitochondria, ROS contribute to the health declines of old age by causing muscle weakness, bone frailty, immune suppression, and even cancer, among other conditions.[10]

Mitohormesis

Mitohormesis is a response of mitochondria to stressors or toxins which so thoroughly repairs their damage that the cell is healthier after the damage than before.[3][4] It is a form of hormesis, which is described above.[23] In fact, such damage may trigger a mitochondrial defensive response not only in the tissues containing the defective mitochondria, but also distant tissues. Evidence exists which shows that mitohormesis may be able to extend lifespan in mammals, but there is no consensus on this view.[11] For mitohormesis to occur, mitochondria must communicate with the cell's nucleus.[4] They appear to use ROS, among other things, as signals for this communication.[3][4] This productive role for ROS may explain why increased ROS sometimes appears to slow aging, rather than aggravate it. Some scientists have suggested that a certain amount of ROS is beneficial, but any greater amounts are harmful.[3]

Inflammation

Mitochondrial dysfunction can contribute to a chronic background level of inflammation some call "inflammaging".[10] As the name suggests, this problem occurs with aging. Inflammaging has been associated with increased morbidity and mortality, but some researchers have found high levels of pro-inflammatory markers in people over 100 years old. This casts some doubt on whether inflammaging truly harms the elderly.[22] Mitochondrial dysfunction contributes to inflammaging by increasing the cell's ROS levels.[10] Increased ROS modulate the expression and activity of a substance called NF-κB, which leads to inflammation.[22] Mitochondrial dysfunction may also contribute to inflammaging through mtDNA; that is, it may cause mitochondria to release mtDNA, which causes an inflammatory response when the immune system mistakes the mtDNA for pathogens.[8][22] Scientists believe this occurs due to mitochondria's bacterial origins.[22]

Mitochondrial dysfunction in disease

Mitochondrial dysfunction contributes to a number of aging-related health problems.[21] Several examples are described below.

Alzheimer's disease

Alzheimer’s disease (AD) is a disease, more common in the elderly, causing deterioration of cognition and memory due to the progressive and selective loss of neurons in the forebrain and other brain areas.[20][22] There are two competing hypotheses as to its cause. The first is that it results primarily from the accumulation of amyloid-beta proteins in the brain; the second is that it results from mitochondrial dysfunction. On the latter view, mitochondrial dysfunction leaves mitochondria incapable of the functions for which they are necessary, destroying neurons and causing AD. Researchers have found impaired energy metabolism in AD patients, as well as mitochondrial abnormalities in their brains, which gives support to this hypothesis. However, it is not fully accepted as a consensus, and the correlation of these conditions with AD does not prove they are its causes.[22]

Parkinson's disease

Parkinson’s disease (PD) is a movement disorder resulting from degenerative loss of certain brain cells involved with the chemical dopamine, in the brain region called the substantia nigra.[6][8] Its main symptoms are: tremor (trembling) in the hands, arms, legs, trunk, and/or head; stiffness of the limbs and trunk; slow movement; and impaired balance and coordination. Besides these main symptoms, other symptoms may include depression and other emotional changes; difficulty walking, swallowing, chewing, or speaking; urinary problems and constipation; skin problems; and sleep disruptions. Symptoms usually begin gradually and get worse over time, and PD is by far most common in the elderly.[20] Evidence exists which suggests that PD is at least partly caused by mitochondrial dysfunction, though it is not conclusive.[21] Scientists speculate that mitochondrial dysfunction harms ATP production and a process called "calcium buffering" (another function of mitochondria), as well as exacerbating oxidative stress (an imbalance between oxidants and antioxidants).[7][19] These processes cause PD by killing brain cells in the substantia nigra, in theory. Recent evidence also suggests that certain processes controlling the distribution and structure of mitochondria are linked with PD.[7]

Osteoporosis

Osteoporosis is a bone disease that develops when bone mineral density and bone mass decrease, or when the quality or structure of bone changes. This can reduce bones' strength, which can increase their risk of breaking. Osteoporosis can strike at any age, but the risk increases with increasing age.[18] Evidence exists which suggests that mitochondrial dysfunction in osteoblasts (cells which produce bone) and osteoclasts (cells which break down bone) contributes to osteoporosis, by mutating the body's mtDNA.[1][9] Specifically, a study of mice found that mice with biological abnormalities causing them to accumulate mtDNA mutations more quickly lost bone at a faster rate than normal mice. They also showed a reduced bone formation rate, reduced osteoblast population densities, and increased osteoclast population densities, among other differences. Researchers involved in the study argued that similar processes could contribute to human osteoporosis.[9]

COVID-19

Note: the below information is on the relationship between COVID-19 and mitochondrial dysfunction. For information on the relationship between COVID-19 and the aging process in general, see [insert link to COVID-19 Longevity Wiki article here].

COVID-19 is a severe form of pneumonia caused by a virus known as SARS-CoV-2. COVID-19 mainly affects the elderly and is responsible for a global pandemic. Many patients infected with the SARS-CoV-2 virus are asymptomatic or show low intensity symptoms, but around 20% of its victims, mainly elderly people, manifest severe symptoms and a high mortality ratio. Mitochondrial dysfunction is associated with some risk factors for COVID-19, and there is some evidence that it contributes to the disease. Some researchers, for example, have suggested that the chronic inflammation caused by mitochondrial dysfunction is responsible for the severe pneumonia, multi-organ failure, and death which accompany COVID-19.[2] However, as SARS-CoV-2 was discovered relatively recently, and the COVID-19 pandemic is a rapidly changing situation, readers should be cautious about drawing conclusions from current data.

References

# Age-related mitochondrial dysfunction as a key factor in COVID-19 disease. (2020). ''Experimental Gerontology, 142'', 111147. <nowiki>https://doi.org/10.1016/j.exger.2020.111147</nowiki>
# Aunan, J. R., Watson, M. M., Hagland, H. R., & Søreide, K. (2016). Molecular and biological hallmarks of ageing. ''British Journal of Surgery, 103''(2), e29–e46. <nowiki>https://doi.org/10.1002/bjs.10053</nowiki>
# Bárcena, C., Mayoral, P., & Quirós, P. M. (2018). Mitohormesis, an antiaging paradigm. In International Review of Cell and Molecular Biology (Vol. 340, pp. 35–77). Elsevier. <nowiki>https://doi.org/10.1016/bs.ircmb.2018.05.002</nowiki>
# Bell, S. M., Barnes, K., De Marco, M., Shaw, P. J., Ferraiuolo, L., Blackburn, D. J., Venneri, A., & Mortiboys, H. (2021). Mitochondrial dysfunction in alzheimer’s disease: A biomarker of the future? Biomedicines, 9(1). <nowiki>https://doi.org/10.3390/biomedicines9010063</nowiki>
# Buneeva, O., Fedchenko, V., Kopylov, A., & Medvedev, A. (2020). Mitochondrial dysfunction in Parkinson’s disease: Focus on mitochondrial DNA. Biomedicines, 8(12), 591. <nowiki>https://doi.org/10.3390/biomedicines8120591</nowiki>
# Chen, C., Turnbull, D. M., & Reeve, A. K. (2019). Mitochondrial dysfunction in Parkinson’s disease—Cause or consequence? Biology, 8(2). <nowiki>https://doi.org/10.3390/biology8020038</nowiki>
# Dingman, M. (2014, November 15). Know your brain: Substantia nigra. Neuroscientifically Challenged. <nowiki>https://www.neuroscientificallychallenged.com/blog/know-your-brain-substantia-nigra</nowiki>
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