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Hallmarks of aging

2021-06-14T06:41:27Z

Skelpie:

Aging is not a single process but is composed of a complex group of interconnected cellular events. The hallmarks of aging are the basic processes underlying aging in different organisms. These hallmarks are associated with major diseases such as cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. In a now widely-cited [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/ 2013 research paper], nine tentative hallmarks were proposed.

== Genomic instability ==
The genome is the total sum of DNA in our body and becomes damaged over time, and genomic instability leading to age-related problems. DNA which carries the information to make proteins that make up cells and tissues.

DNA damage may be caused by UV radiation, X-ray radiation, chemical toxins such as tobacco. The damage can also occur due to normal chemical reactions in our body, known as metabolism, create products (reactive oxygen species) that damage the DNA.

While the body has evolved repair systems to deal with the DNA damage as it arises and special proteins (enzymes) detect and repair broken strands of the DNA. However, the DNA repair processes are not perfect and errors in the DNA (mutations) arise over time. The body generally deals with these cells containing too many mutations through a kind of programmed cell suicide known as apoptosis. These senescent cells result in further age-related problems.

== Telomere Attrition ==
Telomeres are regions of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. They protect the terminal regions of chromosomal DNA from progressive degradation and ensure the integrity of linear chromosomes by preventing DNA repair systems from mistaking the ends of the DNA strand for a double strand break.

Telomere shortening is associated with aging, mortality and aging-related diseases. Normal aging is associated with telomere shortening in both humans and mice, and studies on genetically modified animal models suggest causal links between telomere erosion and aging. Leonard Hayflick demonstrated that a normal human fetal cell population will divide between 40 and 60 times in cell culture before entering a senescence phase. Each time a cell undergoes mitosis, the telomeres on the ends of each chromosome shorten slightly. Cell division will cease once telomeres shorten to a critical length. This is useful when uncontrolled cell proliferation (like in cancer) needs to be stopped, but detrimental when normally functioning cells are unable to divide when necessary.

An enzyme called telomerase elongates telomeres in gametes and embryonic stem cells. Telomerase deficiency in humans has been linked to several aging-related diseases related to loss of regenerative capacity of tissues. It has also been shown that premature aging in telomerase-deficient mice is reverted when telomerase is reactivated.

== Epigenetic alterations ==
Out of all the genes that make up a genome, only a subset are expressed at any given time. The functioning of a genome depends both on the specific order of its nucleotides (genomic factors), and also on which sections of the DNA chain are spooled on histones and thus rendered inaccessible, and which ones are unspooled and available for transcription ('''epi'''genomic factors). Depending on the needs of the specific tissue type and environment that a given cell is in, histones can be modified to turn specific genes on or off as needed. The profile of where, when and to what extent these modifications occur (the epigenetic profile) changes with aging, turning useful genes off and unnecessary ones on, disrupting the normal functioning of the cell.

As an example, sirtuins are a type of protein deacetylases that promote the binding of DNA onto histones and thus turn unnecessary genes off. These enzymes use NAD as a cofactor. As we age, the level of NAD in our cells decreases and so does the ability of sirtuins to turn off unneeded genes at the right time. Decreasing the activity of sirtuins has been associated with accelerated aging and increasing their activity has been shown to stave off several age-related diseases.

== Loss of proteostasis ==
Proteostasis is the homeostatic process of maintaining all the proteins necessary for the functioning of the cell in their proper shape, structure and abundance. Protein misfolding, oxidation, abnormal cleavage or undesired post-translational modification can create dysfunctional or even toxic proteins or protein aggregates that hinder the normal functioning of the cell. Though these proteins are continually removed and recycled, formation of damaged or aggregated proteins increases with age, leading to a gradual loss of proteostasis. This can be slowed or suppressed by caloric restriction or by administration of rapamycin, both through inhibiting the mTOR pathway.

== Deregulated nutrient-sensing ==
Nutrient sensing is a cell's ability to recognize, and respond to, changes in the concentration of macronutrients such as glucose, fatty acids and amino acids. In times of abundance, anabolism is induced through various pathways, the most well-studied among them the mTOR pathway. When energy and nutrients are scarce, the AMPK receptor senses this and switches off mTOR to conserve resources.

In a growing organism, growth and cell proliferation are important and thus mTOR is upregulated. In a fully grown organism, mTOR-activating signals naturally decline during aging. It has been found that forcibly overactivating these pathways in grown mice leads to accelerated aging and increased incidence of cancer. mTOR inhibition methods like dietary restriction or administering rapamycin have been shown to be one of the most robust methods of increasing lifespan in worms, flies and mice.

== Mitochondrial dysfunction ==
The mitochondrion is the powerhouse of the cell. Different human cells contain from 20 to 30 up to several thousand mitochondria, each one converting carbon (in the form of acetyl-CoA) and oxygen into energy (in the form of ATP) and carbon dioxide.

During aging, the efficiency of mitochondria tends to decrease. The reasons for this are still quite unclear, but several mechanisms are suspected - reduced biogenesis, accumulation of damage and mutations in mitochondrial DNA, oxidation of mitochondrial proteins, and defective quality control by mitophagy.

Dysfunctional mitochondria contribute to aging through interfering with intracellular signaling and triggering inflammatory reactions.

== Cellular senescence ==
''See the full article on [[cellular senescence]].''

Under certain conditions, a cell will exit the cell cycle without dying, instead becoming dormant and ceasing its normal function. This is called cellular senescence. Senescence can be induced by several factors, including telomere shortening, DNA damage and stress. Since the immune system is programmed to seek out and eliminate senescent cells, it might be that senescence is one way for the body to rid itself of cells damaged beyond repair.

The links between cell senescence and aging are several:

* The proportion of senescent cells increases with age.
* Senescent cells secrete inflammatory markers which may contribute to aging.
* Clearance of senescent cells has been found to delay the onset of age-related disorders.

== Stem cell exhaustion ==
Stem cells are undifferentiated or partially differentiated cells that can proliferate indefinitely. For the first few days after fertilization, the embryo consists almost entirely of stem cells. As the fetus grows, the cells multiply, differentiate and assume their appropriate function within the organism. In adults, stem cells are mostly located in areas that undergo gradual wear (intestine, lung, mucosa, skin) or need continuous replenishment (red blood cells, immune cells, sperm cells, hair follicles).

Loss of regenerative ability is one of the most obvious consequences of aging. This is largely because the proportion of stem cells and the speed of their division gradually lowers over time. It has been found that stem cell rejuvenation can reverse some of the effects of aging at the organismal level.

== Altered intracellular communication ==
Different tissues and the cells they consist of need to orchestrate their work in a tightly controlled manner so that the organism as a whole can function. One of the main ways this is achieved is through excreting signal molecules into the blood where they make their way to other tissues, affecting their behavior. The profile of these molecules changes as we age.

One of the most prominent changes in cell signaling biomarkers is "inflammaging", the development of a chronic low-grade inflammation throughout the body with advanced age. The normal role of inflammation is to recruit the body's immune system and repair mechanisms to a specific damaged area for as long as the damage and threat are present. The constant presence of inflammation markers throughout the body wears out the immune system and damages healthy tissue.

It's also been found that senescent cells excrete a specific set of molecules called the SASP (Senescence-Associated Secretory Phenotype) which induce senescence in neighboring cells. Conversely, lifespan-extending manipulations targeting one tissue can slow the aging process in other tissues as well.

Hallmarks of aging

2021-06-14T06:39:57Z

Skelpie: