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What is Aging?

Loss of structure and function in aging.
Figures represent percentage of a given function remaining in an average 75-year-old man compared with that found in an average 30-year-old man, the latter value taken as 100%.
Weight of brain 56%
Blood supply to brain 80
Output of heart at rest 70
Number of glomeruli in kidney 56
Glomerular filtration rate 69
Speed of return to normal pH of blood after displacement 17
Number of taste buds 36
Vital capacity 56
Strength of hand grip 55
Maximum O2 uptake during exercise 40
Number of axons in spinal nerve 63
Velocity of nerve impulse 90
Body weight 88
Aging is the progressive loss of physiological functions that increases the probability of death.

This table gives some data. (These data were acquired a long time ago. Modern techniques might give more accurate figures but the interpretation would be the same.)

The decline in function certainly occurs within cells. This is especially true of cells that are no longer in the cell cycle: Tissue and organs made of cells that are replenished by mitosis throughout life. e.g., show far fewer signs of aging.

In the natural world, very few animals live long enough to show signs of aging.

Random mortality from

kills off most animals long before they begin to show signs of aging.

Even for humans, aging has only become common in recent decades.

At the start of the 20th century, infectious diseases such as pneumonia and influenza caused more deaths in the United States than "organic" diseases like cancer. Now the situation is reversed. The availability of effective weapons against infectious disease (e.g., sanitation, antibiotics, and immunization) has greatly increased the average life span (but not maximum life span) and resulted in "organic" diseases like cardiovascular disease and cancer becoming the most common cause of death.

In 1900, a newborn child in the U.S. could look forward to an average life expectancy of only 47 years. Infectious diseases were the major causes of death, killing most people before they reached an age when aging set in.

Three-quarters of a century later, life expectancy had risen to 73 years and "organic" diseases, including all the diseases of aging, had replaced infectious diseases as the major cause of death. By 2018, the life expectancy in the U.S. had risen to 78.5, and coping with an aging population has become a major economic and social challenge in the U.S. [Link]

Is there a limit to our maximum lifespan? I think so.

While life expectancy continues to rise, it is doing so more slowly. And there has been no increase in maximum lifespan; only more people approaching it. I expect that even the healthiest people will live no longer than ~120 years (the best documented record so far is 122 years). Just as we will never see the 100-meter dash run in 3 seconds, so we are unlikely to see anyone surviving much beyond 120 years.

The graph at right shows four representative survival curves. The vertical axis represents the fraction of survivors at each age (on the horizontal axis).

Organisms with survivorship curves between C and D have no opportunity to show the signs of aging.

Aging in Invertebrates

Invertebrate animals have provided some important clues about the aging process.

Aging in Vertebrates

Some cold-blooded vertebrates: have long life spans if they can survive environmental hazards (giant tortoises are known to have reached 177 years of age).

These animals are cold-blooded and grow so slowly that they will probably succumb to environmental hazards before they stop growing and begin to show signs of aging.

The situation is different for birds and mammals.

They are warm-blooded, grow rapidly to adult size and, if protected from environmental hazards, will show signs of aging.

Why Do We Age?

1. Programmed in our genes?

The pros

The cons

As mentioned above, high early mortality from external causes (e.g. predators) has been linked to early aging (in the survivors) in some animals (but the reverse has been found in others).

These contradictory results do not negate the role of genes in aging, but indicate that other environmental factors (e.g. more food left for the survivors) may skew the outcome.

2. The Inevitable Consequence of an Active Life?

The pros


Resveratrol, is a small molecule found in red wine which appears to activate sirtuins mimicking the effects of calorie restriction. Mice given daily doses of resveratrol while indulging in a high-fat diet get fat but avoid the degenerative changes and shortened life span that normally accompany a high-fat diet. But before rushing out to buy red wine, realize that the doses of resveratrol given to the mice were far higher than could be supplied by drinking it. Studies on the effect of resveratrol on extending life span in yeast, Drosophila and C. elegans have produced mixed results.

Why should calorie restriction delay aging?

No one knows for certain, but some mechanisms might be:

The Free Radical Theory of Aging

But damage to DNA probably is the crucial factor in the decline in cell function with age. [Link]

The DNA of the mitochondria (mtDNA) may be at special risk. ROS are produced as an inevitable byproduct of electron transport in the mitochondria [Link] and thus are generated close to the mtDNA. But the products of these genes are essential for electron transport [Link]. So perhaps a positive feedback loop is generated: ROS -> mutations in electron transport genes reducing their efficiency -> more ROS production.

Supporting evidence:

The cons

3. The Accumulation of Senescent Cells?

Chronological Senescence

Once formed, some cells in a mouse or human are never replaced. A neuron formed during embryonic development may still be functioning at the end of life. However, during its life span, damage to its organelles and DNA [Link] may accumulate resulting in a loss of function. This is called chronological senescence. In other tissues, e.g., blood and epithelia, new cells replace old ones throughout life. But even though new, they may have reduced function because of replicative senescence.

Replicative Senescence

One might expect that cells removed from a mouse or human and placed in culture medium could be cultured indefinitely, but that is not the case.

When human fibroblasts, for example, are placed in culture, they proliferate at first, but eventually a time comes when their rate of mitosis slows and finally stops. The cells continue to live for a while, but cannot pass from G1 to the S phase of the cell cycle. This phenomenon is called replicative senescence. Fibroblasts taken from a young human pass through some 60–80 doublings before they reach replicative senescence.

Why should this be?

Cells — unless they retain the enzyme telomerase — lose DNA from the tips of their chromosomes (telomeres) with each cell division. In general, the telomeres in the cells of old animals are much shorter than those in young animals.

A recent study of short-lived versus long-lived birds showed that telomere shortening was faster in the short-lived species. And one species, a petrel which lives four times as long as other birds of its size, actually has telomeres that grew longer with age.

Most somatic cells of the body cease to express telomerase. However, cells genetically manipulated to express telomerase long after they should have stopped, avoid replicative senescence. Germline cells, e.g., spermatogonia, and some stem cells continue to express the enzyme. Some 95% of cancer cells express telomerase.

If telomeres get too short (less than 13 repeats in human cells), chromosome abnormalities — a hallmark of cancer — occur. Cancer can be avoided if the cell senses this dangerous condition and ceases to divide. So telomere shortening may protect against cancer at the price of cell senescence.

Two proteins encoded by tumor suppressor genes

play pivotal roles in stopping the cell cycle. The result: replicative senescence.

So replicative senescence may be the price we pay for removing cells from the cell cycle before they can accumulate the mutations that would turn them into cancer cells.

The role of the tumor suppressor proteins in replicative senescence is mirrored in the intact animal, at least in mice.

The role of telomerase deficiency in mammalian aging.

Mice whose genes for telomerase have been "knocked out" (either Tert−/− or Terc −/− [Link]) show many of the degenerative changes associated with aging.

In the 6 January 2011 issue of Nature, Mariela Jaskelioff and her colleagues (many of the same team that found the results described in the previous section) report that reactivation of telomerase in aged mice reverses many signs of aging.

Their experimental animals were another telomerase-deficient strain of mice; that is, mice that couldn't produce telomerase even in those cells — "adult" stem cells and cells of the germline — that normally retain telomerase activity. The mice were made by "knocking-in" a gene that prevents any expression of telomere reverse transcriptase (TERT) unless an activating drug is given to the animal. Without the drug, these mice live half as long as normal, and as they get older, they display many signs of aging: BUT, if given the activating drug over a four-week period at a time when degenerative changes were already apparent (25-30 weeks), their deterioration stopped and even partially reversed.

How would replicative senescence of cells lead to the deterioration in structure and function of the aging tissues (e.g., skin) in which they reside? In tissues, e.g., skin and other epithelia, where mitosis must continue throughout life to replace the cells that are lost, the accumulation of senescent cells — incapable of further mitosis — could leading to the characteristic changes of aging in that tissue.

An unavoidable tradeoff?

Some of the data so far suggests that

However, other evidence paints a less-gloomy picture. Mice heterozygous for the p53 tumor suppressor gene (p53+/−) develop many cancers when exposed to ionizing radiation. With only a single copy of this tumor suppressor, a single cell is at great risk of losing the remaining copy ("loss of heterozygosity") and starting the growth of a malignant clone. However, if before being irradiated the mice are given resveratrol — to stimulate the production of the anti-aging SIRT1 protein — the incidence of some cancers is reduced and the mice live longer before succumbing to their tumors.

4. The Accumulation of Genetic Errors?

Effect of radiation on aging.
These mice are all 14 months old. As young adults, nine mice were given sublethal doses of radiation and nine others were left as untreated controls. The control mice (left) are still sleek and vigorous at 14 months, while six of the irradiated mice have died and the remaining three show signs of extreme aging (right). [Research photographs of Dr. Howard J. Curtis.]

Peto’s Paradox

The risk of dying from cancer increases with age (graph) not only for humans but also for other mammals. In fact most mammals living protected lives ultimately die of cancer — usually with signs of aging.

Cancer is a genetic disease caused by mutations in oncogenes and tumor suppressor genes.

But this raises a paradox.

If mutations are the ultimate cause of cancer, and perhaps of aging and death, then how have large animals and long-lived animals (often they are the same) managed? Large animals have more cells at risk of mutations (a human has some 1,000 more cells than a mouse) and the cells of long-lived animals have had more time to accumulate mutations (the lifespan of humans is some 30 times that of a mouse). This puzzle is called Peto’s paradox after the epidemiologist who first wrote about it.

But neither prediction turns out to be true.

In a monumental study of 191 species of zoo mammals (thus not dying early from predation, starvation, etc.) found that the risk of dying from cancer

(Reported by Vincze et al. Nature, 13 January 2022)

How could this be?

In another study (reported by Cagan et al., Nature, 21 April 2022), genome sequencing of 16 species of mammal representing

found that the number of mutations in their cells at the end of their lives was remarkably similar from species to species. The rat had the fewest (1,828); the cat the most (5,379) — only a 3-fold difference. All the other animals fell within this range.

What could be the mechanism that permits the cells of a mammal at the end of a long life to have no more mutations than found in mammals with a brief lifespan?

It is estimated that every day across the 6 billion base pairs in a typical mammal cell, intrinsic (e.g. ROS) and extrinsic (e.g., radiation) agents damage each cell’s DNA at some 100,000 places. But almost always these alterations are quickly repaired by the complex machinery of DNA repair. So we must define a mutation as an unrepaired lesion in DNA.

So, do long-lived animals have more efficient DNA repair than short-lived ones?

Why is a mouse as old at 2 years as a human at 70?

Correlation between life span and the relative effectiveness of DNA repair in cells of certain mammals. In each case, cultured cells were irradiated with ultraviolet light and then the efficiency with which they repaired their DNA was determined. (From the work of R. W. Hart and R. B. Setlow, 1974.)
Species Average life span, yr Relative effectiveness of DNA repair
Human 70 50
Elephant 60 47
Cow 30 43
Hamster 4 26
Rat 3 13
Mouse 2 9
Shrew 1 8

If aging represents the inevitable consequence of a failure of DNA repair, why does it occur so much sooner in some mammals (e.g., mice) than in others (e.g., elephants and humans)?

The answer probably lies in the risk of death from external factors (e.g., predation, starvation, cold) in that species.

As noted above, few small mammals ever age because they die early of external causes. These animals are r-strategists, putting their energy into quickly

There is no selective advantage for them to invest in the machinery of efficient DNA repair because they are going to die before mutations become a problem.

Humans, in contrast, are K-strategists. They
Link to a discussion of r-strategists and K-strategists.

Small wonder, then, that evolution in humans (and other long-lived mammals) has selected for genes promoting efficient DNA repair.

The table shows that the efficiency of DNA repair is directly correlated with life span in a variety of mammals.

It is also correlated with lifespan in Pacific rockfishes.


Some 120 species of rockfishes live in the Pacific Ocean. They are all closely related, belonging to the same genus (Sebastes). But they differ greatly in their maximum life spans which range from as little as 11 years to as many as 200 years. Genome sequencing of representative short- and long-lived species revealed that the long-lived species had more genes involved in DNA repair than the short-lived ones. The long-lived genomes were enriched in genes for

This work was reported by Kolora et al. in Science, 12 November 2021.

If increased efficiency of DNA repair is correlated with longer life, is the reverse true? In fact a positive correlation between defects in DNA repair and aging is found in a number of human ailments.

Clues from Premature Aging Syndromes

Humans suffer from a number of rare genetic diseases that, among other things, produce signs of premature aging, e.g., gray hair, wrinkled skin, and shortened life span. In most cases, the mutated genes are ones that have roles to play in maintaining the integrity of the genome, that is, in DNA repair.

So these syndromes suggest that aging may be the consequence not so much of mutations in general, but of mutations in those genes whose products are essential for the error-free of all genes.

Clues from the Transcriptome of Aging Brains

A group of Harvard researchers reported (in the 26 June 2004 issue of Nature) the results of their study of gene expression in the human brain.

They extracted the RNA from autopsied brain tissue of 30 people who had died at ages ranging from 26 to 106. They analyzed the RNA with DNA chips looking for the level of activity of some 11,000 different genes (the transcriptome). A clear pattern emerged.

The level of activity of some 400 genes changed over time.

The transition from the youthful transcriptome to the transcriptome of the aged brain occurred at varying times from as young as 42 to as old at 73.

A study of individual heart muscle cells in young and old mice (Bahar, R. et al., Nature, 22 June 2006) showed that the transcriptome of young cells was quite uniform from cell to cell but that of aged cells was highly variable from one cell to another. Variable gene expression from one cell to the next in a single tissue might well lead to defects in the functioning of that tissue.


Examining the various factors that have been implicated in the aging process suggests that most —perhaps all — are interrelated.

may all play important roles. So the factors described above are by no means mutually exclusive.

The scheme on the right attempts to show how various factors involved in aging interact. Key players are

Stimulatory interactions are shown with blue arrows; inhibitory interactions are shown in red.


Because of the association between telomere shortening and aging, two companies have begun (in 2011) to offer tests of telomere length. How such tests might be useful to the people asking for them remains to be seen.

The Hallmarks of Aging

In the 6 June 2013 issue of Cell, an international group of scientists developed a list of 9 features that characterize aging in animals. (This effort to bring order to such a complex subject is reminiscent of earlier papers in the same journal, The Hallmarks of Cancer.)

They expected that each hallmark would meet at least two of three criteria.
  1. It should be characteristic of normal aging.
  2. Increased expression of the hallmark should result in faster aging.
  3. Efforts to reduce expression of the hallmark should prolong a healthy lifespan ("healthspan").

The 9 hallmarks.

1. Genomic Instability
Meeting the criteria:

  1. Aged cells contain more DNA damage than young ones.
  2. Agents that increase unrepaired damage to DNA, including chromosomal damage (e.g., aneuploidy), hasten aging (as shown above).
  3. Limited evidence that treatments that reduce, for example, chromosome missegregation, prolong healthspan.

2. Telomere Attrition
Meeting the criteria:

  1. The chromosomes of aged cells have shorter telomeres than those of young cells (see above).
  2. Telomerase-deficient mice show premature aging.
  3. Treatments that reactivate telomerase in normal mice delay aging.
3. Epigenetic Alterations
Meeting the criteria:
  1. The patterns of DNA methylation and histone modifications changes as a mammal ages.
    As we humans age, the DNA in our cells accumulates an ever-increasing number of epigenetic changes as measured by the methylation of CpGs. This is true for a wide variety of cell types even those that have been formed recently; that is, the number of epigenetic changes reflects the age of the donor not the age of the cell. The correlation is so good that analysis of these changes in a cell can predict the donor's age sometimes within a matter of months.
  2. Mice that are deficient in the sirtuin SIRT6, an enzyme that deacetylates histones, age more rapidly than normal.
  3. Treatments that increase the activity of sirtuins increase healthspan in mice.
4. Loss of Proteostasis
Proteostasis is the homeostasis of the proteome — the proper balance of the synthesis and degradation of proteins in the cell.
Meeting the criteria:
  1. The clearance of denatured (unfolded) proteins by autophagy and proteasomes, as well as the ability to refolded them with chaperones, all decline with age. The result: toxic protein aggregates that accumulate in aged cells.
  2. Mutant mice with defective chaperone activity age more quickly.
  3. Transgenic Drosophila and C. elegans that overexpress chaperones have increased life spans.
5. Derugulated Nutrient Sensing
Meeting the criteria:
  1. The nutrient sensor TOR ("target of rapamycin"), which promotes anabolism, increases during normal aging (and produces obesity, at least in mice).
  2. Increased activity of TOR accelerates aging in mice.
  3. Examples:
6. Mitochondrial Dysfunction
Meeting the criteria:
  1. The production and efficiency of mitochondria decreases in aging, otherwise normal, mice.
  2. Deleterious mutations in mitochondrial DNA and other defects in mitochondrial function all accelerate aging in mice.
  3. No compelling evidence yet that treatments to improve mitochondrial function increase life span.
7. Cellular Senescence
Meeting the criteria:
  1. Replicative senescence (cells no longer able to enter the cell cycle) sets in much sooner in the cells of aged animals than it does in young animals.
  2. Mice engineered to express abnormally-high levels of p53, a protein that blocks entry into the cell cycle, show many signs of premature aging.
  3. In mice, eliminating senescent cells prevents (in young mice) and partially reverses (in older mice) some of the signs of aging such as cataracts, and loss of adipose tissue and skeletal muscle mass.
8. Stem Cell Exhaustion
Meeting the criteria:
  1. The proliferative capacity of adult stem cells declines with age in the tissues that have been examined.
  2. Deliberately exhausting the pool of stem cells in the Drosophila intestine leads to premature aging.
  3. Transplantation of stem cells from young mice into aged mice improves the degenerative changes of aging and prolongs their life.
9. Altered Intercellular Communication

All cells respond to chemical signals in their environment. These include cytokines secreted by nearby cells (paracrine stimulation).

Meeting the criteria:
  1. Inflammation in various tissues — mediated by the secretion of a variety of cytokines — increases in the aged.
  2. Genetically engineered mice that are unable to down-regulate the mRNAs synthesizing pro-inflammatory cytokines show accelerated aging.
  3. Inhibition of the pro-inflammatory cytokine NF-κB delays aging in mice. Even such a simple anti-inflammatory agent as aspirin seems to prolong life in mice.

Relationships of the Hallmarks

An Elixir of Youth?

Despite years of research, only three interventions have been discovered that slow the aging process and/or prolong life.
  1. Calorie Restriction (CR). Works in all animals tested. [Link]
  2. Rapamycin. Extends lifespan in mice, Drosophila, and C. elegans but does not appear to reverse or even halt the degenerative changes of aging.
  3. Parabiosis. When the circulatory system of a young mouse is joined to that of an old mouse (the technique is called parabiosis), various tissues in the old mouse, e.g., its skeletal muscle, cardiac muscle, liver, and central nervous system, become rejuvenated. A promising candidate for mediating this effect is a protein called GDF11 ("Growth Differentiation Factor 11"). (GDF11 is also known as BMP-11). Injections of recombinant GDF11 are almost as effective as parabiosis. GDF11 probably acts by stimulating the activity of stem cells. However, there is no evidence yet that it increases the lifespan of the mice.

Aging in Unicellular Organisms

It used to be thought that many unicellular organisms, such as yeast and bacteria, were immortal; that is, they If true, every time a cell divides, the two daughter cells would be identical in all respects to the parent (symmetrical division).

But at least for yeast and E. coli, this is not the case.

Yeast cells do age and, as discussed above, have proved useful for studying the aging process. Placing a single yeast cell on solid medium and removing its daughter (the bud) each time one is produced, it turns out that the number of times the mother cell can form a new bud by mitosis is limited. After producing a bud some 20–30 times, the mother cell shows a number of harmful cellular changes (e.g., defective mitochondria) and dies.

But, at least early in her life, the buds are born with the potential of a full life span. So the mitotic division must be asymmetrical with the properties of the bud different from those of its parent. Several mechanisms by which this occurs have now been demonstrated.

Asymmetric division in stem cells. Stem cells are cells that divide asymmetrically to produce a daughter cell that goes on to differentiate and a daughter cell that remains a stem cell [More]. A number of examples have been found — in Drosophila and in mammals — where aging stem cells preferentially deposit their damaged cellular components, e.g. aggregated proteins, in the daughter that will go on to differentiate while keeping undamaged components in the daughter that will remain a stem cell. So like yeast, these stem cells have a mechanism that preferentially protects the "immortal" cell from the inevitable effects of aging.

Aging in E. coli

A similar aging phenomenon has been found in E. coli. When E. coli divides, a septum forms in the middle of the dividing cell and then the two daughter cells are pinched apart. As the cell wall seals the break, the two daughter cells end up with one "old" end and one newly-formed end. When the two daughters go on to divide, the process is repeated. The original old ends gets passed on from generation to generation (rather like immortal strands of DNA).

The diagram shows how during cell division, two new poles are formed, one in each of the progeny cells (new poles shown in green for the first generation; magenta for the second). The other ends of those cells were formed during a previous division.

It has been shown (Stewart EJ, Madden R, Paul G, Taddei F (2005) Aging and Death in an Organism That Reproduces by Morphologically Symmetric Division. PLoS Biol 3(2): e45 doi:10.1371/journal.pbio.0030045) that the cells that inherit an increasingly old pole exhibit a diminished growth rate, decreased offspring production, and an increased incidence of death.

So it appears that the phenomenon — characteristic of all multicellular organisms — of an aging and mortal soma producing germplasm (sperm and eggs) that starts a new youthful generation may have its counterpart in unicellular organisms. Perhaps no single cell can escape the ravages of time on the integrity of its organelles and the molecules.

Aging in Plants

Annuals and Biennials

Annuals, such as many grasses and "weeds" Biennials follow the same pattern, but take two years to do it.

This pattern in clearly programmed in the genes. Even with plentiful moisture, soil minerals, sunlight, and warm temperatures, the plants age and die.


The situation is quite different in perennials. Throughout their lives, woody perennials (trees) produce new vascular tissue, leaves, and flowers each year. They do not show marked signs of aging, although their rate of growth may decline over the years. Finally, disease or inability to support their ever-increasing size against wind or snow load lead to their death.

This picture (courtesy of Walter Gierasch) is of bristlecone pines (Pinus longaeva) growing in the White Mountains of eastern California. Tree-ring analysis shows that some of these trees are more than 4000 years old. But note that no living cells in the tree are more than a few years old.

Even so, how have long-lived plants like these avoided the accumulation — over years of DNA replication as their cells divided — of deleterious mutations that would reduce fitness and life span? Perhaps it is because the cells in plant meristems, where all growth begins [View] are stem cells which divide slowly and like all stem cells, asymmetrically; that is, producing one daughter that will remain a stem cell and one that will begin a phase of rapid mitosis and eventually differentiate into the mature tissues of the plant. If (and this is as yet only a speculation) the division of a meristematic stem cell is asymmetric with respect to the segregation of DNA strands; that is, the stem cell retains the immortal strands of DNA while the cell destined to produce more tissues receives the newly-replicated strands, this would provide an additional mechanism to protect the genome as the years go by.

A Bottom Line?

If you have made it this far, you must agree that aging is an extremely complex process. But one phenomenon seems to lie at the heart of all the others:
the accumulation of

unrepaired DNA damage

in the cells of which the organism is made.

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15 March 2024