Senescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism. There are a number of theories as to why senescence occurs; for example, some posit it is programmed by gene expression changes, others that it is the cumulative damage caused by biological processes. Senescence is not the inevitable fate of all organisms. A variety of organisms, including some cold-blooded animals, have negligible senescence. This fact, and recent scientific successes in rejuvenation and extending the lifespan of model animals[1] (mice, 2.5 times;[2] yeast, 15 times; nematodes, 10 times) have inspired hope that aging may similarly be canceled, reversed or at least significantly delayed in humans.
The word senescence is derived from the Latin word senex, meaning old man, old age, or advanced in age.
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Cellular senescence is the phenomenon by which normal diploid cells lose the ability to divide, normally after about 50 cell divisions in vitro. Some cells become senescent after fewer replications cycles as a result of DNA double strand breaks, toxins, etc. This phenomenon is also known as "replicative senescence", the "Hayflick phenomenon", or the Hayflick limit in honour of Dr. Leonard Hayflick, co-author with Paul Moorhead, of the first paper describing it in 1961.[3]. In response to DNA damage (including shortened telomeres), cells either age or self-destruct (apoptosis, programmed cell death) if the damage cannot be easily repaired. In this 'cellular suicide', the death of one cell, or more, may benefit the organism as a whole. For example, in plants the death of the water-conducting xylem cells (tracheids and vessel elements) allows the cells to function more efficiently and so deliver water to the upper parts of a plant. The ones that do not self-destruct remain until destroyed by outside forces.
Organismal senescence is the aging of whole organisms. In general, aging is characterized by the declining ability to respond to stress, increased homeostatic imbalance, and increased risk of aging-associated diseases. Death is the ultimate consequence of aging, though "old age" is not a scientifically recognized cause of death because there is always a specific proximal cause, such as cancer, heart disease, or liver failure. Aging of whole organisms is therefore a complex process that can be defined as "a progressive deterioration of physiological function, an intrinsic age-related process of loss of viability and increase in vulnerability".[4]
Differences in maximum life span among species correspond to different "rates of aging". For example, inherited differences in the rate of aging make a mouse elderly at 3 years and a human elderly at 80 years.[5] These genetic differences affect a variety of physiological processes, including the efficiency of DNA repair, antioxidant enzymes, and rates of free radical production.
Senescence of the organism gives rise to the Gompertz–Makeham law of mortality, which says that mortality rate rises rapidly with age.
Some animals, such as some reptiles and fish, age slowly (negligible senescence) and exhibit very long lifespans. Some even exhibit "negative senescence", in which mortality falls with age, in disagreement with the Gompertz–Makeham "law".[6]
Whether replicative senescence (Hayflick limit) plays a causative role in organismal aging is at present an active area of investigation.
The process of senescence is complex, and may derive from a variety of different mechanisms and exist for a variety of different reasons. However, senescence is not universal, and scientific evidence suggests that cellular senescence evolved in certain species because it prevents the onset of cancer. In a few simple species, such as Hydra, senescence is negligible and cannot be detected. All such species have no "post-mitotic" cells; they reduce the effect of damaging free radicals by cell division and dilution. They are biologically immortal but not immortal in the traditional sense as they will eventually fall prey to trauma or disease. Moreover, average lifespans can vary greatly within and between species. This suggests that both genetic and environmental factors contribute to aging.
In general, theories that explain senescence have been divided between the programmed and stochastic theories of aging. Programmed theories imply that aging is regulated by biological clocks operating throughout the lifespan. This regulation would depend on changes in gene expression that affect the systems responsible for maintenance, repair, and defense responses. The Reproductive-Cell Cycle Theory suggests that aging is caused by changes in hormonal signaling over the lifespan[7]. Stochastic theories blame environmental impacts on living organisms that induce cumulative damage at various levels as the cause of aging, examples of which ranging from damage to DNA, damage to tissues and cells by oxygen radicals (widely known as free radicals countered by the even more well-known antioxidants), and cross-linking.
However, aging is seen as a progressive failure of homeodynamics (homeostasis) involving genes for the maintenance and repair, stochastic events leading to molecular damage and molecular heterogeneity, and chance events determining the probability of death. Since complex and interacting systems of maintenance and repair comprise the homeodynamic (old term: homeostasis) space of a biological system, aging is considered to be a progressive shrinkage of homeodynamic space mainly due to increased molecular heterogeneity.
A gene can be expressed at various stages of life. Therefore, natural selection can support lethal and harmful alleles, if their expression occurs after reproduction. Senescence may be the product of such selection.[8][9][10] In addition, aging is believed to have evolved because of the increasingly smaller probability of an organism still being alive at older age, due to predation and accidents, both of which may be random and age-invariant. It is thought that strategies that result in a higher reproductive rate at a young age, but shorter overall lifespan, result in a higher lifetime reproductive success and are therefore favoured by natural selection. In essence, aging is, therefore, the result of investing resources in reproduction, rather than maintenance of the body (the "Disposable Soma" theory[11]), in light of the fact that accidents, predation, and disease will eventually kill the organism no matter how much energy is devoted to repair of the body. Various other theories of aging exist, and are not necessarily mutually exclusive.
The geneticist J. B. S. Haldane wondered why the dominant mutation that causes Huntington's disease remained in the population, and why natural selection had not eliminated it. The onset of this neurological disease is (on average) at age 45 and is invariably fatal within 10–20 years. Haldane assumed that, in human prehistory, few survived until age 45. Since few were alive at older ages and their contribution to the next generation was therefore small relative to the large cohorts of younger age groups, the force of selection against such late-acting deleterious mutations was correspondingly small. However, if a mutation affected younger individuals, selection against it would be strong. Therefore, late-acting deleterious mutations could accumulate in populations over evolutionary time through genetic drift. This principle has been demonstrated experimentally. And it is these later-acting deleterious mutations that are believed to allow—even cause—age-related mortality.
Peter Medawar formalised this observation in his mutation accumulation theory of aging.[12][13] "The force of natural selection weakens with increasing age—even in a theoretically immortal population, provided only that it is exposed to real hazards of mortality. If a genetic disaster… happens late enough in individual life, its consequences may be completely unimportant". The 'real hazards of mortality' are, in typical circumstances, predation, disease, and accidents. So, even an immortal population, whose fertility does not decline with time, will have fewer individuals alive in older age groups. This is called 'extrinsic mortality'. Young cohorts, not depleted in numbers yet by extrinsic mortality, contribute far more to the next generation than the few remaining older cohorts, so the force of selection against late-acting deleterious mutations, which affect only these few older individuals, is very weak. The mutations may not be selected against, therefore, and may spread over evolutionary time into the population.
The major testable prediction made by this model is that species that have high extrinsic mortality in nature will age more quickly and have shorter intrinsic lifespans. This is borne out among mammals, the best-studied in terms of life history. There is a correlation among mammals between body size and lifespan, such that larger species live longer than smaller species under controlled/optimum conditions, but there are notable exceptions. For instance, many bats and rodents are of similar size, yet bats live much longer. For instance, the little brown bat, half the size of a mouse, can live 30 years in the wild. A mouse will only live 2–3 years even under optimum conditions. The explanation is that bats have fewer predators, and therefore low extrinsic mortality. More individuals survive to later ages, so the force of selection against late-acting deleterious mutations is stronger. Fewer late-acting deleterious mutations equates to slower aging and therefore a longer lifespan. Birds are also warm-blooded and are similar in size to many small mammals, yet often live 5–10 times as long. They have less predation pressure than ground-dwelling mammals. Seabirds, which, in general, have the fewest predators of all birds, live longest.
When examining the body-size vs. lifespan relationship, one also observes that predatory mammals tend to live longer than prey mammals in a controlled environment, such as a zoo or nature reserve. The explanation for the long lifespans of primates (such as humans, monkeys, and apes) relative to body size is that their intelligence, and often their sociality, help them avoid becoming prey. Being a predator, being smart, and working together all reduce extrinsic mortality.
Another evolutionary theory of aging was proposed by George C. Williams[14] and involves antagonistic pleiotropy. A single gene may affect multiple traits. Some traits that increase fitness early in life may also have negative effects later in life. But, because many more individuals are alive at young ages than at old ages, even small positive effects early can be strongly selected for, and large negative effects later may be very weakly selected against. Williams suggested the following example: Perhaps a gene codes for calcium deposition in bones, which promotes juvenile survival and will therefore be favored by natural selection; however, this same gene promotes calcium deposition in the arteries, causing negative effects in old age. Thus, harmful biological changes in old age may result from selection for pleiotropic genes that are beneficial early in life but harmful later on. In this case, fitness is relatively high when Fisher's reproductive value is high and relatively low when Fisher's reproductive value is low.
A number of genetic components of aging have been identified using model organisms, ranging from the simple budding yeast Saccharomyces cerevisiae to worms such as Caenorhabditis elegans and fruit flies (Drosophila melanogaster). Study of these organisms has revealed the presence of at least two conserved aging pathways.
One of these pathways involves the gene Sir2, a NAD+-dependent histone deacetylase. In yeast, Sir2 is required for genomic silencing at three loci: The yeast mating loci, the telomeres and the ribosomal DNA (rDNA). In some species of yeast, replicative aging may be partially caused by homologous recombination between rDNA repeats; excision of rDNA repeats results in the formation of extrachromosomal rDNA circles (ERCs). These ERCs replicate and preferentially segregate to the mother cell during cell division, and are believed to result in cellular senescence by titrating away (competing for) essential nuclear factors. ERCs have not been observed in other species (nor even all strains of the same yeast species) of yeast (which also display replicative senescence), and ERCs are not believed to contribute to aging in higher organisms such as humans (they have not been shown to accumulate in mammals in a similar manner to yeast). Extrachromosomal circular DNA (eccDNA) has been found in worms, flies, and humans. The origin and role of eccDNA in aging, if any, is unknown.
Despite the lack of a connection between circular DNA and aging in higher organisms, extra copies of Sir2 are capable of extending the lifespan of both worms and flies (though, in flies, this finding has not been replicated by other investigators, and the activator of Sir2 resveratrol does not reproducibly increase lifespan in either species[15]). Whether the Sir2 homologues in higher organisms have any role in lifespan is unclear, but the human SIRT1 protein has been demonstrated to deacetylate p53, Ku70, and the forkhead family of transcription factors. SIRT1 can also regulate acetylates such as CBP/p300, and has been shown to deacetylate specific histone residues.
RAS1 and RAS2 also affect aging in yeast and have a human homologue. RAS2 overexpression has been shown to extend lifespan in yeast.
Other genes regulate aging in yeast by increasing the resistance to oxidative stress. Superoxide dismutase, a protein that protects against the effects of mitochondrial free radicals, can extend yeast lifespan in stationary phase when overexpressed.
In higher organisms, aging is likely to be regulated in part through the insulin/IGF-1 pathway. Mutations that affect insulin-like signaling in worms, flies, and the growth hormone/IGF1 axis in mice are associated with extended lifespan. In yeast, Sir2 activity is regulated by the nicotinamidase PNC1. PNC1 is transcriptionally upregulated under stressful conditions such as caloric restriction, heat shock, and osmotic shock. By converting nicotinamide to niacin, nicotinamide is removed, inhibiting the activity of Sir2. A nicotinamidase found in humans, known as PBEF, may serve a similar function, and a secreted form of PBEF known as visfatin may help to regulate serum insulin levels. It is not known, however, whether these mechanisms also exist in humans, since there are obvious differences in biology between humans and model organisms.
Sir2 activity has been shown to increase under calorie restriction. Due to the lack of available glucose in the cells, more NAD+ is available and can activate Sir2. Resveratrol, a stilbenoid found in the skin of red grapes, was reported to extend the lifespan of yeast, worms, and flies (the lifespan extension in flies and worms have proved irreproducible by independent investigators[15]). It has been shown to activate Sir2 and therefore mimics the effects of calorie restriction, if one accepts that caloric restriction is indeed dependent on Sir2.
Gene expression is imperfectly controlled, and it is possible that random fluctuations in the expression levels of many genes contribute to the aging process as suggested by a study of such genes in yeast.[16] Individual cells, which are genetically identical, none-the-less can have substantially different responses to outside stimuli, and markedly different lifespans, indicating the epigenetic factors play an important role in gene expression and aging as well as genetic factors.
According to the GenAge database of aging-related genes there are over 700 genes associated with aging in model organisms: 555 in the soil roundworm (Caenorhabditis elegans), 87 in the bakers' yeast (Saccharomyces cerevisiae), 75 in the fruit fly (Drosophila melanogaster) and 68 in the mouse (Mus musculus).[17] The following is a list of genes connected to longevity through research on model organisms:
| Podospora | Saccharomyces | Caenorhabditis | Drosophila | Mus |
|---|---|---|---|---|
| grisea | LAG1 | daf-2 | sod1 | Prop-1 |
| LAC1 | age-1/daf-23 | cat1 | p66shc (Not independently verified) | |
| pit-1 | Ghr | |||
| RAS1 | daf-18 | mth | mclk1 | |
| RAS2 | akt-1/akt-2 | |||
| PHB1 | daf-16 | |||
| PHB2 | daf-12 | |||
| CDC7 | ctl-1 | |||
| BUD1 | old-1 | |||
| RTG2 | spe-26 | |||
| RPD3 | clk-1 | |||
| HDA1 | mev-1 | |||
| SIR2 | ||||
| aak-2 | ||||
| SIR4-42 | ||||
| UTH4 | ||||
| YGL023 | ||||
| SGS1 | ||||
| RAD52 | ||||
| FOB1 |
As noted above, senescence is not universal, and senescence is not observed in single-celled organisms that reproduce through the process of cellular mitosis.[18] Moreover, cellular senescence is not observed in several organisms, including perennial plants, sponges, corals, and lobsters. In those species where cellular senescence is observed, cells eventually become post-mitotic when they can no longer replicate themselves through the process of cellular mitosis; i.e., cells experience replicative senescence. How and why some cells become post-mitotic in some species has been the subject of much research and speculation, but (as noted above) it is widely believed that cellular senescence evolved as a way to prevent the onset and spread of cancer. Somatic cells that have divided many times will have accumulated DNA mutations and would therefore be in danger of becoming cancerous if cell division continued.
Lately, the role of telomeres in cellular senescence has aroused general interest, especially with a view to the possible genetically adverse effects of cloning. The successive shortening of the chromosomal telomeres with each cell cycle is also believed to limit the number of divisions of the cell, thus contributing to aging. There have, on the other hand, also been reports that cloning could alter the shortening of telomeres. Some cells do not age and are, therefore, described as being "biologically immortal". It is theorized by some that when it is discovered exactly what allows these cells, whether it be the result of telomere lengthening or not, to divide without limit that it will be possible to genetically alter other cells to have the same capability. It is further theorized that it will eventually be possible to genetically engineer all cells in the human body to have this capability by employing gene therapy and, therefore, stop or reverse aging, effectively making the entire organism potentially immortal.
The length of the telomere strand has senescence effects, telomere shortening activate extensive alterations in alternative RNA splicing that produce senescence toxins such as progerin that degrades the tissue and makes it more susceptible to failure.[19]
Cancer cells are usually immortal. In about 85% of tumors, this evasion of cellular senescence is the result of up-activation of their telomerase genes.[20] This simple observation suggests that reactivation of telomerase in healthy individuals could greatly increase their cancer risk.
Whether cell senescence plays any role in organismal aging is at present unknown, and is an active area of investigation. Mouse mutants lacking telomerase do not immediately show accelerated aging.
One of the earliest aging theories was the Rate of Living Hypothesis described by Raymond Pearl in 1928[21](based on earlier work by Max Rubner), which states that fast basal metabolic rate corresponds to short maximum life span.
While there may be some validity to the idea that for various types of specific damage detailed below that are by-products of metabolism, all other things being equal, a fast metabolism may reduce lifespan, in general this theory does not adequately explain the differences in lifespan either within, or between, species. Calorically-restricted animals process as much, or more, calories per gram of body mass, as their ad libitum fed counterparts, yet exhibit substantially longer lifespans. . Similarly, metabolic rate is a poor predictor of lifespan for birds, bats and other species that, it is presumed, have reduced mortality from predation, and therefore have evolved long lifespans even in the presence of very high metabolic rates.[22] More recently, it was shown that, when modern statistical methods for correcting for the effects of body size and phylogeny are employed, metabolic rate does not correlate with longevity in mammals or birds.[23] (For a critique of the Rate of Living Hypothesis see Living fast, dying when?[24])
With respect to specific types of chemical damage caused by metabolism, it is suggested that damage to long-lived biopolymers, such as structural proteins or DNA, caused by ubiquitous chemical agents in the body such as oxygen and sugars, are in part responsible for aging. The damage can include breakage of biopolymer chains, cross-linking of biopolymers, or chemical attachment of unnatural substituents (haptens) to biopolymers.
Under normal aerobic conditions, approximately 4% of the oxygen metabolized by mitochondria is converted to superoxide ion, which can subsequently be converted to hydrogen peroxide, hydroxyl radical and eventually other reactive species including other peroxides and singlet oxygen, which can, in turn, generate free radicals capable of damaging structural proteins and DNA. Certain metal ions found in the body, such as copper and iron, may participate in the process. (In Wilson's disease, a hereditary defect that causes the body to retain copper, some of the symptoms resemble accelerated senescence.) These processes are termed oxidative damage and are linked to the benefits of nutritionally derived polyphenol antioxidants .
Sugars such as glucose and fructose can react with certain amino acids such as lysine and arginine and certain DNA bases such as guanine to produce sugar adducts, in a process called glycation. These adducts can further rearrange to form reactive species, which can then cross-link the structural proteins or DNA to similar biopolymers or other biomolecules such as non-structural proteins. People with diabetes, who have elevated blood sugar, develop senescence-associated disorders much earlier than the general population, but can delay such disorders by rigorous control of their blood sugar levels. There is evidence that sugar damage is linked to oxidant damage in a process termed glycoxidation.
Free radicals can damage proteins, lipids or DNA. Glycation mainly damages proteins. Damaged proteins and lipids accumulate in lysosomes as lipofuscin. Chemical damage to structural proteins can lead to loss of function; for example, damage to collagen of blood vessel walls can lead to vessel-wall stiffness and, thus, hypertension, and vessel wall thickening and reactive tissue formation (atherosclerosis); similar processes in the kidney can lead to renal failure. Damage to enzymes reduces cellular functionality. Lipid peroxidation of the inner mitochondrial membrane reduces the electric potential and the ability to generate energy. It is probably no accident that nearly all of the so-called "accelerated aging diseases" are due to defective DNA repair enzymes.
It is believed that the impact of alcohol on aging can be partly explained by alcohol's activation of the HPA axis, which stimulates glucocorticoid secretion, long-term exposure to which produces symptoms of aging.[25]
Reliability theory suggests that biological systems start their adult life with a high load of initial damage. Reliability theory is a general theory about systems failure. It allows researchers to predict the age-related failure kinetics for a system of given architecture (reliability structure) and given reliability of its components. Reliability theory predicts that even those systems that composed entirely of non-aging elements (with a constant failure rate) will nevertheless deteriorate (fail more often) with age, if these systems are redundant in irreplaceable elements. Aging, therefore, is a direct consequence of systems.
Reliability theory also predicts the late-life mortality deceleration with subsequent leveling-off, as well as the late-life mortality plateaus, as an inevitable consequence of redundancy exhaustion at extreme old ages. The theory explains why mortality rates increase exponentially with age (the Gompertz law) in many species, by taking into account the initial flaws (defects) in newly formed systems. It also explains why organisms "prefer" to die according to the Gompertz law, while technical devices usually fail according to the Weibull (power) law. Reliability theory allows to specify conditions when organisms die according to the Weibull distribution: Organisms should be relatively free of initial flaws and defects. The theory makes it possible to find a general failure law applicable to all adult and extreme old ages, where the Gompertz and the Weibull laws are just special cases of this more general failure law. The theory explains why relative differences in mortality rates of compared populations (within a given species) vanish with age (compensation law of mortality), and mortality convergence is observed due to the exhaustion of initial differences in redundancy levels.
Recently, a kind of early senescence has been alleged to be a possible unintended outcome of early cloning experiments. The issue was raised in the case of Dolly the sheep, following her death from a contagious lung disease. The claim that Dolly's early death involved premature senescence has been vigorously contested,[26] and Dolly's creator, Dr. Ian Wilmut has expressed the view that her illness and death were probably unrelated to the fact that she was a clone.
A set of rare hereditary (genetic) disorders, each called progeria, has been known for some time. Sufferers exhibit symptoms resembling accelerated aging, including wrinkled skin. The cause of Hutchinson–Gilford progeria syndrome was reported in the journal Nature in May 2003. This report suggests that DNA damage, not oxidative stress, is the cause of this form of accelerated aging.
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