This article is about the aging of whole organisms including animals. For aging specifically in humans, see
Aging. For plants, see
Plant senescence. For cells that stop dividing, see
Cellular senescence. For bacteria, see
Bacterial senescence.
Environmental factors may affect
aging – for example, overexposure to
ultraviolet radiation accelerates
skin aging. Different parts of the body may age at different rates and distinctly, including
the brain,
the cardiovascular system, and muscle. Similarly, functions may distinctly decline with aging, including
movement control and
memory. Two organisms of the same species can also age at different rates, making biological aging and chronological aging distinct concepts.
Aging is characterized by the declining ability to respond to stress, increased
homeostatic imbalance, and increased risk of
aging-associated diseases including
cancer and
heart disease. Aging has been defined as "a progressive deterioration of physiological function, an intrinsic age-related process of loss of viability and increase in vulnerability."[3]
In 2013, a group of scientists defined nine
hallmarks of aging that are common between organisms with emphasis on mammals:
The environment induces damage at various levels, e.g.
damage to DNA, and damage to tissues and cells by oxygen
radicals (widely known as
free radicals), and some of this damage is not repaired and thus accumulates with time.[6]Cloning from
somatic cells rather than germ cells may begin life with a higher initial load of damage.
Dolly the sheep died young from a contagious lung disease, but data on an entire population of cloned individuals would be necessary to measure mortality rates and quantify aging.[citation needed]
The evolutionary theorist George Williams wrote, "It is remarkable that after a seemingly miraculous feat of
morphogenesis, a complex
metazoan should be unable to perform the much simpler task of merely maintaining what is already formed."[7]
Different speeds with which mortality increases with age correspond to different
maximum life span among
species. For example, a
mouse is elderly at 3 years, a
human is elderly at 80 years,[8] and
ginkgo trees show little effect of age even at 667 years.[9]
Almost all organisms senesce, including
bacteria which have asymmetries between "mother" and "daughter" cells upon
cell division, with the mother cell experiencing aging, while the daughter is rejuvenated.[10][11] There is
negligible senescence in some groups, such as the genus Hydra.[12]Planarianflatworms have "apparently limitless
telomere regenerative capacity fueled by a population of highly proliferative adult
stem cells."[13] These planarians are not
biologically immortal, but rather their death rate slowly increases with age. Organisms that are thought to be biologically immortal would, in one instance, be
Turritopsisdohrnii, also known as the "immortal jellyfish", due to its ability to revert to its youth when it undergoes stress during adulthood.[14] The
reproductive system is observed to remain intact, and even the gonads of Turritopsisdohrnii are existing.[15]
Some species exhibit "negative senescence", in which reproduction capability increases or is stable, and mortality falls with age, resulting from the advantages of increased body size during aging.[16]
Theories of aging
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More than 300 different theories have been posited to explain the nature (mechanisms) and causes (reasons for natural emergence or factors) of aging.[17][additional citation(s) needed] Good
theories would both explain past observations and predict the results of future experiments. Some of the theories may complement each other, overlap, contradict, or may not preclude various other theories.[citation needed]
Theories of aging fall into two broad categories, evolutionary theories of aging and mechanistic theories of aging. Evolutionary theories of aging primarily explain why aging happens,[18] but do not concern themselves with the molecular mechanism(s) that drive the process. All evolutionary theories of aging rest on the basic mechanisms that the force of natural selection declines with age.[19][20] Mechanistic theories of aging can be divided into theories that propose aging is programmed, and damage accumulation theories, i.e. those that propose aging to be caused by specific molecular changes occurring over time.
The aging process can be explained with different theories. These are evolutionary theories, molecular theories, system theories and cellular theories. The evolutionary theory of ageing was first proposed in the late 1940s and can be explained briefly by the accumulation of mutations (
evolution of ageing), disposable soma and
antagonistic pleiotropy hypothesis. The molecular theories of ageing include phenomena such as gene regulation (
gene expression), codon restriction,
error catastrophe, somatic mutation, accumulation of genetic material (DNA) damage (
DNA damage theory of aging) and dysdifferentiation. The system theories include the immunologic approach to ageing, rate-of-living and the alterations in neuroendocrinal control mechanisms. (Seehomeostasis). Cellular theory of ageing can be categorized as
telomere theory, free radical theory (
free-radical theory of aging) and
apoptosis. The stem cell theory of aging is also a sub-category of cellular theories.
One theory was proposed by
George C. Williams[7] 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 atherosclerotic 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, selection pressure is relatively high when
Fisher's reproductive value is high and relatively low when Fisher's reproductive value is low.
Cancer versus cellular senescence tradeoff theory of aging
Senescent cells within a
multicellular organism can be purged by competition between cells, but this increases the risk of cancer. This leads to an inescapable dilemma between two possibilities—the accumulation of physiologically useless senescent cells, and cancer—both of which lead to increasing rates of mortality with age.[2]
The disposable soma theory of aging was proposed by
Thomas Kirkwood in 1977.[1][21] The theory suggests that aging occurs due to a strategy in which an individual only invests in maintenance of the soma for as long as it has a realistic chance of survival.[22] A species that uses resources more efficiently will live longer, and therefore be able to pass on genetic information to the next generation. The demands of reproduction are high, so less effort is invested in repair and maintenance of somatic cells, compared to
germline cells, in order to focus on reproduction and species survival.[23]
Programmed aging theories
Programmed theories of aging posit that aging is adaptive, normally invoking selection for
evolvability or
group selection.
One of the most prominent theories of aging was first proposed by Harman in 1956.[25] It posits that
free radicals produced by dissolved oxygen, radiation, cellular respiration and other sources cause damage to the molecular machines in the cell and gradually wear them down. This is also known as
oxidative stress.
There is substantial evidence to back up this theory. Old animals have larger amounts of oxidized proteins, DNA and lipids than their younger counterparts.[26][27]
Chemical damage
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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.[citation needed] 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.[29] In a 2007 analysis 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.[30]
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.[citation needed]
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,
hydroxylradical 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.[6] 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 termed
oxidative stress are linked to the potential benefits of dietary
polyphenolantioxidants, for example in
coffee,[31] and
tea.[32] However their typically positive effects on lifespans when consumption is moderate[33][34][35] have also been explained by effects on
autophagy,[36]glucose metabolism[37] and
AMPK.[38]
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.
DNA damage was proposed in a 2021 review to be the underlying cause of aging because of the mechanistic link of DNA damage to nearly every aspect of the aging phenotype.[41] DNA damage-induced
epigenetic alterations, such as
DNA methylation and many
histone modifications, appear to be of particular importance to the aging process.[41] Evidence for the theory that DNA damage is the fundamental cause of aging was first reviewed in 1981.[42]
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.[43]
Natural selection can support lethal and harmful
alleles, if their effects are felt after reproduction. 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. Therefore, a
genetic load of late-acting deleterious mutations could be substantial at
mutation–selection balance. This concept came to be known as the
selection shadow.[44]
Peter Medawar formalised this observation in his
mutation accumulation theory of aging.[45][46] "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". Age-independent hazards such as predation, disease, and accidents, called '
extrinsic mortality', mean that even a population with
negligible senescence will have fewer individuals alive in older age groups.
Other damage
A study concluded that
retroviruses in the
human genomes can become awakened from dormant states and contribute to aging which can be blocked by
neutralizing antibodies, alleviating "cellular senescence and tissue degeneration and, to some extent, organismal aging".[47]
The
stem cell theory of aging postulates that the
aging process is the result of the inability of various types of
stem cells to continue to replenish the
tissues of an
organism with functional
differentiated cells capable of maintaining that tissue's (or
organ's) original function. Damage and error accumulation in genetic material is always a problem for systems regardless of the age. The number of stem cells in young people is very much higher than older people and thus creates a better and more efficient replacement mechanism in the young contrary to the old. In other words, aging is not a matter of the increase in damage, but a matter of failure to replace it due to a decreased number of stem cells. Stem cells decrease in number and tend to lose the ability to differentiate into
progenies or
lymphoidlineages and
myeloid lineages.
Maintaining the dynamic balance of stem cell pools requires several conditions. Balancing
proliferation and
quiescence along with homing (Seeniche) and self-renewal of
hematopoietic stem cells are favoring elements of stem cell pool maintenance while differentiation,
mobilization and senescence are detrimental elements. These detrimental effects will eventually cause
apoptosis.
There are also several challenges when it comes to therapeutic use of stem cells and their ability to replenish organs and tissues. First, different cells may have different lifespans even though they originate from the same stem cells (SeeT-cells and
erythrocytes), meaning that aging can occur differently in cells that have longer lifespans as opposed to the ones with shorter lifespans. Also, continual effort to replace the somatic cells may cause exhaustion of stem cells.[48]
Hematopoietic stem cell aging
Hematopoietic stem cells (HSCs) regenerate the blood system throughout life and maintain homeostasis.[49] DNA strand breaks accumulate in long term HSCs during aging.[50][51] This accumulation is associated with a broad attenuation of DNA repair and response pathways that depends on HSC quiescence.[51]DNA ligase 4 (Lig4) has a highly specific role in the repair of double-strand breaks by
non-homologous end joining (NHEJ). Lig4 deficiency in the mouse causes a progressive loss of HSCs during aging.[52] These findings suggest that NHEJ is a key determinant of the ability of HSCs to maintain themselves over time.[52]
Hematopoietic stem cell diversity aging
A study showed that the clonal diversity of
stem cells that
produce blood cells gets drastically reduced around age 70 to a faster-growing few, substantiating
a novel theory of ageing which could enable healthy aging.[53][54]
If different individuals age at different rates, then fecundity, mortality, and functional capacity might be better predicted by
biomarkers than by chronological age.[57][58] However,
graying of hair,[59]face aging,
skin wrinkles and other common changes seen with aging are not better indicators of future functionality than chronological age.
Biogerontologists have continued efforts to find and validate biomarkers of aging, but success thus far has been limited.
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There is interest in an
epigenetic clock as a biomarker of aging, based on its ability to predict human chronological age.[61] Basic blood
biochemistry and cell counts can also be used to accurately predict the chronological age.[62] It is also possible to predict the human chronological age using the transcriptomic aging clocks.[63]
There is research and development of further biomarkers, detection systems and software systems to measure biological age of different tissues or systems or overall. For example, a
deep learning (DL) software using anatomic
magnetic resonance images estimated
brain age with relatively high accuracy, including detecting early signs of Alzheimer's disease and varying
neuroanatomical patterns of neurological aging,[64] and a DL tool was reported as to calculate a person's
inflammatory age based on patterns of systemic age-related inflammation.[65]
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.[67] Individual cells, which are genetically identical, nonetheless 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. There is research into
epigenetics of aging.
The ability to repair DNA double-strand breaks declines with aging in mice[68] and humans.[69]
A study indicates that aging may shift activity toward short genes or shorter transcript length and that this can be countered by interventions.[71]
Healthspans and aging in society
Healthspan can broadly be defined as the period of one's life that one is
healthy, such as free of significant diseases[73] or declines of capacities (e.g. of senses,
muscle, endurance and
cognition).
With aging populations, there is a rise of
age-related diseases which puts major burdens on
healthcare systems as well as contemporary economies or contemporary economics and their appendant societal systems.
Healthspan extension and anti-aging research seek to extend the span of health in the old as well as slow aging or its negative impacts such as physical and mental decline. Modern anti-senescent and regenerative technology with augmented decision making could help "responsibly bridge the
healthspan-
lifespan gap for a future of equitable global wellbeing".[74] Aging is "the most prevalent risk factor for chronic disease, frailty and disability, and it is estimated that there will be over 2 billion persons age > 60 by the year
2050", making it a large global health challenge that demands substantial (and well-orchestrated or efficient) efforts, including interventions that alter and target the inborn
aging process.[75]
Biological aging or the LHG comes with a great cost burden to society, including potentially rising health care costs (also depending on types and
costs of treatments).[72][76] This, along with global
quality of life or
wellbeing, highlight the importance of extending healthspans.[72]
Many measures that may extend lifespans may simultaneously also extend healthspans, albeit that is not necessarily the case, indicating that "lifespan can no longer be the sole parameter of interest" in related research.[77] While recent life expectancy increases were not followed by "parallel" healthspan expansion,[72] awareness of the concept and issues of healthspan lags as of 2017.[73] Scientists have noted that "
[c]hronic diseases of aging are increasing and are inflicting untold costs on human quality of life".[76]
Life extension is the concept of extending the human
lifespan, either modestly through improvements in medicine or dramatically by increasing the
maximum lifespan beyond its generally-settled biological limit of
around 125 years.[78] Several researchers in the area, along with "life extensionists", "
immortalists", or "
longevists" (those who wish to achieve longer lives themselves), postulate that future breakthroughs in tissue
rejuvenation,
stem cells,
regenerative medicine,
molecular repair,
gene therapy, pharmaceuticals, and
organ replacement (such as with artificial organs or
xenotransplantations) will eventually enable humans to have indefinite lifespans through complete rejuvenation to a healthy youthful condition (agerasia[79]). The ethical ramifications, if life extension becomes a possibility, are debated by
bioethicists.
The sale of purported anti-aging products such as supplements and hormone replacement is a lucrative global industry. For example, the industry that promotes the use of hormones as a treatment for consumers to slow or reverse the
aging process in the US market generated about $50 billion of revenue a year in 2009.[80] The use of such hormone products has not been proven to be effective or safe.[80][81][82][83]
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