Environmentalfactors may affectaging – for example, overexposure toultraviolet radiation acceleratesskin aging. Different parts of the body may age at different rates and distinctly, includingthe brain,the cardiovascular system, and muscle. Similarly, functions may distinctly decline with aging, includingmovement control andmemory. 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, increasedhomeostatic imbalance, and increased risk ofaging-associated diseases includingcancer andheart 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 ninehallmarks 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 oxygenradicals (widely known asfree radicals), and some of this damage is not repaired and thus accumulates with time.[6]Cloning fromsomatic 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 ofmorphogenesis, a complexmetazoan 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 differentmaximum life span amongspecies. For example, amouse is elderly at 3 years, ahuman is elderly at 80 years,[8] andginkgo trees show little effect of age even at 667 years.[9]
Almost all organisms senesce, includingbacteria which have asymmetries between "mother" and "daughter" cells uponcell division, with the mother cell experiencing aging, while the daughter is rejuvenated.[10][11] There isnegligible senescence in some groups, such as the genusHydra.[12]Planarianflatworms have "apparently limitlesstelomere regenerative capacity fueled by a population of highly proliferative adultstem cells."[13] These planarians are notbiologically immortal, but rather their death rate slowly increases with age. Organisms that are thought to be biologically immortal would, in one instance, beTurritopsisdohrnii, also known as the "immortal jellyfish", due to its ability to revert to its youth when it undergoes stress during adulthood.[14] Thereproductive system is observed to remain intact, and even the gonads ofTurritopsisdohrnii 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]
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] Goodtheories 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 andantagonistic 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 astelomere theory, free radical theory (free-radical theory of aging) andapoptosis. The stem cell theory of aging is also a sub-category of cellular theories.[citation needed]
One theory was proposed byGeorge C. Williams[7] and involvesantagonistic 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 forpleiotropic genes that are beneficial early in life but harmful later on. In this case, selection pressure is relatively high whenFisher'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 amulticellular 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 byThomas 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 togermline cells, in order to focus on reproduction and species survival.[23]
One of the most prominent theories of aging was first proposed by Harman in 1956.[25] It posits thatfree 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 asoxidative 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]
While there may be some validity to the idea that for various types of specific damage detailed below that are by-products ofmetabolism, 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 theirad 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 andphylogeny are employed, metabolic rate does not correlate withlongevity in mammals or birds.[30]
With respect to specific types of chemical damage caused by metabolism, it is suggested that damage to long-livedbiopolymers, such as structuralproteins orDNA, caused by ubiquitous chemical agents in the body such asoxygen andsugars, 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 normalaerobic conditions, approximately 4% of theoxygen metabolized bymitochondria is converted tosuperoxide ion, which can subsequently be converted tohydrogen peroxide,hydroxylradical and eventually other reactive species including otherperoxides andsinglet oxygen, which can, in turn, generatefree radicals capable of damaging structural proteins and DNA.[6] Certain metalions found in the body, such ascopper andiron, may participate in the process. (InWilson's disease, ahereditary defect that causes the body to retain copper, some of the symptoms resemble accelerated senescence.) These processes termedoxidative stress are linked to the potential benefits of dietarypolyphenolantioxidants, for example incoffee,[31] andtea.[32] However their typically positive effects on lifespans when consumption is moderate[33][34][35] have also been explained by effects onautophagy,[36]glucose metabolism[37] andAMPK.[38]
Sugars such asglucose andfructose can react with certainamino acids such aslysine andarginine and certain DNA bases such asguanine to produce sugar adducts, in a process calledglycation. 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 withdiabetes, who have elevatedblood 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 termedglycoxidation.
It is believed that theimpact of alcohol on aging can be partly explained by alcohol's activation of theHPA axis, which stimulatesglucocorticoid secretion, long-term exposure to which produces symptoms of aging.[41]
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.[42] Slower rate of accumulation ofDNA damage as measured by the DNA damage marker gamma H2AX in leukocytes was found to correlate with longer lifespans in comparisons ofdolphins,goats,reindeer,American flamingos andgriffon vultures.[43] DNA damage-inducedepigenetic alterations, such asDNA methylation and manyhistone modifications, appear to be of particular importance to the aging process.[42] Evidence for the theory that DNA damage is the fundamental cause of aging was first reviewed in 1981.[44]
Natural selection can support lethal and harmfulalleles, if their effects are felt after reproduction. The geneticistJ. B. S. Haldane wondered why the dominant mutation that causesHuntington'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, agenetic load of late-acting deleterious mutations could be substantial atmutation–selection balance. This concept came to be known as theselection shadow.[45]
Peter Medawar formalised this observation in hismutation accumulation theory of aging.[46][47] "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 withnegligible senescence will have fewer individuals alive in older age groups.
A study concluded thatretroviruses in thehuman genomes can become awakened from dormant states and contribute to aging which can be blocked byneutralizing antibodies, alleviating "cellular senescence and tissue degeneration and, to some extent, organismal aging".[48]
Thestem cell theory of aging postulates that theaging process is the result of the inability of various types ofstem cells to continue to replenish thetissues of anorganism with functionaldifferentiated cells capable of maintaining that tissue's (ororgan'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 intoprogenies orlymphoidlineages andmyeloid lineages.
Maintaining the dynamic balance of stem cell pools requires several conditions. Balancingproliferation andquiescence along with homing (Seeniche) and self-renewal ofhematopoietic stem cells are favoring elements of stem cell pool maintenance while differentiation,mobilization and senescence are detrimental elements. These detrimental effects will eventually causeapoptosis.
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 anderythrocytes), 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.[49]
Hematopoietic stem cell aging
Hematopoietic stem cells (HSCs) regenerate the blood system throughout life and maintain homeostasis.[50] DNA strand breaks accumulate in long term HSCs during aging.[51][52] This accumulation is associated with a broad attenuation of DNA repair and response pathways that depends on HSC quiescence.[52]DNA ligase 4 (Lig4) has a highly specific role in the repair of double-strand breaks bynon-homologous end joining (NHEJ). Lig4 deficiency in the mouse causes a progressive loss of HSCs during aging.[53] These findings suggest that NHEJ is a key determinant of the ability of HSCs to maintain themselves over time.[53]
Hematopoietic stem cell diversity aging
A study showed that the clonal diversity ofstem cells thatproduce blood cells gets drastically reduced around age 70to a faster-growing few, substantiatinga novel theory of ageing which could enable healthy aging.[54][55]
If different individuals age at different rates, then fecundity, mortality, and functional capacity might be better predicted bybiomarkers than by chronological age.[58][59] However,graying of hair,[60]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.
There is interest in anepigenetic clock as a biomarker of aging, based on its ability to predict human chronological age.[62] Basic bloodbiochemistry and cell counts can also be used to accurately predict the chronological age.[63] It is also possible to predict the human chronological age using transcriptomic aging clocks.[64]
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, adeep learning (DL) software using anatomicmagnetic resonance images estimatedbrain age with relatively high accuracy, including detecting early signs of Alzheimer's disease and varyingneuroanatomical patterns of neurological aging,[65] and a DL tool was reported as to calculate a person'sinflammatory age based on patterns of systemic age-related inflammation.[66]
Aging clocks have been used to evaluate impacts of interventions on humans, includingcombination therapies.[67][additional citation(s) needed] Employing aging clocks to identify and evaluate longevity interventions represents a fundamental goal in aging biology research. However, achieving this goal requires overcoming numerous challenges and implementing additional validation steps.[68][69]
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.[70] Individual cells, which are genetically identical, nonetheless can have substantially different responses to outside stimuli, and markedly different lifespans, indicating theepigenetic factors play an important role ingene expression and aging as well as genetic factors. There is research intoepigenetics of aging.
The ability to repair DNA double-strand breaks declines with aging in mice[71] and humans.[72]
Past and projected age of the human world population through time as of 2021[75]Healthspan-lifespan gap (LHG)[75]Healthspan extension relies on the unison of social, clinical and scientific programs or domains of work.[75]
Healthspan can broadly be defined as the period of one's life that one ishealthy, such as free of significant diseases[76] or declines of capacities (e.g. of senses,muscle, endurance andcognition).
With aging populations, there is a rise ofage-related diseases which puts major burdens onhealthcare 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 thehealthspan-lifespan gap for a future of equitable global wellbeing".[77] 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 year2050", making it a large global health challenge that demands substantial (and well-orchestrated or efficient) efforts, including interventions that alter and target the inbornaging process.[78]
Biological aging or the LHG comes with a great cost burden to society, including potentially rising health care costs (also depending on types andcosts of treatments).[75][79] This, along with globalquality of life orwellbeing, highlight the importance of extending healthspans.[75]
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.[80] While recent life expectancy increases were not followed by "parallel" healthspan expansion,[75] awareness of the concept and issues of healthspan lags as of 2017.[76] Scientists have noted that "[c]hronic diseases of aging are increasing and are inflicting untold costs on human quality of life".[79]
Life extension is the concept of extending the humanlifespan, either modestly through improvements in medicine or dramatically by increasing themaximum lifespan beyond its generally-settled biological limit ofaround 125 years.[81] 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 tissuerejuvenation,stem cells,regenerative medicine,molecular repair,gene therapy, pharmaceuticals, andorgan replacement (such as with artificial organs orxenotransplantations) will eventually enable humans to have indefinite lifespans through complete rejuvenation to a healthy youthful condition (agerasia[82]). The ethical ramifications, if life extension becomes a possibility, are debated bybioethicists.
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 theaging process in the US market generated about $50 billion of revenue a year in 2009.[83] The use of such hormone products has not been proven to be effective or safe.[83][84][85][86]
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