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Senescence

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This article is about the aging of whole organisms including animals. For aging specifically in humans, seeAgeing.For plants, seePlant senescence.For cells that stop dividing, seeCellular senescence.For bacteria, seeBacterial senescence.

Senescence(/sɪˈnɛsəns/) orbiological agingis the gradual deterioration offunctionalcharacteristics in living organisms. Wholeorganismsenescence involves an increase indeath ratesor a decrease infecunditywith increasing age, at least in the later part of an organism'slife cycle.[1][2]However, the resulting effects of senescence can be delayed. The 1934 discovery thatcalorie restrictioncanextend lifespansby 50% in rats, the existence of species havingnegligible senescence,and the existence of potentially immortal organisms such as members of thegenusHydrahave motivated research intodelaying senescenceand thusage-related diseases.Rare human mutations can causeaccelerated aging diseases.

Environmentalfactorsmay affectaging– for example, overexposure toultraviolet radiationacceleratesskin 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 controlandmemory.Two organisms of the same species can also age at different rates, making biological aging and chronological aging distinct concepts.

Definition and characteristics

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Organismal senescenceis the aging of whole organisms. Actuarial senescence can be defined as an increase in mortality or a decrease infecunditywith age. TheGompertz–Makeham law of mortalitysays that the age-dependent component of themortality rateincreases exponentiallywith age.

Agingis characterized by the declining ability to respond to stress, increasedhomeostaticimbalance, and increased risk ofaging-associated diseasesincludingcancerandheart 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 agingthat are common between organisms with emphasis on mammals:

In a decadal update, three hallmarks have been added, totaling 12 proposed hallmarks:

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]Cloningfromsomatic cellsrather than germ cells may begin life with a higher initial load of damage.Dolly the sheepdied 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 complexmetazoanshould be unable to perform the much simpler task of merely maintaining what is already formed. "[7]

Variation among species

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Further information:Longevity § Non-human biological longevity

Different speeds with which mortality increases with age correspond to differentmaximum life spanamongspecies.For example, amouseis elderly at 3 years, ahumanis elderly at 80 years,[8]andginkgotrees show little effect of age even at 667 years.[9]

Almost all organisms senesce, includingbacteriawhich have asymmetries between "mother" and "daughter" cells uponcell division,with the mother cell experiencing aging, while the daughter is rejuvenated.[10][11]There isnegligible senescencein some groups, such as the genusHydra.[12]Planarianflatwormshave "apparently limitlesstelomereregenerative 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 systemis observed to remain intact, and even the gonads ofTurritopsisdohrniiare 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]Goodtheorieswould 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.

This section is an excerpt fromStem cell theory of aging § Other theories of aging.[edit]
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 astelomeretheory, 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]

Evolutionary aging theories

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Main article:Evolution of ageing

Antagonistic pleiotropy

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Main article:Antagonistic pleiotropy hypothesis

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 forpleiotropicgenes that are beneficial early in life but harmful later on. In this case, selection pressure is relatively high whenFisher's reproductive valueis high and relatively low when Fisher's reproductive value is low.

Cancer versus cellular senescence tradeoff theory of aging

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Main article:Immunosenescence

Senescent cells within amulticellular organismcan 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]

Disposable soma

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Main article:Disposable soma theory of aging

The disposable soma theory of aging was proposed byThomas Kirkwoodin 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]

Programmed aging theories

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Programmed theories of aging posit that aging is adaptive, normally invoking selection forevolvabilityorgroup selection.

Thereproductive-cell cycle theorysuggests that aging is regulated by changes in hormonal signaling over the lifespan.[24]

Damage accumulation theories

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The free radical theory of aging

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Main article:Free-radical theory of aging

One of the most prominent theories of aging was first proposed by Harman in 1956.[25]It posits thatfree radicalsproduced 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]

Chemical damage

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See also:DNA damage theory of aging
ElderlyKlamathwoman photographed byEdward S. Curtisin 1924

One of the earliest aging theories was theRate of Living Hypothesisdescribed byRaymond Pearlin 1928[28](based on earlier work byMax Rubner), which states that fastbasal metabolic ratecorresponds to shortmaximum life span.

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 restrictedanimals process as much, or more, calories per gram of body mass, as theirad libitumfed 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 andphylogenyare employed, metabolic rate does not correlate withlongevityin 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 structuralproteinsorDNA,caused by ubiquitous chemical agents in the body such asoxygenandsugars,are in part responsible for aging. The damage can include breakage of biopolymer chains,cross-linkingof biopolymers, or chemical attachment of unnatural substituents (haptens) to biopolymers.[citation needed] Under normalaerobicconditions, approximately 4% of theoxygenmetabolized bymitochondriais converted tosuperoxideion, which can subsequently be converted tohydrogen peroxide,hydroxylradicaland eventually other reactive species including otherperoxidesandsinglet oxygen,which can, in turn, generatefree radicalscapable of damaging structural proteins and DNA.[6]Certain metalionsfound in the body, such ascopperandiron,may participate in the process. (InWilson's disease,ahereditary defectthat causes the body to retain copper, some of the symptoms resemble accelerated senescence.) These processes termedoxidative stressare 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]

Sugarssuch asglucoseandfructosecan react with certainamino acidssuch aslysineandarginineand certain DNA bases such asguanineto 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.

Free radicalscan damage proteins,lipidsorDNA.Glycationmainly damages proteins. Damaged proteins and lipids accumulate inlysosomesaslipofuscin.Chemical damage to structural proteins can lead to loss of function; for example, damage tocollagenofblood vesselwalls can lead to vessel-wall stiffness and, thus,hypertension,and vessel wall thickening and reactive tissue formation (atherosclerosis); similar processes in thekidneycan lead tokidney failure.Damage toenzymesreduces cellular functionality. Lipidperoxidationof the innermitochondrial membranereduces theelectric potentialand the ability to generate energy. It is probably no accident that nearly all of the so-called "accelerated aging diseases"are due to defectiveDNA repairenzymes.[39][40]

It is believed that theimpact of alcohol on agingcan be partly explained by alcohol's activation of theHPA axis,which stimulatesglucocorticoidsecretion, long-term exposure to which produces symptoms of aging.[41]

DNA damage

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DNA damagewas 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 damageas measured by the DNA damage marker gamma H2AX in leukocytes was found to correlate with longer lifespans in comparisons ofdolphins,goats,reindeer,American flamingosandgriffon vultures.[43]DNA damage-inducedepigeneticalterations, such asDNA methylationand manyhistonemodifications, 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]

Mutation accumulation

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Main article:Mutation accumulation theory

Natural selectioncan support lethal and harmfulalleles,if their effects are felt after reproduction. The geneticistJ. B. S. Haldanewondered why the dominant mutation that causesHuntington's diseaseremained 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 loadof late-acting deleterious mutations could be substantial atmutation–selection balance.This concept came to be known as theselection shadow.[45]

Peter Medawarformalised this observation in hismutation accumulation theoryof 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 senescencewill have fewer individuals alive in older age groups.

Other damage

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A study concluded thatretrovirusesin thehuman genomescan 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]

Stem cell theories of aging

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This section is an excerpt fromStem cell theory of aging.[edit]

Thestem cell theory of agingpostulates that theaging processis the result of the inability of various types ofstem cellsto continue to replenish thetissuesof anorganismwith functionaldifferentiated cellscapable 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 intoprogeniesorlymphoidlineagesandmyeloidlineages.

Maintaining the dynamic balance of stem cell pools requires several conditions. Balancingproliferationandquiescencealong with homing (Seeniche) and self-renewal ofhematopoietic stem cellsare favoring elements of stem cell pool maintenance while differentiation,mobilizationand 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-cellsanderythrocytes), 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 cellsthatproduce blood cellsgets drastically reduced around age 70to a faster-growing few,substantiatinga noveltheory of ageing which could enable healthy aging.[54][55]
Hematopoietic mosaic loss of chromosome Y
A 2022 study showed thatblood cells'loss of the Y chromosomeina subset of cells,called 'mosaic loss of chromosome Y' (mLOY) and reportedly affecting at least 40% of 70 years-old men to some degree, contributes tofibrosis,heart risks,and mortality in a causal way.[56][57]

Biomarkers of aging

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Main article:Biomarkers of aging

If different individuals age at different rates, then fecundity, mortality, and functional capacity might be better predicted bybiomarkersthan by chronological age.[58][59]However,graying of hair,[60]face aging,skin wrinklesand other common changes seen with aging are not better indicators of future functionality than chronological age.Biogerontologistshave continued efforts to find and validate biomarkers of aging, but success thus far has been limited.

Levels ofCD4andCD8memory T cellsandnaive T cellshave been used to give good predictions of the expected lifespan of middle-aged mice.[61]

Aging clocks

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There is interest in anepigenetic clockas a biomarker of aging, based on its ability to predict human chronological age.[62]Basic bloodbiochemistryand 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 imagesestimatedbrain agewith relatively high accuracy, including detecting early signs of Alzheimer's disease and varyingneuroanatomicalpatterns of neurological aging,[65]and a DL tool was reported as to calculate a person'sinflammatory agebased 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]Exmploying 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]

Genetic determinants of aging

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Main article:Genetics of aging

A number of genetic components of aging have been identified using model organisms, ranging from the simple buddingyeastSaccharomyces cerevisiaeto worms such asCaenorhabditis elegansandfruit flies(Drosophila melanogaster). Study of these organisms has revealed the presence of at least two conserved aging pathways.

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 theepigeneticfactors play an important role ingene expressionand 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]

A set of rare hereditary (genetics) disorders, each calledprogeria,has been known for some time. Sufferers exhibit symptoms resemblingaccelerated aging,includingwrinkled skin.The cause ofHutchinson–Gilford progeria syndromewas reported in the journalNaturein May 2003.[73] This report suggests thatDNA damage,notoxidative stress,is the cause of this form of accelerated aging.

A study indicates that aging may shift activity toward short genes or shorter transcript length and that this can be countered by interventions.[74]

Healthspans and aging in society

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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).

These paragraphs are an excerpt fromGlobal health § Multimorbidity, age-related diseases and aging.[edit]
With aging populations,there is a rise ofage-related diseaseswhich puts major burdens onhealthcare systemsas well as contemporary economies or contemporary economics and their appendant societal systems.Healthspan extension and anti-aging researchseek 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-lifespangap 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 inbornagingprocess.[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 lifeorwellbeing,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 agingare increasing and are inflicting untold costs on human quality of life ".[79]

Interventions

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This section is an excerpt fromLife extension.[edit]

Life extensionis the concept of extending the humanlifespan,either modestly through improvements in medicine or dramatically by increasing themaximum lifespanbeyond 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,molecularrepair,gene therapy,pharmaceuticals, andorganreplacement (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 theagingprocess 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]

See also

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