Senescence

{{short description|Deterioration of function with age}} {{about|the aging of whole organisms including animals|aging specifically in humans|Ageing|plants|Plant senescence|cells that stop dividing|Cellular senescence|bacteria|Bacterial senescence}} {{Use American English|date=May 2024}} {{Use dmy dates|date=May 2024}} {{cs1 config|name-list-style=vanc|display-authors=3}}

thumb | right | alt=Supercentenarian Ann Alexendar Pouder Ann Poudar (Ann Alexander Pouder) (Q1808329) (8 April 1807 – 10 July 1917), photographed on her 110th birthday. | Supercentenarian Ann Alexendar Pouder Ann Poudar (Ann Alexander Pouder) (Q1808329) (8 April 1807 – 10 July 1917), photographed on her 110th birthday. '''Senescence''' ({{IPAc-en|,|s|ɪ|ˈ|n|ɛ|s|ə|n|s}}) or '''biological aging''' is the gradual deterioration of functional characteristics in living organisms. Whole organism senescence involves an increase in death rates or a decrease in fecundity with increasing age, at least in the later part of an organism's life cycle.<ref name=":0">{{Cite journal|last=Kirkwood|first=T. B. L.|date=1977|title=Evolution of ageing|journal=Nature|volume=270|issue=5635|pages=301–4|doi=10.1038/270301a0|pmid=593350|bibcode=1977Natur.270..301K|s2cid=492012}}</ref><ref name="nelson_2017">{{cite journal | vauthors = Nelson P, Masel J | title = Intercellular competition and the inevitability of multicellular aging | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 49 | pages = 12982–7 | date = December 2017 | pmid = 29087299 | pmc = 5724245 | doi = 10.1073/pnas.1618854114 | bibcode = 2017PNAS..11412982N | doi-access = free }}</ref> However, the effects of senescence can be delayed. The 1934 discovery that calorie restriction can extend lifespans by 50% in rats, the existence of species having negligible senescence, and the existence of potentially immortal organisms such as members of the genus ''Hydra'' have motivated research into delaying senescence and thus age-related diseases. Rare human mutations can cause accelerated aging diseases.

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.

==Definition and characteristics== ''Organismal senescence'' is the aging of whole organisms. Actuarial senescence can be defined as an increase in mortality or a decrease in fecundity with age. The Gompertz–Makeham law of mortality says that the age-dependent component of the mortality rate increases exponentially with age.

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."<ref>{{Cite web |title=Aging and Gerontology Glossary |url=http://www.senescence.info/glossary.html |access-date=26 February 2011 |archive-date=19 October 2019 |archive-url=https://web.archive.org/web/20191019200702/http://www.senescence.info/glossary.html |url-status=live }}</ref>

In 2013, a group of scientists defined nine hallmarks of aging that are common between organisms with emphasis on mammals: * genomic instability, * telomere attrition, * epigenetic alterations, * loss of proteostasis, * deregulated nutrient sensing, * mitochondrial dysfunction, * cellular senescence, * stem cell exhaustion, * altered intercellular communication<ref name="pmid23746838">{{cite journal | vauthors = López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G | title = The hallmarks of aging | journal = Cell | volume = 153 | issue = 6 | pages = 1194–217 | date = June 2013 | pmid = 23746838 | pmc = 3836174 | doi = 10.1016/j.cell.2013.05.039 }}</ref>

In a decadal update, three hallmarks have been added, totaling 12 proposed hallmarks: * disabled macroautophagy * chronic inflammation * dysbiosis<ref name="10.1016/j.cell.2022.11.001">{{cite journal |last1=López-Otín |first1=Carlos |last2=Blasco |first2=Maria A. |last3=Partridge |first3=Linda |last4=Serrano |first4=Manuel |last5=Kroemer |first5=Guido |title=Hallmarks of aging: An expanding universe |journal=Cell |date=19 January 2023 |volume=186 |issue=2 |pages=243–278 |doi=10.1016/j.cell.2022.11.001 |pmid=36599349 |s2cid=255394876 |language=English |doi-access=free }}</ref>

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.<ref name="pmid1383772">{{cite journal |vauthors=Holmes GE, Bernstein C, Bernstein H |title=Oxidative and other DNA damages as the basis of aging: a review |journal=Mutat. Res. |volume=275 |issue=3–6 |pages=305–15 |date=September 1992 |pmid=1383772 |doi= 10.1016/0921-8734(92)90034-m}}</ref> 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|date=December 2019}}

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."<ref name = "Williams_1957">{{cite journal | vauthors = Williams GC | year = 1957 | title = Pleiotropy, natural selection, and the evolution of senescence | journal = Evolution | volume = 11 | issue = 4| pages = 398–411 | doi = 10.2307/2406060 | jstor = 2406060 }}</ref>

==Variation among species== {{Further|Longevity#Non-human biological longevity}} 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,<ref>{{cite journal | vauthors = Austad SN | title = Comparative biology of aging | journal = The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences | volume = 64 | issue = 2 | pages = 199–201 | date = February 2009 | pmid = 19223603 | pmc = 2655036 | doi = 10.1093/gerona/gln060 }}</ref> and ginkgo trees show little effect of age even at 667 years.<ref name="Wang">{{cite journal | vauthors = Wang L, Cui J, Jin B, Zhao J, Xu H, Lu Z, Li W, Li X, Li L, Liang E, Rao X, Wang S, Fu C, Cao F, Dixon RA, Lin J | title = Multifeature analyses of vascular cambial cells reveal longevity mechanisms in old ''Ginkgo biloba'' trees | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 117 | issue = 4 | pages = 2201–10 | date = January 2020 | pmid = 31932448 | pmc = 6995005 | doi = 10.1073/pnas.1916548117 | bibcode = 2020PNAS..117.2201W | doi-access = free }}</ref>

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.<ref>{{cite journal | vauthors = Ackermann M, Stearns SC, Jenal U | title = Senescence in a bacterium with asymmetric division | journal = Science | volume = 300 | issue = 5627 | page = 1920 | date = June 2003 | pmid = 12817142 | doi = 10.1126/science.1083532 | bibcode = 2003Sci...300.1920A | s2cid = 34770745 }}</ref><ref>{{cite journal | vauthors = Stewart EJ, Madden R, Paul G, Taddei F | title = Aging and death in an organism that reproduces by morphologically symmetric division | journal = PLOS Biology | volume = 3 | issue = 2 | article-number = e45 | date = February 2005 | pmid = 15685293 | pmc = 546039 | doi = 10.1371/journal.pbio.0030045 | doi-access = free }}</ref> There is negligible senescence in some groups, such as the genus ''Hydra''.<ref name="Dańko Kozłowski Schaible 2015 pp. 137–149">{{cite journal | vauthors = Dańko MJ, Kozłowski J, Schaible R | title = Unraveling the non-senescence phenomenon in Hydra | journal = Journal of Theoretical Biology | volume = 382 | pages = 137–49 | date = October 2015 | pmid = 26163368 | doi = 10.1016/j.jtbi.2015.06.043 | bibcode = 2015JThBi.382..137D | doi-access = free }}</ref> Planarian flatworms have "apparently limitless telomere regenerative capacity fueled by a population of highly proliferative adult stem cells."<ref>{{cite journal | vauthors = Tan TC, Rahman R, Jaber-Hijazi F, Felix DA, Chen C, Louis EJ, Aboobaker A | title = Telomere maintenance and telomerase activity are differentially regulated in asexual and sexual worms | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 11 | pages = 4209–14 | date = March 2012 | pmid = 22371573 | pmc = 3306686 | doi = 10.1073/pnas.1118885109 | bibcode = 2012PNAS..109.4209T | doi-access = free }}</ref> 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 ''Turritopsis'' ''dohrnii'', also known as the "immortal jellyfish", due to its ability to revert to its youth when it undergoes stress during adulthood.<ref>{{cite journal | vauthors = Lisenkova AA, Grigorenko AP, Tyazhelova TV, Andreeva TV, Gusev FE, Manakhov AD, Goltsov AY, Piraino S, Miglietta MP, Rogaev EI | title = Complete mitochondrial genome and evolutionary analysis of Turritopsis dohrnii, the "immortal" jellyfish with a reversible life-cycle | journal = Molecular Phylogenetics and Evolution | volume = 107 | pages = 232–8 | date = February 2017 | pmid = 27845203 | doi = 10.1016/j.ympev.2016.11.007 | doi-access = free | bibcode = 2017MolPE.107..232L }}</ref> The reproductive system is observed to remain intact, and even the gonads of ''Turritopsis'' ''dohrnii'' exist.<ref>{{cite journal | vauthors = Piraino S, Boero F, Aeschbach B, Schmid V | title = Reversing the Life Cycle: Medusae Transforming into Polyps and Cell Transdifferentiation in Turritopsis nutricula (Cnidaria, Hydrozoa) | journal = The Biological Bulletin | volume = 190 | issue = 3 | pages = 302–312 | date = June 1996 | pmid = 29227703 | doi = 10.2307/1543022 | jstor = 1543022 | bibcode = 1996BiolB.190..302P }}</ref>

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.<ref>{{cite journal | vauthors = Vaupel JW, Baudisch A, Dölling M, Roach DA, Gampe J | title = The case for negative senescence | journal = Theoretical Population Biology | volume = 65 | issue = 4 | pages = 339–51 | date = June 2004 | pmid = 15136009 | doi = 10.1016/j.tpb.2003.12.003 | bibcode = 2004TPBio..65..339W }}</ref>

== Theories of aging == {{Expand section|date=March 2023}} {{Unsolved|biology|Why does biological aging occur?}} More than 300 different theories have been posited to explain the nature (mechanisms) and causes (reasons for natural emergence or factors) of aging.<ref>{{cite journal | vauthors = Viña J, Borrás C, Miquel J | title = Theories of ageing | journal = IUBMB Life | volume = 59 | issue = 4–5 | pages = 249–54 | date = 2007 | pmid = 17505961 | doi = 10.1080/15216540601178067 | doi-access = free }}</ref>{{additional citation needed|date=March 2023}} 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|date=March 2023}}

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,<ref>{{Cite journal|last1=Kirkwood|first1=Thomas B. L.|last2=Austad|first2=Steven N.|date=2000|title=Why do we age?|journal=Nature|volume=408|issue=6809|pages=233–8|doi=10.1038/35041682|pmid=11089980|bibcode=2000Natur.408..233K|s2cid=2579770}}</ref> 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.<ref>{{Cite book |author-link=Peter Medawar |last=Medawar |first=Peter Brian |title=An unsolved problem of biology|date=1952|publisher=Published for the College by H.K. Lewis|oclc=869293719 }}</ref><ref>{{Cite book|last=Rose|first=Michael R.|title=Evolutionary biology of aging|date=1991|publisher=Oxford University Press|isbn=1-4237-6520-6|oclc=228167629}}</ref> 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.

=== Evolutionary aging theories === {{Main|Evolution of ageing}}

====Antagonistic pleiotropy==== {{Main|Antagonistic pleiotropy hypothesis}} One theory was proposed by George C. Williams<ref name = "Williams_1957" /> 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==== {{Main|Immunosenescence}} 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.<ref name="nelson_2017" />

==== Disposable soma ==== {{Main|Disposable soma theory of aging}} The disposable soma theory of aging was proposed by Thomas Kirkwood in 1977.<ref name=":0" /><ref>{{Cite book|first=Tom|last=Kirkwood|title=Time of Our Lives: the Science of Human Aging.|date=2006|publisher=Oxford University Press|isbn=978-0-19-802939-7|oclc=437175125}}</ref> 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.<ref>{{cite journal | vauthors = Hammers M, Richardson DS, Burke T, Komdeur J | title = The impact of reproductive investment and early-life environmental conditions on senescence: support for the disposable soma hypothesis | journal = Journal of Evolutionary Biology | volume = 26 | issue = 9 | pages = 1999–2007 | date = September 2013 | pmid = 23961923 | doi = 10.1111/jeb.12204 | bibcode = 2013JEBio..26.1999H | hdl-access = free | s2cid = 46466320 | hdl = 11370/9cc6749c-f67d-40ab-a253-a06650c32102 }}</ref> 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 the repair and maintenance of somatic cells, compared to germline cells, to focus on reproduction and species survival.<ref>{{cite journal | vauthors = Kirkwood TB, Rose MR | title = Evolution of senescence: late survival sacrificed for reproduction | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 332 | issue = 1262 | pages = 15–24 | date = April 1991 | pmid = 1677205 | doi = 10.1098/rstb.1991.0028 | bibcode = 1991RSPTB.332...15K }}</ref>

=== Programmed aging theories === Programmed theories of aging posit that aging is adaptive, normally invoking selection for evolvability or group selection.

The reproductive-cell cycle theory suggests that aging is regulated by changes in hormonal signaling over the lifespan.<ref name="pmid20851172">{{cite journal | vauthors = Atwood CS, Bowen RL | title = The reproductive-cell cycle theory of aging: an update | journal = Experimental Gerontology | volume = 46 | issue = 2–3 | pages = 100–7 | year = 2011 | pmid = 20851172 | doi = 10.1016/j.exger.2010.09.007 | s2cid = 20998909 }}</ref>

=== Damage accumulation theories ===

==== The free radical theory of aging ==== {{Main|Free-radical theory of aging}} One of the most prominent theories of aging was first proposed by Harman in 1956.<ref>{{cite journal | vauthors = Harman D | title = Aging: a theory based on free radical and radiation chemistry | journal = Journal of Gerontology | volume = 11 | issue = 3 | pages = 298–300 | date = July 1956 | pmid = 13332224 | doi = 10.1093/geronj/11.3.298 | hdl = 2027/mdp.39015086547422 | hdl-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Stadtman ER | title = Protein oxidation and aging | journal = Science | volume = 257 | issue = 5074 | pages = 1220–4 | date = August 1992 | pmid = 1355616 | doi = 10.1126/science.1355616 | bibcode = 1992Sci...257.1220S | url = https://zenodo.org/record/1230934 | access-date = 21 July 2021 | archive-date = 31 July 2021 | archive-url = https://web.archive.org/web/20210731091110/https://zenodo.org/record/1230934 | url-status = live }}</ref><ref>{{cite journal | vauthors = Sohal RS, Agarwal S, Dubey A, Orr WC | title = Protein oxidative damage is associated with life expectancy of houseflies | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 15 | pages = 7255–9 | date = August 1993 | pmid = 8346242 | pmc = 47115 | doi = 10.1073/pnas.90.15.7255 | bibcode = 1993PNAS...90.7255S | doi-access = free }}</ref>

====Chemical damage==== {{See also|DNA damage theory of aging}} [[Image:Edward S. Curtis Collection People 086.jpg|thumb|upright=.8|Elderly Klamath woman photographed by Edward S. Curtis in 1924]] One of the earliest aging theories was the ''Rate of Living Hypothesis'' described by Raymond Pearl in 1928<ref>{{Cite book| vauthors = Pearl R |title=The Rate of Living, Being an Account of Some Experimental Studies on the Biology of Life Duration|publisher=Alfred A. Knopf|year=1928|location=New York|lccn=28000834}}{{Page needed|date=September 2010}}</ref> (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.{{Citation needed|date=March 2009}} 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.<ref>{{cite journal | vauthors = Brunet-Rossinni AK, Austad SN | title = Ageing studies on bats: a review | journal = Biogerontology | volume = 5 | issue = 4 | pages = 211–22 | year = 2004 | pmid = 15314271 | doi = 10.1023/B:BGEN.0000038022.65024.d8 | s2cid = 22755811 }}</ref> 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.<ref>{{cite journal | vauthors = de Magalhães JP, Costa J, Church GM | title = An analysis of the relationship between metabolism, developmental schedules, and longevity using phylogenetic independent contrasts | journal = The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences | volume = 62 | issue = 2 | pages = 149–60 | date = February 2007 | pmid = 17339640 | pmc = 2288695 | doi = 10.1093/gerona/62.2.149 | citeseerx = 10.1.1.596.2815 }}</ref>

Concerning 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|date=December 2019}} 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.<ref name="pmid1383772" /> 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 polyphenol antioxidants, for example in coffee,<ref>{{cite journal | vauthors = Freedman ND, Park Y, Abnet CC, Hollenbeck AR, Sinha R | title = Association of coffee drinking with total and cause-specific mortality | journal = The New England Journal of Medicine | volume = 366 | issue = 20 | pages = 1891–904 | date = May 2012 | pmid = 22591295 | pmc = 3439152 | doi = 10.1056/NEJMoa1112010 }}</ref> and tea.<ref>{{cite journal | vauthors = Yang Y, Chan SW, Hu M, Walden R, Tomlinson B | title = Effects of some common food constituents on cardiovascular disease | journal = ISRN Cardiology | volume = 2011 | article-number = 397136 | year = 2011 | pmid = 22347642 | pmc = 3262529 | doi = 10.5402/2011/397136 | doi-access = free }}</ref> However their typically positive effects on lifespans when consumption is moderate<ref>{{cite journal |last1=Poole |first1=Robin |last2=Kennedy |first2=Oliver J. |last3=Roderick |first3=Paul |last4=Fallowfield |first4=Jonathan A. |last5=Hayes |first5=Peter C. |last6=Parkes |first6=Julie |title=Coffee consumption and health: umbrella review of meta-analyses of multiple health outcomes |journal=BMJ |date=22 November 2017 |volume=359 |article-number=j5024 |doi=10.1136/bmj.j5024 |pmid=29167102 |pmc=5696634 }}</ref><ref>{{cite journal |last1=O'Keefe |first1=James H. |last2=DiNicolantonio |first2=James J. |last3=Lavie |first3=Carl J. |title=Coffee for Cardioprotection and Longevity |journal=Progress in Cardiovascular Diseases |date=1 May 2018 |volume=61 |issue=1 |pages=38–42 |doi=10.1016/j.pcad.2018.02.002 |pmid=29474816 }}</ref><ref>{{cite journal |last1=Grosso |first1=Giuseppe |last2=Godos |first2=Justyna |last3=Galvano |first3=Fabio |last4=Giovannucci |first4=Edward L. |title=Coffee, Caffeine, and Health Outcomes: An Umbrella Review |journal=Annual Review of Nutrition |date=21 August 2017 |volume=37 |issue=1 |pages=131–156 |doi=10.1146/annurev-nutr-071816-064941 |pmid=28826374 }}</ref> have also been explained by effects on autophagy,<ref>{{cite journal |last1=Dirks-Naylor |first1=Amie J. |title=The benefits of coffee on skeletal muscle |journal=Life Sciences |date=15 December 2015 |volume=143 |pages=182–6 |doi=10.1016/j.lfs.2015.11.005 |pmid=26546720 }}</ref> glucose metabolism<ref>{{cite journal |last1=Reis |first1=Caio E. G. |last2=Dórea |first2=José G. |last3=da Costa |first3=Teresa H. M. |title=Effects of coffee consumption on glucose metabolism: A systematic review of clinical trials |journal=Journal of Traditional and Complementary Medicine |date=1 July 2019 |volume=9 |issue=3 |pages=184–191 |doi=10.1016/j.jtcme.2018.01.001 |pmid=31193893 |pmc=6544578 }}</ref> and AMPK.<ref>{{cite journal |last1=Loureiro |first1=Laís Monteiro Rodrigues |last2=Reis |first2=Caio Eduardo Gonçalves |last3=Costa |first3=Teresa Helena Macedo da |title=Effects of Coffee Components on Muscle Glycogen Recovery: A Systematic Review |journal=International Journal of Sport Nutrition and Exercise Metabolism |date=1 May 2018 |volume=28 |issue=3 |pages=284–293 |doi=10.1123/ijsnem.2017-0342 |pmid=29345166 }}</ref>

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 kidney 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.<ref name="KimuraSuzuki2008">{{cite book|vauthors=Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K|url=https://books.google.com/books?id=arjZMwAACAAJ&pg=PA1|title=New Research on DNA Damage|publisher=Nova Science Publishers|year=2008|isbn=978-1-60456-581-2|veditors=Kimura H, Suzuki A|pages=1–47|chapter=Cancer and aging as consequences of un-repaired DNA damage.|chapter-url=https://www.novapublishers.com/catalog/product_info.php?products_id=43247|access-date=4 February 2016|archive-date=15 November 2023|archive-url=https://web.archive.org/web/20231115062953/https://books.google.com/books?id=arjZMwAACAAJ&pg=PA1|url-status=live}}</ref><ref name="pmid27164092">{{cite journal | vauthors = Pan MR, Li K, Lin SY, Hung WC | title = Connecting the Dots: From DNA Damage and Repair to Aging | journal = International Journal of Molecular Sciences | volume = 17 | issue = 5 | page = 685 | date = May 2016 | pmid = 27164092 | pmc = 4881511 | doi = 10.3390/ijms17050685 | doi-access = free }}</ref>

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.<ref>{{cite journal | vauthors = Spencer RL, Hutchison KE | title = Alcohol, aging, and the stress response | journal = Alcohol Research & Health | volume = 23 | issue = 4 | pages = 272–83 | year = 1999 | pmid = 10890824 | pmc = 6760387 | url = http://pubs.niaaa.nih.gov/publications/arh23-4/272-283.pdf | access-date = 8 April 2008 | archive-date = 11 December 2018 | archive-url = https://web.archive.org/web/20181211163358/http://pubs.niaaa.nih.gov/publications/arh23-4/272-283.pdf }}</ref>

====DNA damage====

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.<ref name="Schumacher2021">{{Cite journal |last1=Schumacher |first1=Björn |last2=Pothof |first2=Joris |last3=Vijg |first3=Jan |last4=Hoeijmakers |first4=Jan H. J. |date=April 2021 |title=The central role of DNA damage in the ageing process |journal=Nature |volume=592 |issue=7856 |pages=695–703 |doi=10.1038/s41586-021-03307-7 |pmc=9844150 |pmid=33911272|bibcode=2021Natur.592..695S }}</ref> Slower rate of accumulation of DNA damage as measured by the DNA damage marker gamma H2AX in leukocytes was found to correlate with longer lifespans in comparisons of dolphins, goats, reindeer, American flamingos and griffon vultures.<ref>{{cite journal |vauthors=Whittemore K, Martínez-Nevado E, Blasco MA |title=Slower rates of accumulation of DNA damage in leukocytes correlate with longer lifespans across several species of birds and mammals |journal=Aging (Albany NY) |volume=11 |issue=21 |pages=9829–45 |date=November 2019 |pmid=31730540 |pmc=6874430 |doi=10.18632/aging.102430 }}</ref> DNA damage-induced epigenetic alterations, such as DNA methylation and many histone modifications, appear to be of particular importance to the aging process.<ref name = Schumacher2021/> Evidence for the theory that DNA damage is the fundamental cause of aging was first reviewed in 1981.<ref>{{Cite journal |last1=Gensler |first1=H. L. |last2=Bernstein |first2=H. |date=September 1981 |title=DNA damage as the primary cause of aging |journal=The Quarterly Review of Biology |volume=56 |issue=3 |pages=279–303 |doi=10.1086/412317 |pmid=7031747|s2cid=20822805 }}</ref>

====Mutation accumulation==== {{Main|Mutation accumulation theory}} 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.<ref>{{cite web |title=The Evolution of Aging |vauthors=Fabian D, Flatt T |date=2011 |work=Nature Education |url=https://core.ac.uk/download/pdf/190039034.pdf}}</ref>

Peter Medawar formalised this observation in his mutation accumulation theory of aging.<ref>{{Cite journal| vauthors = Medawar PB |year=1946 |title=Old age and natural death |journal=Modern Quarterly |volume=1 |pages=30–56}}</ref><ref>{{harvnb|Medawar|1952}}{{Page needed|date=September 2010}}</ref> "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".<ref>{{cite journal |last1=Liu |first1=Xiaoqian |last2=Liu |first2=Zunpeng |last3=Wu |first3=Zeming |last4=Ren |first4=Jie |last5=Fan |first5=Yanling |last6=Sun |first6=Liang |last7=Cao |first7=Gang |last8=Niu |first8=Yuyu |last9=Zhang |first9=Baohu |last10=Ji |first10=Qianzhao |last11=Jiang |first11=Xiaoyu |last12=Wang |first12=Cui |last13=Wang |first13=Qiaoran |last14=Ji |first14=Zhejun |last15=Li |first15=Lanzhu |last16=Esteban |first16=Concepcion Rodriguez |last17=Yan |first17=Kaowen |last18=Li |first18=Wei |last19=Cai |first19=Yusheng |last20=Wang |first20=Si |last21=Zheng |first21=Aihua |last22=Zhang |first22=Yong E. |last23=Tan |first23=Shengjun |last24=Cai |first24=Yingao |last25=Song |first25=Moshi |last26=Lu |first26=Falong |last27=Tang |first27=Fuchou |last28=Ji |first28=Weizhi |last29=Zhou |first29=Qi |last30=Belmonte |first30=Juan Carlos Izpisua |last31=Zhang |first31=Weiqi |last32=Qu |first32=Jing |last33=Liu |first33=Guang-Hui |title=Resurrection of endogenous retroviruses during aging reinforces senescence |journal=Cell |date=19 January 2023 |volume=186 |issue=2 |pages=287–304.e26 |doi=10.1016/j.cell.2022.12.017 |pmid=36610399 |s2cid=232060038 |language=English |doi-access=free }} * Expert explanation of the study: {{cite news |title=Aging and Retroviruses |url=https://www.science.org/content/blog-post/aging-and-retroviruses |access-date=17 February 2023 |work=Science |archive-date=17 February 2023 |archive-url=https://web.archive.org/web/20230217232037/https://www.science.org/content/blog-post/aging-and-retroviruses |url-status=live }}</ref>

=== Stem cell theories of aging === {{Excerpt|Stem cell theory of aging}} ;Hematopoietic stem cell aging {{Excerpt|Stem cell theory of aging|Hematopoietic stem cell aging|hat=no}} ;Hematopoietic stem cell diversity aging {{Excerpt|Stem cell theory of aging|Hematopoietic stem cell diversity aging|hat=no}} ;Hematopoietic mosaic loss of chromosome Y {{Excerpt|Stem cell theory of aging|Hematopoietic mosaic loss of chromosome Y|hat=no}}

==Biomarkers of aging== {{Main|Biomarkers of aging}}

If different individuals age at different rates, then fecundity, mortality, and functional capacity might be better predicted by biomarkers than by chronological age.<ref name="Gasmi">{{cite journal | vauthors = Gasmi A, Chirumbolo S, Peana M, Mujawdiya PK, Dadar M, Menzel A, Bjørklund G | title = Biomarkers of Senescence during Aging as Possible Warnings to Use Preventive Measures | journal = Current Medicinal Chemistry | volume = 28 | issue = 8 | pages = 1471–88 | date = 2020-09-17 | pmid = 32942969 | doi = 10.2174/0929867327999200917150652 | s2cid = 221789280 }}</ref><ref name="BakerGT">{{cite journal | vauthors = Baker GT, Sprott RL | title = Biomarkers of aging | journal = Experimental Gerontology | volume = 23 | issue = 4–5 | pages = 223–39 | year = 1988 | pmid = 3058488 | doi = 10.1016/0531-5565(88)90025-3 | s2cid = 31039588 | url = https://zenodo.org/record/1258547 | access-date = 12 July 2019 | archive-date = 24 October 2021 | archive-url = https://web.archive.org/web/20211024064308/https://zenodo.org/record/1258547 | url-status = live }}</ref> However, graying of hair,<ref>{{cite journal | vauthors = Van Neste D, Tobin DJ | title = Hair cycle and hair pigmentation: dynamic interactions and changes associated with aging | journal = Micron | volume = 35 | issue = 3 | pages = 193–200 | year = 2004 | pmid = 15036274 | doi = 10.1016/j.micron.2003.11.006 }}</ref> 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.

Levels of CD4 and CD8 memory T cells and naive T cells have been used to give good predictions of the expected lifespan of middle-aged mice.<ref>{{cite journal | vauthors = Miller RA | title = Biomarkers of aging: prediction of longevity by using age-sensitive T-cell subset determinations in a middle-aged, genetically heterogeneous mouse population | journal = The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences | volume = 56 | issue = 4 | pages = B180-6 | date = April 2001 | pmid = 11283189 | pmc = 7537444 | doi = 10.1093/gerona/56.4.b180 | doi-access = free }}</ref>

=== Aging clocks === There is increasing interest in epigenetic clocks as biomarkers of aging, based on their ability to predict human chronological age. Many epigenetic aging clocks are based on DNA methylation,<ref>{{cite journal |last1=Naue |first1=Jana |title=Getting the chronological age out of DNA: using insights of age-dependent DNA methylation for forensic DNA applications |journal=Genes & Genomics |date=October 2023 |volume=45 |issue=10 |pages=1239–1261 |doi=10.1007/s13258-023-01392-8|pmid=37253906 |pmc=10504122 }}</ref><ref name="10.1038/s41576-018-0004-3">{{cite journal | vauthors = Horvath S, Raj K | title = DNA methylation-based biomarkers and the epigenetic clock theory of ageing | journal = Nat Rev Genet | date = 2018 | volume = 19 | issue = 6 | pages = 371–384 | doi = 10.1038/s41576-018-0004-3 | pmid = 29643443 }}</ref> but alternative epigenetic clocks are also starting to emerge, e.g. based on nucleosome positioning derived from cell-free DNA.<ref name="10.1111/acel.14100">{{cite journal | vauthors = Shtumpf M, Jeong S, Bikova M, Mamayusupova H, Ruje L, Teif VB | title = Aging clock based on nucleosome reorganisation derived from cell-free DNA | journal = Aging Cell | date = 2024 | volume = 23 | issue = 5 | article-number = e14100 | pmid = 38337183 | pmc = 11113261 | doi = 10.1111/acel.14100 }}</ref> Basic blood biochemistry and cell counts can also be used to accurately predict the chronological age.<ref name="pmid27191382">{{cite journal | vauthors = Putin E, Mamoshina P, Aliper A, Korzinkin M, Moskalev A, Kolosov A, Ostrovskiy A, Cantor C, Vijg J, Zhavoronkov A | title = Deep biomarkers of human aging: Application of deep neural networks to biomarker development | journal = Aging | volume = 8 | issue = 5 | pages = 1021–33 | date = May 2016 | pmid = 27191382 | pmc = 4931851 | doi = 10.18632/aging.100968 }}</ref> It is also possible to predict the human chronological age using transcriptomic aging clocks.<ref>{{cite journal | vauthors = Peters MJ, Joehanes R, Pilling LC, Schurmann C, Conneely KN, Powell J, Reinmaa E, Sutphin GL, Zhernakova A, Schramm K, Wilson YA, Kobes S, Tukiainen T, Ramos YF, Göring HH, Fornage M, Liu Y, Gharib SA, Stranger BE, De Jager PL, Aviv A, Levy D, Murabito JM, Munson PJ, Huan T, Hofman A, Uitterlinden AG, Rivadeneira F, van Rooij J, Stolk L, Broer L, Verbiest MM, Jhamai M, Arp P, Metspalu A, Tserel L, Milani L, Samani NJ, Peterson P, Kasela S, Codd V, Peters A, Ward-Caviness CK, Herder C, Waldenberger M, Roden M, Singmann P, Zeilinger S, Illig T, Homuth G, Grabe HJ, Völzke H, Steil L, Kocher T, Murray A, Melzer D, Yaghootkar H, Bandinelli S, Moses EK, Kent JW, Curran JE, Johnson MP, Williams-Blangero S, Westra HJ, McRae AF, Smith JA, Kardia SL, Hovatta I, Perola M, Ripatti S, Salomaa V, Henders AK, Martin NG, Smith AK, Mehta D, Binder EB, Nylocks KM, Kennedy EM, Klengel T, Ding J, Suchy-Dicey AM, Enquobahrie DA, Brody J, Rotter JI, Chen YD, Houwing-Duistermaat J, Kloppenburg M, Slagboom PE, Helmer Q, den Hollander W, Bean S, Raj T, Bakhshi N, Wang QP, Oyston LJ, Psaty BM, Tracy RP, Montgomery GW, Turner ST, Blangero J, Meulenbelt I, Ressler KJ, Yang J, Franke L, Kettunen J, Visscher PM, Neely GG, Korstanje R, Hanson RL, Prokisch H, Ferrucci L, Esko T, Teumer A, van Meurs JB, Johnson AD | title = The transcriptional landscape of age in human peripheral blood | journal = Nature Communications | volume = 6 | article-number = 8570 | date = October 2015 | pmid = 26490707 | pmc = 4639797 | doi = 10.1038/ncomms9570 | bibcode = 2015NatCo...6.8570. }}</ref>

There is research and development of further biomarkers, detection systems, and software systems to measure the 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,<ref>{{cite journal |last1=Yin |first1=Chenzhong |last2=Imms |first2=Phoebe |last3=Cheng |first3=Mingxi |display-authors=et al. |title=Anatomically interpretable deep learning of brain age captures domain-specific cognitive impairment |journal=Proceedings of the National Academy of Sciences |date=10 January 2023 |volume=120 |issue=2 |article-number=e2214634120 |doi=10.1073/pnas.2214634120 |doi-access=free |pmid=36595679 |pmc=9926270 |bibcode=2023PNAS..12014634Y }} * University press release: {{cite news |title=How old is your brain, really? AI-powered analysis accurately reflects risk of cognitive decline and Alzheimer's disease |url=https://medicalxpress.com/news/2023-01-brain-ai-powered-analysis-accurately-cognitive.html |access-date=17 February 2023 |work=University of Southern California via medicalxpress.com |archive-date=17 February 2023 |archive-url=https://web.archive.org/web/20230217232042/https://medicalxpress.com/news/2023-01-brain-ai-powered-analysis-accurately-cognitive.html |url-status=live }} * News article about the study: {{cite news |title=KI kann wahres Alter des Hirns bestimmen |url=https://www.deutschlandfunknova.de/nachrichten/alterungsprozess-ki-kann-wahres-alter-des-hirns-bestimmen |access-date=17 February 2023 |work=Deutschlandfunk Nova |language=de |archive-date=17 February 2023 |archive-url=https://web.archive.org/web/20230217232037/https://www.deutschlandfunknova.de/nachrichten/alterungsprozess-ki-kann-wahres-alter-des-hirns-bestimmen |url-status=live }}</ref> and a DL tool was reported as to calculate a person's inflammatory age based on patterns of systemic age-related inflammation.<ref>{{cite journal |last1=Sayed |first1=Nazish |last2=Huang |first2=Yingxiang |last3=Nguyen |first3=Khiem |last4=Krejciova-Rajaniemi |first4=Zuzana |last5=Grawe |first5=Anissa P. |last6=Gao |first6=Tianxiang |last7=Tibshirani |first7=Robert |last8=Hastie |first8=Trevor |last9=Alpert |first9=Ayelet |last10=Cui |first10=Lu |last11=Kuznetsova |first11=Tatiana |last12=Rosenberg-Hasson |first12=Yael |last13=Ostan |first13=Rita |last14=Monti |first14=Daniela |last15=Lehallier |first15=Benoit |last16=Shen-Orr |first16=Shai S. |last17=Maecker |first17=Holden T. |last18=Dekker |first18=Cornelia L. |last19=Wyss-Coray |first19=Tony |last20=Franceschi |first20=Claudio |last21=Jojic |first21=Vladimir |last22=Haddad |first22=François |last23=Montoya |first23=José G. |last24=Wu |first24=Joseph C. |last25=Davis |first25=Mark M. |last26=Furman |first26=David |title=An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging |journal=Nature Aging |date=July 2021 |volume=1 |issue=7 |pages=598–615 |doi=10.1038/s43587-021-00082-y |pmid=34888528 |pmc=8654267 |doi-access=free }} * News article about the study: {{cite news |title=Tool that calculates immune system age could predict frailty and disease |url=https://newatlas.com/science/stanford-immune-system-age-biomarker-blood-test/ |access-date=26 July 2021 |work=New Atlas |date=13 July 2021 |archive-date=26 July 2021 |archive-url=https://web.archive.org/web/20210726110032/https://newatlas.com/science/stanford-immune-system-age-biomarker-blood-test/ |url-status=live }}</ref>

Aging clocks have been used to evaluate the impacts of interventions on humans, including combination therapies.<ref>{{cite journal |title=Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial |journal=Aging |year=2021 |pmid=33844651 |url=https://www.aging-us.com/article/202913/text |access-date=28 June 2021 |last1=Fitzgerald |first1=K. N. |last2=Hodges |first2=R. |last3=Hanes |first3=D. |last4=Stack |first4=E. |last5=Cheishvili |first5=D. |last6=Szyf |first6=M. |last7=Henkel |first7=J. |last8=Twedt |first8=M. W. |last9=Giannopoulou |first9=D. |last10=Herdell |first10=J. |last11=Logan |first11=S. |last12=Bradley |first12=R. |volume=13 |issue=7 |pages=9419–32 |doi=10.18632/aging.202913 |pmc=8064200 |archive-date=2 June 2021 |archive-url=https://web.archive.org/web/20210602114006/https://www.aging-us.com/article/202913/text |url-status=live }}</ref>{{additional citation needed|date=March 2023}} 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.<ref>{{Cite journal |last1=Moqri |first1=Mahdi |last2=Herzog |first2=Chiara |last3=Poganik |first3=Jesse R. |last4=Justice |first4=Jamie |last5=Belsky |first5=Daniel W. |last6=Higgins-Chen |first6=Albert |last7=Moskalev |first7=Alexey |last8=Fuellen |first8=Georg |last9=Cohen |first9=Alan A. |last10=Bautmans |first10=Ivan |last11=Widschwendter |first11=Martin |last12=Ding |first12=Jingzhong |last13=Fleming |first13=Alexander |last14=Mannick |first14=Joan |last15=Han |first15=Jing-Dong Jackie |date=August 2023 |title=Biomarkers of aging for the identification and evaluation of longevity interventions |journal=Cell |volume=186 |issue=18 |pages=3758–75 |doi=10.1016/j.cell.2023.08.003 |pmid=37657418 |pmc=11088934 }}</ref><ref>{{Cite journal |last1=Moqri |first1=Mahdi |last2=Herzog |first2=Chiara |last3=Poganik |first3=Jesse R. |last4=Ying |first4=Kejun |last5=Justice |first5=Jamie N. |last6=Belsky |first6=Daniel W. |last7=Higgins-Chen |first7=Albert T. |last8=Chen |first8=Brian H. |last9=Cohen |first9=Alan A. |last10=Fuellen |first10=Georg |last11=Hägg |first11=Sara |last12=Marioni |first12=Riccardo E. |last13=Widschwendter |first13=Martin |last14=Fortney |first14=Kristen |last15=Fedichev |first15=Peter O. |date=February 2024 |title=Validation of biomarkers of aging |journal=Nature Medicine |volume=30 |issue=2 |pages=360–372 |doi=10.1038/s41591-023-02784-9 |issn=1546-170X |pmid=38355974|pmc=11090477 }}</ref>

==Genetic determinants of aging == {{Main|Genetics of aging}}

Several 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.

Gene expression is imperfectly controlled, and random fluctuations in the expression levels of many genes may contribute to the aging process, as suggested by a study of such genes in yeast.<ref>{{cite journal | vauthors = Ryley J, Pereira-Smith OM | title = Microfluidics device for single cell gene expression analysis in Saccharomyces cerevisiae | journal = Yeast | volume = 23 | issue = 14–15 | pages = 1065–73 | year = 2006 | pmid = 17083143 | doi = 10.1002/yea.1412 | s2cid = 31356425 }}</ref> 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<ref name="pmid25033455">{{cite journal |vauthors=Vaidya A, Mao Z, Tian X, Spencer B, Seluanov A, Gorbunova V |title=Knock-in reporter mice demonstrate that DNA repair by non-homologous end joining declines with age |journal=PLOS Genet. |volume=10 |issue=7 |article-number=e1004511 |date=July 2014 |pmid=25033455 |pmc=4102425 |doi=10.1371/journal.pgen.1004511 |doi-access=free }}</ref> and humans.<ref name="pmid27391797">{{cite journal |vauthors=Li Z, Zhang W, Chen Y, Guo W, Zhang J, Tang H, Xu Z, Zhang H, Tao Y, Wang F, Jiang Y, Sun FL, Mao Z |title=Impaired DNA double-strand break repair contributes to the age-associated rise of genomic instability in humans |doi-access=free |journal=Cell Death Differ. |volume=23 |issue=11 |pages=1765–77 |date=November 2016 |pmid=27391797 |pmc=5071568 |doi=10.1038/cdd.2016.65 }}</ref>

A set of rare hereditary (genetics) 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.<ref>{{cite journal | vauthors = Mounkes LC, Kozlov S, Hernandez L, Sullivan T, Stewart CL | title = A progeroid syndrome in mice is caused by defects in A-type lamins | journal = Nature | volume = 423 | issue = 6937 | pages = 298–301 | date = May 2003 | pmid = 12748643 | doi = 10.1038/nature01631 | s2cid = 4360055 | bibcode = 2003Natur.423..298M | url = https://zenodo.org/record/1233263 |via=Zenodo |s2cid-access=free | access-date = 21 July 2021 | archive-date = 30 May 2022 | archive-url = https://web.archive.org/web/20220530212807/https://zenodo.org/record/1233263 | url-status = live }}</ref> This report suggests that DNA damage, not oxidative 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.<ref>{{cite journal |last1=Stoeger |first1=Thomas |last2=Grant |first2=Rogan A. |last3=McQuattie-Pimentel |first3=Alexandra C. |last4=Anekalla |first4=Kishore R. |last5=Liu |first5=Sophia S. |last6=Tejedor-Navarro |first6=Heliodoro |last7=Singer |first7=Benjamin D. |last8=Abdala-Valencia |first8=Hiam |last9=Schwake |first9=Michael |last10=Tetreault |first10=Marie-Pier |last11=Perlman |first11=Harris |last12=Balch |first12=William E. |last13=Chandel |first13=Navdeep S. |last14=Ridge |first14=Karen M. |last15=Sznajder |first15=Jacob I. |last16=Morimoto |first16=Richard I. |last17=Misharin |first17=Alexander V. |last18=Budinger |first18=G. R. Scott |last19=Nunes Amaral |first19=Luis A. |title=Aging is associated with a systemic length-associated transcriptome imbalance |journal=Nature Aging |date=December 2022 |volume=2 |issue=12 |pages=1191–1206 |doi=10.1038/s43587-022-00317-6 |pmid=37118543 |pmc=10154227 |doi-access=free}} * University press release: {{cite news |title=Aging is driven by unbalanced genes, finds AI analysis of multiple species |url=https://phys.org/news/2022-12-aging-driven-unbalanced-genes-ai.html |access-date=18 January 2023 |work=Northwestern University |via=phys.org |date=December 9, 2022 |archive-date=2 February 2023 |archive-url=https://web.archive.org/web/20230202173100/https://phys.org/news/2022-12-aging-driven-unbalanced-genes-ai.html |url-status=live }} * News article about the study: {{cite news |last1=Kwon |first1=Diana |title=Aging Is Linked to More Activity in Short Genes Than in Long Genes |url=https://www.scientificamerican.com/article/aging-is-linked-to-more-activity-in-short-genes-than-in-long-genes/ |url-access=subscription |date=January 6, 2023 |access-date=18 January 2023 |work=Scientific American |archive-date=17 January 2023 |archive-url=https://web.archive.org/web/20230117052143/https://www.scientificamerican.com/article/aging-is-linked-to-more-activity-in-short-genes-than-in-long-genes/ |url-status=live }}</ref>

== Healthspans and aging in society == [[File:Global aging demographics.webp|thumb|Past and projected age of the human world population through time as of 2021<ref name="10.1038/s41536-021-00169-5">{{cite journal |last1=Garmany |first1=Armin |last2=Yamada |first2=Satsuki |last3=Terzic |first3=Andre |title=Longevity leap: mind the healthspan gap |journal=npj Regenerative Medicine |date=23 September 2021 |volume=6 |issue=1 |page=57 |doi=10.1038/s41536-021-00169-5 |pmid=34556664 |pmc=8460831 |doi-access=free}} * Non-profit hospital press release: {{cite news |first1=Susan |last1=Buckles |title=A regenerative reset for aging » Center for Regenerative Biotherapeutics |url=https://regenerativemedicineblog.mayoclinic.org/2021/10/07/a-regenerative-reset-for-aging |date=October 7, 2021 |access-date=1 March 2023 |work=Mayo Clinic |archive-date=1 March 2023 |archive-url=https://web.archive.org/web/20230301172642/https://regenerativemedicineblog.mayoclinic.org/2021/10/07/a-regenerative-reset-for-aging/ |url-status=live }}</ref>]] thumb|Healthspan-lifespan gap (LHG)<ref name="10.1038/s41536-021-00169-5"/> thumb|Healthspan extension relies on the unison of social, clinical and scientific programs or domains of work.<ref name="10.1038/s41536-021-00169-5"/> Healthspan can broadly be defined as the period of one's life that one is healthy, such as being free of significant diseases<ref name="importance"/> or declines of capacities (e.g., senses such as hearing, muscle, endurance and cognition). {{Excerpt|Global health|Multimorbidity, age-related diseases and aging|paragraphs=2|only=paragraphs}} 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).<ref name="10.1038/s41536-021-00169-5"/><ref name="10.1016/j.tcb.2016.05.002"/> This, along with global quality of life or wellbeing, highlight the importance of extending healthspans.<ref name="10.1038/s41536-021-00169-5"/>

Although interventions which extend lifespan may also extend healthspan, this is not always the case, suggesting that "lifespan can no longer be the sole parameter of interest," in related research.<ref>{{cite journal |last1=Bansal |first1=Ankita |last2=Zhu |first2=Lihua J. |last3=Yen |first3=Kelvin |last4=Tissenbaum |first4=Heidi A. |title=Uncoupling lifespan and healthspan in Caenorhabditis elegans longevity mutants |journal=Proceedings of the National Academy of Sciences |date=20 January 2015 |volume=112 |issue=3 |pages=E277-86 |doi=10.1073/pnas.1412192112 |pmid=25561524 |pmc=4311797 |bibcode=2015PNAS..112E.277B |doi-access=free }}</ref> When increases in life expectancy outpaced improvements in healthspan,<ref name="10.1038/s41536-021-00169-5"/> public awareness of these 'healthspan lags' began rising around 2017.<ref name="importance">{{cite web |title=Healthspan is more important than lifespan, so why don't more people know about it? |url=https://publichealth.wustl.edu/heatlhspan-is-more-important-than-lifespan-so-why-dont-more-people-know-about-it/ |work=Institute for Public Health |publisher=Washington University in St. Louis |date=May 30, 2017 |first1=Tim |last1=Peterson |agency=Harvey A. Friedman Center for Aging |access-date=1 March 2023 |archive-date=1 March 2023 |archive-url=https://web.archive.org/web/20230301172634/https://publichealth.wustl.edu/heatlhspan-is-more-important-than-lifespan-so-why-dont-more-people-know-about-it/ |url-status=live }}</ref> Scientists have noted that "Chronic diseases of aging are increasing and are inflicting untold costs on human quality of life".<ref name="10.1016/j.tcb.2016.05.002">{{cite journal |last1=Hansen |first1=Malene |last2=Kennedy |first2=Brian K. |title=Does Longer Lifespan Mean Longer Healthspan? |journal=Trends in Cell Biology |date=1 August 2016 |volume=26 |issue=8 |pages=565–8 |doi=10.1016/j.tcb.2016.05.002 |pmid=27238421 |pmc=4969078 |language=English }}</ref>

== Interventions == {{Excerpt|Life extension}}

==See also== {{div col|colwidth=22em}} * Anti-aging movement * Antimuscarinics * Dementia * DNA repair * Geriatrics * Gerontology * Homeostatic capacity * Immortality * Index of topics related to life extension * Mitohormesis * Old age * Phenoptosis * Plant senescence * Programmed cell death  * Strategies for engineered negligible senescence (SENS) * Sub-lethal damage * Transgenerational design * Timeline of senescence research {{div col end}}

==References== {{Reflist}}

==External links== {{Wiktionary}} {{Commons category}}

Category:Senescence Category:Ailments of unknown cause Category:Cellular processes  Category:Old age Category:Causes of death