Editing Senescence (section)

=== 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 [[Radical (chemistry)|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 people|Klamath]] woman photographed by [[Edward S. Curtis]] in 1924]]
One of the earliest aging theories was the ''[[Rate-of-living theory|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. [[Calorie restriction|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 [[Phylogenetic tree|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>

With respect to specific types of chemical damage caused by metabolism, it is suggested that damage to long-lived [[biopolymer]]s, such as structural [[protein]]s or [[DNA damage theory of aging|DNA]], caused by ubiquitous chemical agents in the body such as [[oxygen]] and [[sugar]]s, are in part responsible for aging. The damage can include breakage of biopolymer chains, [[cross-link]]ing of biopolymers, or chemical attachment of unnatural substituents ([[hapten]]s) to biopolymers.{{citation needed|date=December 2019}}
Under normal [[wikt:aerobic|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 (chemistry)|radical]] and eventually other reactive species including other [[peroxide]]s and [[singlet oxygen]], which can, in turn, generate [[radical (chemistry)|free radical]]s capable of damaging structural proteins and DNA.<ref name="pmid1383772" /> Certain metal [[ion]]s found in the body, such as [[copper]] and [[iron]], may participate in the process. (In [[Wilson's disease]], a [[genetic disorder|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]] [[antioxidant]]s, 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 [[green tea|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 | pages = 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 |pages=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 [[AMP-activated protein kinase|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>

[[Sugar]]s such as [[glucose]] and [[fructose]] can react with certain [[amino acid]]s 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 ''[[Advanced glycation endproduct|glycoxidation]]''.

[[Reactive oxygen species|Free radicals]] can damage proteins, [[lipid]]s or [[DNA damage theory of aging|DNA]]. [[Glycation]] mainly damages proteins. Damaged proteins and lipids accumulate in [[lysosome]]s 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 [[enzyme]]s reduces cellular functionality. Lipid [[redox|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 disease]]s" 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=978-1604565812|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 | pages = 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 | url-status = dead }}</ref>

====DNA damage====

[[DNA damage (naturally occurring)|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 (naturally occurring)|DNA damage]] as measured by the DNA damage marker gamma H2AX in leukocytes was found to correlate with longer lifespans in comparisons of [[dolphin]]s, [[goat]]s, [[reindeer]], [[American flamingo]]s and [[Eurasian griffon vulture|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 [[epigenetics|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 |url=https://pubmed.ncbi.nlm.nih.gov/7031747/ |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 [[allele]]s, 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 [[Evolution of ageing#Mutation accumulation|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 [[retrovirus]]es in the [[human genome]]s can become awakened from dormant states and contribute to aging which can be blocked by [[Neutralizing antibody|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>