DNA damage theory of aging

{{further|DNA repair|DNA damage (naturally occurring)|Mutation}}

File:8-Oxo-2'-deoxyguanosine.svg

To understand the DNA damage theory of aging it is important to distinguish between DNA damage and mutation, the two major types of errors that occur in DNA. Damage and mutation are fundamentally different. DNA damage is any physical abnormality in the DNA, such as single and double strand breaks, 8-hydroxydeoxyguanosine residues and polycyclic aromatic hydrocarbon adducts. DNA damage can be recognized by enzymes, and thus can be correctly repaired using the complementary undamaged strand in DNA as a template or an undamaged sequence in a homologous chromosome if it is available for copying. If a cell retains DNA damage, transcription of a gene can be prevented and thus translation into a protein will also be blocked. Replication may also be blocked and/or the cell may die. Descriptions of reduced function, characteristic of aging and associated with accumulation of DNA damage, are described in the next section.{{cn|date=November 2024}}

In contrast to DNA damage, a mutation is a change in the base sequence of the DNA. A mutation cannot be recognized by enzymes once the base change is present in both DNA strands, and thus a mutation cannot be repaired. At the cellular level, mutations can cause alterations in protein function and regulation. Mutations are replicated when the cell replicates. In a population of cells, mutant cells will increase or decrease in frequency according to the effects of the mutation on the ability of the cell to survive and reproduce. Although distinctly different from each other, DNA damages and mutations are related because DNA damages often cause errors of DNA synthesis during replication or repair and these errors are a major source of mutation.{{cn|date=November 2024}}

Given these properties of DNA damage and mutation, it can be seen that DNA damages are a special problem in non-dividing or slowly dividing cells, where unrepaired damages will tend to accumulate over time. On the other hand, in rapidly dividing cells, unrepaired DNA damages that do not kill the cell by blocking replication will tend to cause replication errors and thus mutation. The great majority of mutations that are not neutral in their effect are deleterious to a cell's survival. Thus, in a population of cells comprising a tissue with replicating cells, mutant cells will tend to be lost. However, infrequent mutations that provide a survival advantage will tend to clonally expand at the expense of neighboring cells in the tissue. This advantage to the cell is disadvantageous to the whole organism, because such mutant cells can give rise to cancer. Thus, DNA damages in frequently dividing cells, because they give rise to mutations, are a prominent cause of cancer. In contrast, DNA damages in infrequently dividing cells are likely a prominent cause of aging.{{cn|date=November 2024}}

The first person to suggest that DNA damage, as distinct from mutation, is the primary cause of aging was Alexander in 1967.{{cite conference | pmid = 4860956 | volume=21 | title=The role of DNA lesions in the processes leading to aging in mice | year=1967 | pages=29–50 | journal=Symp Soc Exp Biol | last1 = Alexander | first1 = P.}} By the early 1980s there was significant experimental support for this idea in the literature.{{cite journal | last1 = Gensler | first1 = H. L. | last2 = Bernstein | first2 = H. | date = September 1981 | title = DNA damage as the primary cause of aging | journal = Q Rev Biol | volume = 56 | issue = 3 | pages = 279–303 | doi = 10.1086/412317 | pmid = 7031747 | s2cid = 20822805 }} By the early 1990s experimental support for this idea was substantial, and furthermore it had become increasingly evident that oxidative DNA damage, in particular, is a major cause of aging.{{cite book|last1=Bernstein|first1=C.|last2=Bernstein|first2=H.|year=1991|title=Aging, Sex, and DNA Repair|publisher=Academic Press|location=San Diego|isbn=978-0-12-092860-6|url=https://books.google.com/books?id=BaXYYUXy71cC&pg=PA3}}{{cite journal | pmid = 1944345 | volume=250 | issue=1–2 | title=Endogenous mutagens and the causes of aging and cancer | year=1991 | pages=3–16 | doi=10.1016/0027-5107(91)90157-j | journal=Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis | last1 = Ames | first1 = B. N. | last2 = Gold | first2 = L. S.| bibcode=1991MRFMM.250....3A | url=https://zenodo.org/record/1258240 }}{{cite journal | pmid = 1383773 | volume=275 | issue=3–6 | title=DNA damage and repair in brain: relationship to aging | date=September 1992 | pages=317–329 | doi=10.1016/0921-8734(92)90035-N | journal=Mutation Research/DNAging | last1 = Rao | first1 = K. S. | last2 = Loeb | first2 = L. A.}}{{cite journal | pmid = 8367443 | pmc=47258 | volume=90 | issue=17 | title=Oxidants, antioxidants, and the degenerative diseases of aging | date=September 1993 | pages=7915–22 | doi=10.1073/pnas.90.17.7915 | journal=Proceedings of the National Academy of Sciences | last1 = Ames | first1 = B. N. | last2 = Shigenaga | first2 = M. K. | last3 = Hagen | first3 = T. M.| bibcode=1993PNAS...90.7915A | doi-access=free }}{{overcite|date=November 2024}}

In a series of articles from 1970 to 1977, PV Narasimh Acharya, Phd. (1924–1993) theorized and presented evidence that cells undergo "irreparable DNA damage", whereby DNA crosslinks occur when both normal cellular repair processes fail and cellular apoptosis does not occur. Specifically, Acharya noted that double-strand breaks and a "cross-linkage joining both strands at the same point is irreparable because neither strand can then serve as a template for repair. The cell will die in the next mitosis or in some rare instances, mutate."{{cite journal |last=Acharya | first=P. V. |title=The isolation and partial characterization of age-correlated oligo-deoxyribo-ribonucleotides with covalently linked aspartyl-glutamyl polypeptides |journal=Johns Hopkins Med. J. Suppl. |issue=1 |pages=254–260 |year=1972 |pmid=5055816 }}{{cite journal|last1=Acharya|first1=P. V.|last2=Ashman|first2=S. M.|last3=Bjorksten|first3=J|title=The isolation and partial characterization of age-correlated oligo-deoxyribo-ribo nucleo peptides|journal=Finska Kemists Medd|volume=81|number=3|year=1972}}{{cite conference|last=Acharya|first=P. V. N.|title=Isolation and Partial Characterization of Age-Correlated Oligo-nucleotides with Covalently Bound Peptides|journal=14th Nordic Congress|location=Umeå, Sweden|date=June 19, 1971}}{{cite conference|last=Acharya|first=P. V. N.|title=DNA-damage: The Cause of Aging|journal=Ninth International Congress of Biochemistry|location=Stockholm|date=July 1–7, 1973}}{{cite journal | last1 = Acharya | first1 = P. V. N. | year = 1977 | title = Irreparable DNA-damage by Industrial Pollutants in Pre-mature Aging, Chemical Carcinogenesis and Cardiac Hypertrophy: Experiments and Theory | journal = Israel Journal of Medical Sciences | volume = 13 | page = 441 }}{{overcite|date=November 2024}}

{{further|DNA damage (naturally occurring)}}

In tissues composed of non- or infrequently replicating cells, DNA damage can accumulate with age and lead either to loss of cells, or, in surviving cells, loss of gene expression. Accumulated DNA damage is usually measured directly. Numerous studies of this type have indicated that oxidative damage to DNA is particularly important.{{Cite journal | last1 = Sinha | first1 = Jitendra Kumar | last2 = Ghosh | first2 = Shampa | last3 = Swain | first3 = Umakanta | last4 = Giridharan | first4 = Nappan Veethil | last5 = Raghunath | first5 = Manchala | title =Increased macromolecular damage due to oxidative stress in the neocortex and hippocampus of WNIN/Ob, a novel rat model of premature aging | journal = Neuroscience | volume = 269 | pages = 256–64 | date= 2014 | pmid = 24709042 | doi = 10.1016/j.neuroscience.2014.03.040 | s2cid = 9934178 }} The loss of expression of specific genes can be detected at both the mRNA level and protein level. {{cn|date=November 2024}}

Other form of age-associated changes in gene expression is increased transcriptional variability, that was found first in a selected panel of genes in heart cells {{cite journal |vauthors=Bahar R, Hartmann CH, Rodriguez KA, Denny AD, Busuttil RA, Dollé ME, Calder RB, Chisholm GB, Pollock BH, Klein CA, Vijg J |title=Increased cell-to-cell variation in gene expression in ageing mouse heart |journal=Nature |volume=441 |issue=7096 |pages=1011–4 |date=June 2006 |pmid=16791200 |doi=10.1038/nature04844 |bibcode=2006Natur.441.1011B |hdl=10029/5612 |hdl-access=free }} and, more recently, in the whole transcriptomes of immune cells,{{cite journal |vauthors=Martinez-Jimenez CP, Eling N, Chen HC, Vallejos CA, Kolodziejczyk AA, Connor F, Stojic L, Rayner TF, Stubbington MJ, Teichmann SA, de la Roche M, Marioni JC, Odom DT |title=Aging increases cell-to-cell transcriptional variability upon immune stimulation |journal=Science |volume=355 |issue=6332 |pages=1433–6 |date=March 2017 |pmid=28360329 |pmc=5405862 |doi=10.1126/science.aah4115 |bibcode=2017Sci...355.1433M }} and human pancreas cells.{{cite journal |vauthors=Enge M, Arda HE, Mignardi M, Beausang J, Bottino R, Kim SK, Quake SR |title=Single-Cell Analysis of Human Pancreas Reveals Transcriptional Signatures of Aging and Somatic Mutation Patterns |journal=Cell |volume=171 |issue=2 |pages=321–330.e14 |date=October 2017 |pmid=28965763 |pmc=6047899 |doi=10.1016/j.cell.2017.09.004 }}

{{further|Aging brain}}

The adult brain is composed in large part of terminally differentiated non-dividing neurons. Many of the conspicuous features of aging reflect a decline in neuronal function. Accumulation of DNA damage with age in the mammalian brain has been reported during the period 1971 to 2008 in at least 29 studies.{{cite book |vauthors=Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K |chapter=1. Cancer and aging as consequences of un-repaired DNA damage |editor-first=Honoka |editor-last=Kimura |editor2-first=Aoi |editor2-last=Suzuki |title=New Research on DNA Damages |publisher=Nova Science |date=2008 |isbn= 978-1-60456-581-2 |oclc=213848806 |pages=1–47 }} This DNA damage includes the oxidized nucleoside 8-oxo-2'-deoxyguanosine (8-oxo-dG), single- and double-strand breaks, DNA-protein crosslinks and malondialdehyde adducts (reviewed in Bernstein et al.). Increasing DNA damage with age has been reported in the brains of the mouse, rat, gerbil, rabbit, dog, and human.

Rutten et al.{{cite journal | last1 = Rutten | first1 = BP | last2 = Schmitz | first2 = C | last3 = Gerlach | first3 = OH | last4 = Oyen | first4 = HM | last5 = de Mesquita | first5 = EB | last6 = Steinbusch | first6 = HW | last7 = Korr | first7 = H | date = Jan 2007 | title = The aging brain: accumulation of DNA damage or neuron loss? | journal = Neurobiol Aging | volume = 28 | issue = 1| pages = 91–8 | doi = 10.1016/j.neurobiolaging.2005.10.019 | pmid = 16338029 | s2cid = 14620944 }} showed that single-strand breaks accumulate in the mouse brain with age. Young 4-day-old rats have about 3,000 single-strand breaks and 156 double-strand breaks per neuron, whereas in rats older than 2 years the level of damage increases to about 7,400 single-strand breaks and 600 double-strand breaks per neuron.{{cite journal |vauthors=Mandavilli BS, Rao KS |title=Accumulation of DNA damage in aging neurons occurs through a mechanism other than apoptosis |journal=J. Neurochem. |volume=67 |issue=4 |pages=1559–65 |year=1996 |pmid=8858940 |doi= 10.1046/j.1471-4159.1996.67041559.x|s2cid=42442582 }} Sen et al.{{cite journal | last1 = Sen | first1 = T | last2 = Jana | first2 = S | last3 = Sreetama | first3 = S | last4 = Chatterjee | first4 = U | last5 = Chakrabarti | first5 = S | date = Mar 2007 | title = Gene-specific oxidative lesions in aged rat brain detected by polymerase chain reaction inhibition assay | journal = Free Radic. Res. | volume = 41 | issue = 3| pages = 288–94 | doi = 10.1080/10715760601083722 | pmid = 17364957 | s2cid = 23610941 }} showed that DNA damages which block the polymerase chain reaction in rat brain accumulate with age. Swain and Rao observed marked increases in several types of DNA damages in aging rat brain, including single-strand breaks, double-strand breaks and modified bases (8-OHdG and uracil).{{cite journal | last1 = Swain | first1 = U | last2 = Subba Rao | first2 = K | date = Aug 2011 | title = Study of DNA damage via the comet assay and base excision repair activities in rat brain neurons and astrocytes during aging | journal = Mech Ageing Dev | volume = 132 | issue = 8–9| pages = 374–81 | doi = 10.1016/j.mad.2011.04.012 | pmid = 21600238 | s2cid = 22466782 }} Wolf et al.{{cite journal | last1 = Wolf | first1 = FI | last2 = Fasanella | first2 = S | last3 = Tedesco | first3 = B | last4 = Cavallini | first4 = G | last5 = Donati | first5 = A | last6 = Bergamini | first6 = E | last7 = Cittadini | first7 = A | date = Mar 2005 | title = Peripheral lymphocyte 8-OHdG levels correlate with age-associated increase of tissue oxidative DNA damage in Sprague-Dawley rats. Protective effects of caloric restriction | journal = Exp Gerontol | volume = 40 | issue = 3| pages = 181–8 | doi = 10.1016/j.exger.2004.11.002 | pmid = 15763395 | s2cid = 23752647 }} also showed that the oxidative DNA damage 8-OHdG accumulates in rat brain with age. Similarly, it was shown that as humans age from 48 to 97 years, 8-OHdG accumulates in the brain.{{cite journal | last1 = Mecocci | first1 = P | last2 = MacGarvey | first2 = U | last3 = Kaufman | first3 = AE | last4 = Koontz | first4 = D | last5 = Shoffner | first5 = JM | last6 = Wallace | first6 = DC | last7 = Beal | first7 = MF | date = Oct 1993 | title = Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain | journal = Ann Neurol | volume = 34 | issue = 4| pages = 609–16 | doi = 10.1002/ana.410340416 | pmid = 8215249 | s2cid = 25479410 }}

Lu et al.{{cite journal | last1 = Lu | first1 = T | last2 = Pan | first2 = Y | last3 = Kao | first3 = SY | last4 = Li | first4 = C | last5 = Kohane | first5 = I | last6 = Chan | first6 = J | last7 = Yankner | first7 = BA | date = Jun 2004 | title = Gene regulation and DNA damage in the ageing human brain | journal = Nature | volume = 429 | issue = 6994| pages = 883–91 | doi = 10.1038/nature02661 | pmid = 15190254 | bibcode = 2004Natur.429..883L | s2cid = 1867993 }} studied the transcriptional profiles of the human frontal cortex of individuals ranging from 26 to 106 years of age. This led to the identification of a set of genes whose expression was altered after age 40. These genes play central roles in synaptic plasticity, vesicular transport and mitochondrial function. In the brain, promoters of genes with reduced expression have markedly increased DNA damage. In cultured human neurons, these gene promoters are selectively damaged by oxidative stress. Thus Lu et al. concluded that DNA damage may reduce the expression of selectively vulnerable genes involved in learning, memory and neuronal survival, initiating a program of brain aging that starts early in adult life.{{cn|date=November 2024}}

{{further|Muscle}}

Muscle strength, and stamina for sustained physical effort, decline in function with age in humans and other species. Skeletal muscle is a tissue composed largely of multinucleated myofibers, elements that arise from the fusion of mononucleated myoblasts. Accumulation of DNA damage with age in mammalian muscle has been reported in at least 18 studies since 1971. Hamilton et al.{{cite journal | last1 = Hamilton | first1 = M. L. | last2 = Van Remmen | first2 = H. | last3 = Drake | first3 = J. A. | last4 = Yang | first4 = H. | last5 = Guo | first5 = Z. M. | last6 = Kewitt | first6 = K. | last7 = Walter | first7 = C. A. | last8 = Richardson | first8 = A. | date = August 2001 | title = Does oxidative damage to DNA increase with age? | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 18| pages = 10469–74 | doi = 10.1073/pnas.171202698 | pmid = 11517304 | pmc=56984| bibcode = 2001PNAS...9810469H | doi-access = free }} reported that the oxidative DNA damage 8-OHdG accumulates in heart and skeletal muscle (as well as in brain, kidney and liver) of both mouse and rat with age. In humans, increases in 8-OHdG with age were reported for skeletal muscle.{{cite journal | pmid = 9895220 | volume=26 | issue=3–4 | title=Age-dependent increases in oxidative damage to DNA, lipids, and proteins in human skeletal muscle. | date=February 1999 | journal=Free Radic Biol Med | pages=303–8 | doi=10.1016/s0891-5849(98)00208-1 | last1 = Mecocci | first1 = P. | last2 = Fanó | first2 = G. | last3 = Fulle | first3 = S. | last4 = MacGarvey | first4 = U. | last5 = Shinobu | first5 = L. | last6 = Polidori | first6 = M. C. | last7 = Cherubini | first7 = A | last8 = Vecchiet | first8 = J. | last9 = Senin | first9 = U. | last10 = Beal | first10 = M. F.}} Catalase is an enzyme that removes hydrogen peroxide, a reactive oxygen species, and thus limits oxidative DNA damage. In mice, when catalase expression is increased specifically in mitochondria, oxidative DNA damage (8-OHdG) in skeletal muscle is decreased and lifespan is increased by about 20%.{{cite journal | last1 = Schriner | first1 = S. E. | last2 = Linford | first2 = NJ | last3 = Martin | first3 = G. M. | last4 = Treuting | first4 = P. | last5 = Ogburn | first5 = C. E. | last6 = Emond | first6 = M. | last7 = Coskun | first7 = P. E. | last8 = Ladiges | first8 = W. | last9 = Wolf | first9 = N. | last10 = Van Remmen | first10 = H. | last11 = Wallace | first11 = D. C. | last12 = Rabinovitch | first12 = P. S. | date = June 2005 | title = Extension of murine life span by overexpression of catalase targeted to mitochondria | journal = Science | volume = 308 | issue = 5730| pages = 1909–11 | doi = 10.1126/science.1106653 | pmid = 15879174 | bibcode = 2005Sci...308.1909S | s2cid = 38568666 }}{{cite journal | last1 = Linford | first1 = N. J. | last2 = Schriner | first2 = S. E. | last3 = Rabinovitch | first3 = P. S. | date = March 2006 | title = Oxidative damage and aging: spotlight on mitochondria | journal = Cancer Res. | volume = 66 | issue = 5| pages = 2497–9 | doi = 10.1158/0008-5472.CAN-05-3163 | pmid = 16510562 | doi-access = free }} These findings suggest that mitochondria are a significant source of the oxidative damages contributing to aging.{{cn|date=November 2024}}

Protein synthesis and protein degradation decline with age in skeletal and heart muscle, as would be expected, since DNA damage blocks gene transcription. In 2005, Piec et al.{{cite journal | last1 = Piec | first1 = I. | last2 = Listrat | first2 = A. | last3 = Alliot | first3 = J. | last4 = Chambon | first4 = C. | last5 = Taylor | first5 = R. G. | last6 = Bechet | first6 = D. | date = July 2005 | title = Differential proteome analysis of aging in rat skeletal muscle | journal = FASEB J | volume = 19 | issue = 9| pages = 1143–5 | doi = 10.1096/fj.04-3084fje | doi-access = free | pmid = 15831715 | s2cid = 33187815 }} found numerous changes in protein expression in rat skeletal muscle with age, including lower levels of several proteins related to myosin and actin. Force is generated in striated muscle by the interactions between myosin thick filaments and actin thin filaments.{{cn|date=November 2024}}

{{further|Liver}}

Liver hepatocytes do not ordinarily divide and appear to be terminally differentiated, but they retain the ability to proliferate when injured. With age, the mass of the liver decreases, blood flow is reduced, metabolism is impaired, and alterations in microcirculation occur. At least 21 studies have reported an increase in DNA damage with age in liver. For instance, Helbock et al.{{cite journal | pmid = 9419368 | pmc=18204 | volume=95 | issue=1 | title=DNA oxidation matters: the HPLC-electrochemical detection assay of 8-oxo-deoxyguanosine and 8-oxo-guanine | date=January 1998 | pages=288–93 | journal=Proc. Natl. Acad. Sci. U.S.A. | doi=10.1073/pnas.95.1.288 | last1 = Helbock | first1 = HJ | last2 = Beckman | first2 = KB | last3 = Shigenaga | first3 = MK | bibcode=1998PNAS...95..288H | doi-access=free }} estimated that the steady state level of oxidative DNA base alterations increased from 24,000 per cell in the liver of young rats to 66,000 per cell in the liver of old rats.

One or two months after inducing DNA double-strand breaks in the livers of young mice, the mice showed multiple symptoms of aging similar to those seen in untreated livers of normally aged control mice.{{cite journal |vauthors=White RR, Milholland B, de Bruin A, Curran S, Laberge RM, van Steeg H, Campisi J, Maslov AY, Vijg J |title=Controlled induction of DNA double-strand breaks in the mouse liver induces features of tissue ageing |journal=Nat Commun |volume=6 |issue= |pages=6790 |date=April 2015 |pmid=25858675 |pmc=4394211 |doi=10.1038/ncomms7790 |bibcode=2015NatCo...6.6790W }}

{{further|Kidney}}

In kidney, changes with age include reduction in both renal blood flow and glomerular filtration rate, and impairment in the ability to concentrate urine and to conserve sodium and water. DNA damages, particularly oxidative DNA damages, increase with age (at least 8 studies). For instance Hashimoto et al.{{cite journal | pmid = 17785942 | volume=32 | issue=3 | title=DNA damage measured by comet assay and 8-OH-dG formation related to blood chemical analyses in aged rats. | date=Aug 2007 | journal=J Toxicol Sci | pages=249–59 | doi=10.2131/jts.32.249 | last1 = Hashimoto | first1 = K | last2 = Takasaki | first2 = W | last3 = Sato | first3 = I | last4 = Tsuda | first4 = S| doi-access = free }} showed that 8-OHdG accumulates in rat kidney DNA with age.{{cn|date=November 2024}}

{{further|Stem cell|Stem cell theory of aging}}

Tissue-specific stem cells produce differentiated cells through a series of increasingly more committed progenitor intermediates. In hematopoiesis (blood cell formation), the process begins with long-term hematopoietic stem cells that self-renew and also produce progeny cells that upon further replication go through a series of stages leading to differentiated cells without self-renewal capacity. In mice, deficiencies in DNA repair appear to limit the capacity of hematopoietic stem cells to proliferate and self-renew with age.{{cite journal | last1 = Rossi | first1 = DJ | last2 = Bryder | first2 = D | last3 = Seita | first3 = J | last4 = Nussenzweig | first4 = A | last5 = Hoeijmakers | first5 = J | last6 = Weissman | first6 = IL | date = Jun 2007 | title = Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age | journal = Nature | volume = 447 | issue = 7145| pages = 725–9 | doi = 10.1038/nature05862 | pmid = 17554309 | bibcode = 2007Natur.447..725R | s2cid = 4416445 }} Sharpless and Depinho reviewed evidence that hematopoietic stem cells, as well as stem cells in other tissues, undergo intrinsic aging.{{cite journal | last1 = Sharpless | first1 = NE | last2 = DePinho | first2 = RA | date = Sep 2007 | title = How stem cells age and why this makes us grow old | journal = Nat Rev Mol Cell Biol | volume = 8 | issue = 9| pages = 703–13 | doi = 10.1038/nrm2241 | pmid = 17717515 | s2cid = 36305591 }} They speculated that stem cells grow old, in part, as a result of DNA damage. DNA damage may trigger signalling pathways, such as apoptosis, that contribute to depletion of stem cell stocks. This has been observed in several cases of accelerated aging and may occur in normal aging too.

A key aspect of hair loss with age is the aging of the hair follicle.{{cite journal|author-link2=Cheng-Ming Chuong |vauthors=Lei M, Chuong CM |title=STEM CELLS. Aging, alopecia, and stem cells |journal=Science |volume=351 |issue=6273 |pages=559–60 |year=2016 |pmid=26912687 |doi=10.1126/science.aaf1635 |bibcode=2016Sci...351..559L |doi-access=free }} Ordinarily, hair follicle renewal is maintained by the stem cells associated with each follicle. Aging of the hair follicle appears to be due to the DNA damage that accumulates in renewing stem cells during aging.{{cite journal |vauthors=Matsumura H, Mohri Y, Binh NT, Morinaga H, Fukuda M, Ito M, Kurata S, Hoeijmakers J, Nishimura EK |title=Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis |journal=Science |volume=351 |issue=6273 |pages=aad4395 |year=2016 |pmid=26912707 |doi=10.1126/science.aad4395 |s2cid=5078019 }}

{{further|Evolution of ageing}}

A related theory is that mutation, as distinct from DNA damage, is the primary cause of aging. A comparison of somatic mutation rate across several mammal species found that the total number of accumulated mutations at the end of lifespan was roughly equal across a broad range of lifespans.{{Cite journal |last1=Cagan |first1=Alex |last2=Baez-Ortega |first2=Adrian |last3=Brzozowska |first3=Natalia |last4=Abascal |first4=Federico |last5=Coorens |first5=Tim H. H. |last6=Sanders |first6=Mathijs A. |last7=Lawson |first7=Andrew R. J. |last8=Harvey |first8=Luke M. R. |last9=Bhosle |first9=Shriram |last10=Jones |first10=David |last11=Alcantara |first11=Raul E. |date=April 2022 |title=Somatic mutation rates scale with lifespan across mammals |journal=Nature |language=en |volume=604 |issue=7906 |pages=517–524 |doi=10.1038/s41586-022-04618-z|pmid=35418684 |pmc=9021023 |bibcode=2022Natur.604..517C |issn=1476-4687}} The authors state that this strong relationship between somatic mutation rate and lifespan across different mammalian species suggests that evolution may constrain somatic mutation rates, perhaps by selection acting on different DNA repair pathways.{{cn|date=July 2022}}

As discussed above, mutations tend to arise in frequently replicating cells as a result of errors of DNA synthesis when template DNA is damaged, and can give rise to cancer. However, in mice there is no increase in mutation in the brain with aging.{{cite journal | last1 = Dollé | first1 = ME | last2 = Giese | first2 = H | last3 = Hopkins | first3 = CL | last4 = Martus | first4 = HJ | last5 = Hausdorff | first5 = JM | last6 = Vijg | first6 = J | date = Dec 1997 | title = Rapid accumulation of genome rearrangements in liver but not in brain of old mice | journal = Nat Genet | volume = 17 | issue = 4| pages = 431–4 | doi = 10.1038/ng1297-431 | pmid = 9398844 | s2cid = 20773771 }}{{cite journal | pmid = 10757770 | pmc=1460990 | volume=154 | issue=3 | title=Mutation frequency and specificity with age in liver, bladder and brain of lacI transgenic mice | date=March 2000 | pages=1291–300 | journal=Genetics | last1 = Stuart | first1 = GR | last2 = Oda | first2 = Y | last3 = de Boer | first3 = JG | last4 = Glickman | first4 = BW| doi=10.1093/genetics/154.3.1291 }}{{cite journal | last1 = Hill | first1 = KA | last2 = Halangoda | first2 = A | last3 = Heinmoeller | first3 = PW | last4 = Gonzalez | first4 = K | last5 = Chitaphan | first5 = C | last6 = Longmate | first6 = J | last7 = Scaringe | first7 = WA | last8 = Wang | first8 = JC | last9 = Sommer | first9 = SS | date = Jun 2005 | title = Tissue-specific time courses of spontaneous mutation frequency and deviations in mutation pattern are observed in middle to late adulthood in Big Blue mice | journal = Environ Mol Mutagen | volume = 45 | issue = 5| pages = 442–54 | doi = 10.1002/em.20119 | pmid = 15690342 | bibcode = 2005EnvMM..45..442H | s2cid = 32204458 }} Mice defective in a gene (Pms2) that ordinarily corrects base mispairs in DNA have about a 100-fold elevated mutation frequency in all tissues, but do not appear to age more rapidly.{{cite journal | pmid = 9096356 | volume=94 | issue=7 | title=Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2. | date=Apr 1997 | pages=3122–7 | doi=10.1073/pnas.94.7.3122 | pmc=20332 | journal=Proceedings of the National Academy of Sciences | last1 = Narayanan | first1 = L | last2 = Fritzell | first2 = JA | last3 = Baker | first3 = SM | last4 = Liskay | first4 = RM | last5 = Glazer | first5 = PM| bibcode=1997PNAS...94.3122N | doi-access=free }} On the other hand, mice defective in one particular DNA repair pathway show clear premature aging, but do not have elevated mutation.{{cite journal | last1 = Dollé | first1 = ME | last2 = Busuttil | first2 = RA | last3 = Garcia | first3 = AM | last4 = Wijnhoven | first4 = S | last5 = van Drunen | first5 = E | last6 = Niedernhofer | first6 = LJ | last7 = van der Horst | first7 = G | last8 = Hoeijmakers | first8 = JH | last9 = van Steeg | first9 = H | last10 = Vijg | first10 = J | date = Apr 2006 | title = Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice | journal = Mutat. Res. | volume = 596 | issue = 1–2| pages = 22–35 | doi = 10.1016/j.mrfmmm.2005.11.008 | pmid = 16472827 | bibcode = 2006MRFMM.596...22D }}

One variation of the idea that mutation is the basis of aging, that has received much attention, is that mutations specifically in mitochondrial DNA are the cause of aging. Several studies have shown that mutations accumulate in mitochondrial DNA in infrequently replicating cells with age. DNA polymerase gamma is the enzyme that replicates mitochondrial DNA. A mouse mutant with a defect in this DNA polymerase is only able to replicate its mitochondrial DNA inaccurately, so that it sustains a 500-fold higher mutation burden than normal mice. These mice showed no clear features of rapidly accelerated aging.{{cite journal | last1 = Vermulst | first1 = M | last2 = Bielas | first2 = JH | last3 = Kujoth | first3 = GC | last4 = Ladiges | first4 = WC | last5 = Rabinovitch | first5 = PS | last6 = Prolla | first6 = TA | last7 = Loeb | first7 = LA | date = Apr 2007 | title = Mitochondrial point mutations do not limit the natural lifespan of mice | journal = Nat Genet | volume = 39 | issue = 4| pages = 540–3 | doi = 10.1038/ng1988 | pmid = 17334366 | s2cid = 291780 }} Overall, the observations discussed in this section indicate that mutations are not the primary cause of aging.{{cn|date=November 2024}}

{{further|Calorie restriction}}

In rodents, caloric restriction slows aging and extends lifespan. At least 4 studies have shown that caloric restriction reduces 8-OHdG damages in various organs of rodents. One of these studies showed that caloric restriction reduced accumulation of 8-OHdG with age in rat brain, heart and skeletal muscle, and in mouse brain, heart, kidney and liver. More recently, Wolf et al. showed that dietary restriction reduced accumulation of 8-OHdG with age in rat brain, heart, skeletal muscle, and liver. Thus reduction of oxidative DNA damage is associated with a slower rate of aging and increased lifespan.{{cn|date=November 2024}}

{{further|DNA repair-deficiency disorder}}

If DNA damage is the underlying cause of aging, it would be expected that humans with inherited defects in the ability to repair DNA damages should age at a faster pace than persons without such a defect. Numerous examples of rare inherited conditions with DNA repair defects are known. Several of these show multiple striking features of premature aging, and others have fewer such features. Perhaps the most striking premature aging conditions are Werner syndrome (mean lifespan 47 years), Huchinson–Gilford progeria (mean lifespan 13 years), and Cockayne syndrome (mean lifespan 13 years).{{cn|date=November 2024}}

Werner syndrome is due to an inherited defect in an enzyme (a helicase and exonuclease) that acts in base excision repair of DNA (e.g. see Harrigan et al.{{cite journal | last1 = Harrigan | first1 = JA | last2 = Wilson | first2 = DM | last3 = Prasad | first3 = R | last4 = Opresko | first4 = PL | last5 = Beck | first5 = G | last6 = May | first6 = A | last7 = Wilson | first7 = SH | last8 = Bohr | first8 = VA | date = Jan 2006 | title = The Werner syndrome protein operates in base excision repair and cooperates with DNA polymerase beta | journal = Nucleic Acids Res. | volume = 34 | issue = 2| pages = 745–54 | doi = 10.1093/nar/gkj475 | pmid = 16449207 | pmc=1356534}}).

Huchinson–Gilford progeria is due to a defect in Lamin A protein which forms a scaffolding within the cell nucleus to organize chromatin and is needed for repair of double-strand breaks in DNA.{{cite journal | last1 = Liu | first1 = Y | last2 = Wang | first2 = Y | last3 = Rusinol | first3 = AE | last4 = Sinensky | first4 = MS | last5 = Liu | first5 = J | last6 = Shell | first6 = SM | last7 = Zou | first7 = Y | date = Feb 2008 | title = Involvement of xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A | journal = FASEB J | volume = 22 | issue = 2| pages = 603–11 | doi = 10.1096/fj.07-8598com | doi-access = free | pmid = 17848622 | pmc=3116236}} A-type lamins promote genetic stability by maintaining levels of proteins that have key roles in the DNA repair processes of non-homologous end joining and homologous recombination.{{cite journal |vauthors=Redwood AB, Perkins SM, Vanderwaal RP, Feng Z, Biehl KJ, Gonzalez-Suarez I, Morgado-Palacin L, Shi W, Sage J, Roti-Roti JL, Stewart CL, Zhang J, Gonzalo S |title=A dual role for A-type lamins in DNA double-strand break repair |journal=Cell Cycle |volume=10 |issue=15 |pages=2549–60 |year=2011 |pmid=21701264 |pmc=3180193 |doi=10.4161/cc.10.15.16531 }} Mouse cells deficient for maturation of prelamin A show increased DNA damage and chromosome aberrations and are more sensitive to DNA damaging agents.{{cite journal |vauthors=Liu B, Wang J, Chan KM, Tjia WM, Deng W, Guan X, Huang JD, Li KM, Chau PY, Chen DJ, Pei D, Pendas AM, Cadiñanos J, López-Otín C, Tse HF, Hutchison C, Chen J, Cao Y, Cheah KS, Tryggvason K, Zhou Z |title=Genomic instability in laminopathy-based premature aging |journal=Nat. Med. |volume=11 |issue=7 |pages=780–5 |year=2005 |pmid=15980864 |doi=10.1038/nm1266 |s2cid=11798376 }}

Cockayne Syndrome is due to a defect in a protein necessary for the repair process, transcription coupled nucleotide excision repair, which can remove damages, particularly oxidative DNA damages, that block transcription.{{cite journal | last1 = D'Errico | first1 = M | last2 = Parlanti | first2 = E | last3 = Teson | first3 = M | last4 = Degan | first4 = P | last5 = Lemma | first5 = T | last6 = Calcagnile | first6 = A | last7 = Iavarone | first7 = I | last8 = Jaruga | first8 = P | last9 = Ropolo | first9 = M | last10 = Pedrini | first10 = AM | last11 = Orioli | first11 = D | last12 = Frosina | first12 = G | last13 = Zambruno | first13 = G | last14 = Dizdaroglu | first14 = M | last15 = Stefanini | first15 = M | last16 = Dogliotti | first16 = E | date = Jun 2007 | title = The role of CSA in the response to oxidative DNA damage in human cells | journal = Oncogene | volume = 26 | issue = 30| pages = 4336–43 | doi = 10.1038/sj.onc.1210232 | pmid = 17297471 | doi-access = free }}

In addition to these three conditions, several other human syndromes, that also have defective DNA repair, show several features of premature aging. These include ataxia–telangiectasia, Nijmegen breakage syndrome, some subgroups of xeroderma pigmentosum, trichothiodystrophy, Fanconi anemia, Bloom syndrome and Rothmund–Thomson syndrome.{{cn|date=November 2024}}

File:Ku bound to DNA.png

In addition to human inherited syndromes, experimental mouse models with genetic defects in DNA repair show features of premature aging and reduced lifespan.(e.g. refs.{{cite journal |vauthors=Vogel H, Lim DS, Karsenty G, Finegold M, Hasty P |title=Deletion of Ku86 causes early onset of senescence in mice |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=96 |issue=19 |pages=10770–5 |year=1999 |pmid=10485901 |pmc=17958 |doi= 10.1073/pnas.96.19.10770|bibcode=1999PNAS...9610770V |doi-access=free }}{{cite journal | last1 = Niedernhofer | first1 = LJ | last2 = Garinis | first2 = GA | last3 = Raams | first3 = A | last4 = Lalai | first4 = AS | last5 = Robinson | first5 = AR | last6 = Appeldoorn | first6 = E | last7 = Odijk | first7 = H | last8 = Oostendorp | first8 = R | last9 = Ahmad | first9 = A | last10 = van Leeuwen | first10 = W | last11 = Theil | first11 = AF | last12 = Vermeulen | first12 = W | last13 = van der Horst | first13 = GT | last14 = Meinecke | first14 = P | last15 = Kleijer | first15 = WJ | last16 = Vijg | first16 = J | last17 = Jaspers | first17 = NG | last18 = Hoeijmakers | first18 = JH | date = Dec 2006 | title = A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis | journal = Nature | volume = 444 | issue = 7122| pages = 1038–43 | doi = 10.1038/nature05456 | pmid = 17183314 | bibcode = 2006Natur.444.1038N | s2cid = 4358515 }}{{cite journal | last1 = Mostoslavsky | first1 = R | last2 = Chua | first2 = KF | last3 = Lombard | first3 = DB | last4 = Pang | first4 = WW | last5 = Fischer | first5 = MR | last6 = Gellon | first6 = L | last7 = Liu | first7 = P | last8 = Mostoslavsky | first8 = G | last9 = Franco | first9 = S | last10 = Murphy | first10 = MM | last11 = Mills | first11 = KD | last12 = Patel | first12 = P | last13 = Hsu | first13 = JT | last14 = Hong | first14 = AL | last15 = Ford | first15 = E | last16 = Cheng | first16 = HL | last17 = Kennedy | first17 = C | last18 = Nunez | first18 = N | last19 = Bronson | first19 = R | last20 = Frendewey | first20 = D | last21 = Auerbach | first21 = W | last22 = Valenzuela | first22 = D | last23 = Karow | first23 = M | last24 = Hottiger | first24 = MO | last25 = Hursting | first25 = S | last26 = Barrett | first26 = JC | last27 = Guarente | first27 = L | last28 = Mulligan | first28 = R | last29 = Demple | first29 = B | last30 = Yancopoulos | first30 = GD | last31 = Alt | first31 = FW | date = Jan 2006 | title = Genomic instability and aging-like phenotype in the absence of mammalian SIRT6 | journal = Cell | volume = 124 | issue = 2| pages = 315–29 | doi = 10.1016/j.cell.2005.11.044 | pmid = 16439206 | s2cid = 18517518 | doi-access = free }}) In particular, mutant mice defective in Ku70, or Ku80, or double mutant mice deficient in both Ku70 and Ku80 exhibit early aging.{{cite journal |vauthors=Li H, Vogel H, Holcomb VB, Gu Y, Hasty P |title=Deletion of Ku70, Ku80, or both causes early aging without substantially increased cancer |journal=Mol. Cell. Biol. |volume=27 |issue=23 |pages=8205–14 |year=2007 |pmid=17875923 |pmc=2169178 |doi=10.1128/MCB.00785-07 }} The mean lifespans of the three mutant mouse strains were similar to each other, at about 37 weeks, compared to 108 weeks for the wild-type control. Six specific signs of aging were examined, and the three mutant mice were found to display the same aging signs as the control mice, but at a much earlier age. Cancer incidence was not increased in the mutant mice. Ku70 and Ku80 form the heterodimer Ku protein essential for the non-homologous end joining (NHEJ) pathway of DNA repair, active in repairing DNA double-strand breaks. This suggests an important role of NHEJ in longevity assurance.{{cn|date=November 2024}}

Many authors have noted an association between defects in the DNA damage response and premature aging (see e.g.{{cite journal |vauthors=Bonsignore LA, Tooley JG, Van Hoose PM, Wang E, Cheng A, Cole MP, Schaner Tooley CE |title=NRMT1 knockout mice exhibit phenotypes associated with impaired DNA repair and premature aging |journal=Mech. Ageing Dev. |volume=146–148 |pages=42–52 |year=2015 |pmid=25843235 |pmc=4457563 |doi=10.1016/j.mad.2015.03.012 }}{{cite journal |vauthors=Ruzankina Y, Pinzon-Guzman C, Asare A, Ong T, Pontano L, Cotsarelis G, Zediak VP, Velez M, Bhandoola A, Brown EJ |title=Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss |journal=Cell Stem Cell |volume=1 |issue=1 |pages=113–26 |year=2007 |pmid=18371340 |pmc=2920603 |doi=10.1016/j.stem.2007.03.002 }}{{cite journal |vauthors=Holcomb VB, Vogel H, Hasty P |title=Deletion of Ku80 causes early aging independent of chronic inflammation and Rag-1-induced DSBs |journal=Mech. Ageing Dev. |volume=128 |issue=11–12 |pages=601–8 |year=2007 |pmid=17928034 |pmc=2692937 |doi=10.1016/j.mad.2007.08.006 }}{{cite journal |vauthors=Dollé ME, Kuiper RV, Roodbergen M, Robinson J, de Vlugt S, Wijnhoven SW, Beems RB, de la Fonteyne L, de With P, van der Pluijm I, Niedernhofer LJ, Hasty P, Vijg J, Hoeijmakers JH, van Steeg H |title=Broad segmental progeroid changes in short-lived Ercc1(-/Δ7) mice |journal=Pathobiol Aging Age Relat Dis |volume=1 |page= 7219|year=2011 |pmid=22953029 |pmc=3417667 |doi=10.3402/pba.v1i0.7219 }}).{{overcite|date=November 2024}} If a DNA repair protein is deficient, unrepaired DNA damages tend to accumulate.{{cite journal |vauthors=Musich PR, Zou Y |title=DNA-damage accumulation and replicative arrest in Hutchinson-Gilford progeria syndrome |journal=Biochem. Soc. Trans. |volume=39 |issue=6 |pages=1764–9 |year=2011 |pmid=22103522 |pmc=4271832 |doi=10.1042/BST20110687 }} Such accumulated DNA damages appear to cause features of premature aging (segmental progeria). Table 1 lists 18 DNA repair proteins which, when deficient, cause numerous features of premature aging.

Table 2 lists DNA repair proteins whose increased expression is connected to extended longevity.

{{further|Maximum life span}}

Studies comparing DNA repair capacity in different mammalian species have shown that repair capacity correlates with lifespan. The initial study of this type, by Hart and Setlow,{{cite journal | pmid = 4526202 | volume=71 | issue=6 | title=Correlation between deoxyribonucleic acid excision-repair and life-span in a number of mammalian species. | date=Jun 1974 | pages=2169–73 | doi=10.1073/pnas.71.6.2169 | journal=Proceedings of the National Academy of Sciences | pmc=388412 | last1 = Hart | first1 = RW | last2 = Setlow | first2 = RB| bibcode=1974PNAS...71.2169H | doi-access=free }} showed that the ability of skin fibroblasts of seven mammalian species to perform DNA repair after exposure to a DNA damaging agent correlated with lifespan of the species. The species studied were shrew, mouse, rat, hamster, cow, elephant and human. This initial study stimulated many additional studies involving a wide variety of mammalian species, and the correlation between repair capacity and lifespan generally held up. In one of the more recent studies, Burkle et al.{{cite journal | last1 = Bürkle | first1 = A | last2 = Brabeck | first2 = C | last3 = Diefenbach | first3 = J | last4 = Beneke | first4 = S | date = May 2005 | title = The emerging role of poly(ADP-ribose) polymerase-1 in longevity | journal = Int J Biochem Cell Biol | volume = 37 | issue = 5| pages = 1043–53 | doi = 10.1016/j.biocel.2004.10.006 | pmid = 15743677 }} studied the level of a particular enzyme, Poly ADP ribose polymerase, which is involved in repair of single-strand breaks in DNA. They found that the lifespan of 13 mammalian species correlated with the activity of this enzyme.{{cn|date=November 2024}}

The DNA repair transcriptomes of the liver of humans, naked mole-rats and mice were compared.{{cite journal |vauthors=MacRae SL, Croken MM, Calder RB, Aliper A, Milholland B, White RR, Zhavoronkov A, Gladyshev VN, Seluanov A, Gorbunova V, Zhang ZD, Vijg J |title=DNA repair in species with extreme lifespan differences |journal=Aging |volume=7 |issue=12 |pages=1171–84 |year=2015 |pmid=26729707 |pmc=4712340 |doi=10.18632/aging.100866 }} The maximum lifespans of humans, naked mole-rat, and mouse are respectively ~120, 30 and 3 years. The longer-lived species, humans and naked mole rats expressed DNA repair genes, including core genes in several DNA repair pathways, at a higher level than did mice. In addition, several DNA repair pathways in humans and naked mole-rats were up-regulated compared with mouse. These findings suggest that increased DNA repair facilitates greater longevity.{{cn|date=November 2024}}

Over the past decade, a series of papers have shown that the mitochondrial DNA (mtDNA) base composition correlates with animal species maximum life span.{{cite journal |doi=10.1089/rej.2006.9.223 |pmid=16706648 |title=Mitochondrial genome anatomy and species-specific lifespan |journal=Rejuvenation Res |volume=9 |issue=2 |pages=223–6 |year=2006|last1=Lehmann |first1=Gilad |last2=Budovsky |first2=Arie |last3=Muradian |first3=K. Muradian |last4=Fraifeld |first4=Vadim E. }}{{cite journal |doi=10.1089/rej.2008.0676 |pmid=18442324 |title=Do mitochondrial DNA and metabolic rate complement each other in determination of the mammalian maximum longevity? |journal=Rejuvenation Res |volume=11 |issue=2 |pages=409–417|year=2008|last1=Lehmann |first1=Gilad |last2=Segal |first2=Elena |last3=Muradian |first3=K. Muradian |last4=Fraifeld |first4=Vadim E. }}{{cite journal |doi=10.3389/fgene.2013.00111 |pmid=23781235 |title=Telomere length and body temperature-independent determinants of mammalian longevity? |journal=Front Genet |volume=4 |issue=111 |pages=111 |year=2013 |last1=Lehmann |first1=Gilad |last2=Muradian |first2=K. Muradian |last3=Fraifeld |first3=Vadim E. |pmc=3680702|doi-access=free }}{{cite journal |doi=10.1093/nar/gkv1187 |pmid=26590258 |title=MitoAge: a database for comparative analysis of mitochondrial DNA, with a special focus on animal longevity. |journal=Nucleic Acids Res |volume=44 |issue=D1 |year=2016|last1=Toren |first1=Dmitri |last2=Barzilay |first2=Thomer |last3=Tacutu |first3=Robi |last4= Lehmann |first4=Gilad |last5= Muradian |first5=Khachik K. |last6= Fraifeld |first6=Vadim E. |pmc=4702847 |pages=D1262–5}}{{overcite|date=November 2024}} The mitochondrial DNA base composition is thought to reflect its nucleotide-specific (guanine, cytosine, thymidine and adenine) different mutation rates (i.e., accumulation of guanine in the mitochondrial DNA of an animal species is due to low guanine mutation rate in the mitochondria of that species).{{cn|date=November 2024}}

The rate of accumulation of DNA damage (double-strand breaks) in the leukocytes of dolphins, goats, reindeer, American flamingos, and griffon vultures was compared to the longevity of individuals of these different species.{{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 }} The species with longer lifespans were found to have slower accumulation of DNA damage, a finding consistent with the DNA damage theory of aging. In healthy humans after age 50, endogenous DNA single- and double-strand breaks increase linearly, and other forms of DNA damage also increase with age in blood mononuclear cells.{{cite journal |vauthors=Vlachogiannis NI, Ntouros PA, Pappa M, Kravvariti E, Kostaki EG, Fragoulis GE, Papanikolaou C, Mavroeidi D, Bournia VK, Panopoulos S, Laskari K, Arida A, Gorgoulis VG, Tektonidou MG, Paraskevis D, Sfikakis PP, Souliotis VL |title=Chronological Age and DNA Damage Accumulation in Blood Mononuclear Cells: A Linear Association in Healthy Humans after 50 Years of Age |journal=Int J Mol Sci |volume=24 |issue=8 |date=April 2023 |page=7148 |pmid=37108309 |pmc=10138488 |doi=10.3390/ijms24087148 |doi-access=free |url=}} Also, after age 50 DNA repair capability decreases with age.

In mice, the DNA repair process of non-homologous end-joining that repairs DNA double strand breaks, declines in efficiency from 1.8-3.8-fold, depending on the specific tissue, when 5 month old animals are compared to 24 month old animals.{{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 |pages=e1004511 |date=July 2014 |pmid=25033455 |doi=10.1371/journal.pgen.1004511 |doi-access=free |pmc=4102425 |url=}} A study of fibroblast cells from humans varying in age from 16-75 years showed that the efficiency and fidelity of non-homologous end joining, and the efficiency of homologous recombinational DNA repair decline with age leading to increased sensitivity to ionizing radiation in older individuals.{{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 |journal=Cell Death Differ |volume=23 |issue=11 |pages=1765–77 |date=November 2016 |pmid=27391797 |doi=10.1038/cdd.2016.65 |pmc=5071568 |url=}} In middle aged human adults, oxidative DNA damage was found to be greater among individuals who were both frail and living in poverty.{{cite journal |vauthors=Smith JT, Noren Hooten N, Mode NA, Zonderman AB, Ezike N, Kaushal S, Evans MK |title=Frailty, sex, and poverty are associated with DNA damage and repair in frail, middle-aged urban adults |journal=DNA Repair (Amst) |volume=129 |issue= |pages=103530 |date=September 2023 |pmid=37437502 |doi=10.1016/j.dnarep.2023.103530 |pmc=10807508 }}

{{primary sources|section|date=July 2017}}

Lymphoblastoid cell lines established from blood samples of humans who lived past 100 years (centenarians) have significantly higher activity of the DNA repair protein Poly (ADP-ribose) polymerase (PARP) than cell lines from younger individuals (20 to 70 years old).{{cite journal |vauthors=Muiras ML, Müller M, Schächter F, Bürkle A |title=Increased poly(ADP-ribose) polymerase activity in lymphoblastoid cell lines from centenarians |journal=J. Mol. Med. |volume=76 |issue=5 |pages=346–54 |year=1998 |pmid=9587069 |doi= 10.1007/s001090050226|s2cid=24616650 }}{{medrs|date=July 2017}} The lymphocytic cells of centenarians have characteristics typical of cells from young people, both in their capability of priming the mechanism of repair after H₂O₂ sublethal oxidative DNA damage and in their PARP capacity.{{cite journal |journal=Nutrients |title=Biomarkers of aging: from function to molecular biology |vauthors=Wagner KH, Cameron-Smith D, Wessner B, Franzke B |date=2 June 2016 |volume=8 |issue=6 |doi=10.3390/nu8060338 |pmid=27271660 |pmc=4924179 |page=338|doi-access=free }}

Among centenarians, those with the most severe cognitive impairment have the lowest activity of the central DNA repair enzyme apurinic/apyrimidinc (AP) endonuclease 1.{{cite journal |vauthors=Sanchez-Roman I, Ferrando B, Holst CM, Mengel-From J, Rasmussen SH, Thinggaard M, Bohr VA, Christensen K, Stevnsner T |title=Molecular markers of DNA repair and brain metabolism correlate with cognition in centenarians |journal=Geroscience |volume=44 |issue=1 |pages=103–125 |date=February 2022 |pmid=34966960 |pmc=8810979 |doi=10.1007/s11357-021-00502-2 |url=}} AP endonuclease I is employed in the DNA base excision repair pathway and its main role is the repair of damaged or mismatched nucleotides in DNA.

{{primary sources|section|date=July 2017}}

As women age, they experience a decline in reproductive performance leading to menopause. This decline is tied to a decline in the number of ovarian follicles. Although 6 to 7 million oocytes are present at mid-gestation in the human ovary,{{cite journal |journal= Journal of Human Reproductive Sciences|date=Apr–Jun 2016 |volume=9|issue=2|pages=63–9|doi=10.4103/0974-1208.183514 |title=Poor ovarian reserve |author=Jirge PR |pmid=27382229 |pmc=4915288 |doi-access=free }} only about 500 (about 0.05%) of these ovulate, and the rest are lost. The decline in ovarian reserve appears to occur at an increasing rate with age,{{cite journal |vauthors=Hansen KR, Knowlton NS, Thyer AC, Charleston JS, Soules MR, Klein NA |title=A new model of reproductive aging: the decline in ovarian non-growing follicle number from birth to menopause |journal=Hum. Reprod. |volume=23 |issue=3 |pages=699–708 |year=2008 |pmid=18192670 |doi=10.1093/humrep/dem408 |doi-access=free }} and leads to nearly complete exhaustion of the reserve by about age 51. As ovarian reserve and fertility decline with age, there is also a parallel increase in pregnancy failure and meiotic errors resulting in chromosomally abnormal conceptions.

BRCA1 and BRCA2 are homologous recombination repair genes. The role of declining ATM-Mediated DNA double strand DNA break (DSB) repair in oocyte aging was first proposed by Kutluk Oktay, MD, PhD based on his observations that women with BRCA mutations produced fewer oocytes in response to ovarian stimulation repair.{{Cite journal|last1=Oktay|first1=Kutluk|last2=Kim|first2=Ja Yeon|last3=Barad|first3=David|last4=Babayev|first4=Samir N.|date=2010-01-10|title=Association of BRCA1 mutations with occult primary ovarian insufficiency: a possible explanation for the link between infertility and breast/ovarian cancer risks|journal=Journal of Clinical Oncology|volume=28|issue=2|pages=240–4|doi=10.1200/JCO.2009.24.2057|issn=1527-7755|pmc=3040011|pmid=19996028}}{{Cite journal|last1=Oktay|first1=Kutluk|last2=Turan|first2=Volkan|last3=Titus|first3=Shiny|last4=Stobezki|first4=Robert|last5=Liu|first5=Lin|date=September 2015|title=BRCA Mutations, DNA Repair Deficiency, and Ovarian Aging|journal=Biology of Reproduction|volume=93|issue=3|pages=67|doi=10.1095/biolreprod.115.132290|issn=0006-3363|pmc=4710189|pmid=26224004}}{{Cite journal|last1=Lin|first1=Wayne|last2=Titus|first2=Shiny|last3=Moy|first3=Fred|last4=Ginsburg|first4=Elizabeth S.|last5=Oktay|first5=Kutluk|date=October 1, 2017|title=Ovarian Aging in Women With BRCA Germline Mutations|journal=The Journal of Clinical Endocrinology and Metabolism|volume=102|issue=10|pages=3839–47|doi=10.1210/jc.2017-00765|issn=1945-7197|pmc=5630253|pmid=28938488}} His laboratory has further studied this hypothesis and provided an explanation for the decline in ovarian reserve with age.{{cite journal |vauthors=Titus S, Li F, Stobezki R, Akula K, Unsal E, Jeong K, Dickler M, Robson M, Moy F, Goswami S, Oktay K |title=Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans |journal=Sci Transl Med |volume=5 |issue=172 |pages=172ra21 |year=2013 |pmid=23408054 |doi=10.1126/scitranslmed.3004925 |pmc=5130338}} They showed that as women age, double-strand breaks accumulate in the DNA of their primordial follicles. Primordial follicles are immature primary oocytes surrounded by a single layer of granulosa cells. An enzyme system is present in oocytes that normally accurately repairs DNA double-strand breaks. This repair system is referred to as homologous recombinational repair, and it is especially active during meiosis. Titus et al. from Oktay Laboratory also showed that expression of four key DNA repair genes that are necessary for homologous recombinational repair (BRCA1, MRE11, Rad51 and ATM) decline in oocytes with age. This age-related decline in ability to repair double-strand damages can account for the accumulation of these damages, which then likely contributes to the decline in ovarian reserve as further explained by Turan and Oktay.{{Cite journal|last1=Turan|first1=Volkan|last2=Oktay|first2=Kutluk|date=2020-01-01|title=BRCA-related ATM-mediated DNA double-strand break repair and ovarian aging|journal=Human Reproduction Update|language=en|volume=26|issue=1|pages=43–57|doi=10.1093/humupd/dmz043|pmid=31822904|pmc=6935693|issn=1355-4786}}

Women with an inherited mutation in the DNA repair gene BRCA1 undergo menopause prematurely,{{cite journal |vauthors=Rzepka-Górska I, Tarnowski B, Chudecka-Głaz A, Górski B, Zielińska D, Tołoczko-Grabarek A |title=Premature menopause in patients with BRCA1 gene mutation |journal=Breast Cancer Res. Treat. |volume=100 |issue=1 |pages=59–63 |year=2006 |pmid=16773440 |doi=10.1007/s10549-006-9220-1 |s2cid=19572648 }} suggesting that naturally occurring DNA damages in oocytes are repaired less efficiently in these women, and this inefficiency leads to early reproductive failure. Genomic data from about 70,000 women were analyzed to identify protein-coding variation associated with age at natural menopause.{{cite journal |vauthors=Day FR, Ruth KS, Thompson DJ, et al. |title=Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair |journal=Nat. Genet. |volume=47 |issue=11 |pages=1294–303 |year=2015 |pmid=26414677 |pmc=4661791 |doi=10.1038/ng.3412 }} Pathway analyses identified a major association with DNA damage response genes, particularly those expressed during meiosis and including a common coding variant in the BRCA1 gene.

The most important risk factor for cardiovascular problems is chronological aging. Several research groups have reviewed evidence for a key role of DNA damage in vascular aging.{{cite journal |vauthors=Wu H, Roks AJ |title=Genomic instability and vascular aging: a focus on nucleotide excision repair |journal=Trends Cardiovasc. Med. |volume=24 |issue=2 |pages=61–8 |year=2014 |pmid=23953979 |doi=10.1016/j.tcm.2013.06.005 }}{{cite journal |vauthors=Bautista-Niño PK, Portilla-Fernandez E, Vaughan DE, Danser AH, Roks AJ |title=DNA damage: a main determinant of vascular aging |journal=Int J Mol Sci |volume=17 |issue=5 |page= 748|year=2016 |pmid=27213333 |pmc=4881569 |doi=10.3390/ijms17050748 |doi-access=free }}{{cite journal |vauthors=Shah AV, Bennett MR |title=DNA damage-dependent mechanisms of ageing and disease in the macro- and microvasculature |journal=Eur. J. Pharmacol. |volume= 816|pages= 116–128|year=2017 |pmid=28347738 |doi=10.1016/j.ejphar.2017.03.050 |s2cid=1034518 |url=https://www.repository.cam.ac.uk/handle/1810/264776}}

Atherosclerotic plaque contains vascular smooth muscle cells, macrophages and endothelial cells and these have been found to accumulate 8-oxoG, a common type of oxidative DNA damage.{{cite journal |vauthors=Uryga AK, Bennett MR |title=Ageing induced vascular smooth muscle cell senescence in atherosclerosis |journal=J Physiol |volume=594 |issue=8 |pages=2115–24 |date=15 April 2016 |pmid=26174609 |doi=10.1113/JP270923 |pmc=4933105}} DNA strand breaks also increased in atherosclerotic plaques, thus linking DNA damage to plaque formation.

Werner syndrome (WS), a premature aging condition in humans, is caused by a genetic defect in a RecQ helicase that is employed in several DNA repair processes. WS patients develop a substantial burden of atherosclerotic plaques in their coronary arteries and aorta. These findings link excessive unrepaired DNA damage to premature aging and early atherosclerotic plaque development.{{cn|date=November 2024}}

Endogenous, naturally occurring DNA damages are frequent, and in humans include an average of about 10,000 oxidative damages per day and 50 double-strand DNA breaks per cell cycle.{{cn|date=November 2024}}

Several reviews{{Cite journal |doi = 10.1016/j.mrrev.2017.09.005|pmid = 31395351|pmc = 6690501|title = The emerging role of epigenetic modifiers in repair of DNA damage associated with chronic inflammatory diseases|journal = Mutation Research/Reviews in Mutation Research|volume = 780|pages = 69–81|year = 2019|last1 = Ding|first1 = Ning|last2 = Maiuri|first2 = Ashley R.|last3 = o'Hagan|first3 = Heather M.| bibcode=2019MRRMR.780...69D }}{{cite journal |vauthors=Chiba T, Marusawa H, Ushijima T |title=Inflammation-associated cancer development in digestive organs: mechanisms and roles for genetic and epigenetic modulation |journal=Gastroenterology |volume=143 |issue=3 |pages=550–563 |year=2012 |pmid=22796521 |doi=10.1053/j.gastro.2012.07.009 |hdl=2433/160134 |s2cid=206226588 |hdl-access=free }}{{cite journal |vauthors=Nishida N, Kudo M |title=Alteration of Epigenetic Profile in Human Hepatocellular Carcinoma and Its Clinical Implications |journal=Liver Cancer |volume=3 |issue=3–4 |pages=417–27 |year=2014 |pmid=26280003 |pmc=4531427 |doi=10.1159/000343860 }} summarize evidence that the methylation enzyme DNMT1 is recruited to sites of oxidative DNA damage. Recruitment of DNMT1 leads to DNA methylation at the promoters of genes to inhibit transcription during repair. In addition, the 2018 review describes recruitment of DNMT1 during repair of DNA double-strand breaks. DNMT1 localization results in increased DNA methylation near the site of recombinational repair, associated with altered expression of the repaired gene. In general, repair-associated hyper-methylated promoters are restored to their former methylation level after DNA repair is complete. However, these reviews also indicate that transient recruitment of epigenetic modifiers can occasionally result in subsequent stable epigenetic alterations and gene silencing after DNA repair has been completed.{{cn|date=November 2024}}

In human and mouse DNA, cytosine followed by guanine (CpG) is the least frequent dinucleotide, making up less than 1% of all dinucleotides (see CG suppression). At most CpG sites cytosine is methylated to form 5-methylcytosine. As indicated in the article CpG site, in mammals, 70% to 80% of CpG cytosines are methylated. However, in vertebrates there are CpG islands, about 300 to 3,000 base pairs long, with interspersed DNA sequences that deviate significantly from the average genomic pattern by being CpG-rich. These CpG islands are predominantly nonmethylated.{{cite journal |vauthors=Deaton AM, Bird A |title=CpG islands and the regulation of transcription |journal=Genes Dev. |volume=25 |issue=10 |pages=1010–22 |date=May 2011 |pmid=21576262 |pmc=3093116 |doi=10.1101/gad.2037511 }} In humans, about 70% of promoters located near the transcription start site of a gene (proximal promoters) contain a CpG island (see CpG islands in promoters). If the initially nonmethylated CpG sites in a CpG island become largely methylated, this causes stable silencing of the associated gene.{{cn|date=November 2024}}

For humans, after adulthood is reached and during subsequent aging, the majority of CpG sequences slowly lose methylation (called epigenetic drift). However, the CpG islands that control promoters tend to gain methylation with age.{{cite journal |vauthors=Jones MJ, Goodman SJ, Kobor MS |title=DNA methylation and healthy human aging |journal=Aging Cell |volume=14 |issue=6 |pages=924–32 |date=December 2015 |pmid=25913071 |pmc=4693469 |doi=10.1111/acel.12349 }} The gain of methylation at CpG islands in promoter regions is correlated with age, and has been used to create an epigenetic clock (see article Epigenetic clock).

There may be some relationship between the epigenetic clock and epigenetic alterations accumulating after DNA repair. Both unrepaired DNA damage accumulated with age and accumulated methylation of CpG islands would silence genes in which they occur, interfere with protein expression, and contribute to the aging phenotype.{{cn|date=November 2024}}

{{columns-list|

• Mitochondrial theory of ageing
• Aging brain
• Biological immortality
• DNA damage (naturally occurring)
• DNA repair
• Heavy metals
• Life expectancy
• Longevity
• Longevity quotient
• Maximum life span
• Rejuvenation
• Senescence
• Telomere

}}

{{Reflist|32em}}

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Category:DNA

Category:Programmed cell death

Category:Proximate theories of biological ageing

Category:Senescence

Category:Theories of biological ageing

Category:Theories of ageing