Hypothesis that aging is caused by accumulated DNA damage
The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear DNA damage can contribute to aging, nuclear DNA is the main subject of this analysis. Nuclear DNA damage can contribute to aging either indirectly (by increasing apoptosis or cellular senescence) or directly (by increasing cell dysfunction).[1][2][3][4]
Several review articles have shown that deficient DNA repair, allowing greater accumulation of DNA damage, causes premature aging; and that increased DNA repair facilitates greater longevity, e.g.[5][6] Mouse models of nucleotide-excision–repair syndromes reveal a striking correlation between the degree to which specific DNA repair pathways are compromised and the severity of accelerated aging, strongly suggesting a causal relationship.[7] Human population studies show that single-nucleotide polymorphisms in DNA repair genes, causing up-regulation of their expression, correlate with increases in longevity.[8] Lombard et al. compiled a lengthy list of mouse mutational models with pathologic features of premature aging, all caused by different DNA repair defects.[9] Freitas and de Magalhães presented a comprehensive review and appraisal of the DNA damage theory of aging, including a detailed analysis of many forms of evidence linking DNA damage to aging.[2] As an example, they described a study showing that centenarians of 100 to 107 years of age had higher levels of two DNA repair enzymes, PARP1 and Ku70, than general-population old individuals of 69 to 75 years of age.[10][2] Their analysis supported the hypothesis that improved DNA repair leads to longer life span. Overall, they concluded that while the complexity of responses to DNA damage remains only partly understood, the idea that DNA damage accumulation with age is the primary cause of aging remains an intuitive and powerful one.[2]
In humans and other mammals, DNA damage occurs frequently and DNA repair processes have evolved to compensate.[11] In estimates made for mice, DNA lesions occur on average 25 to 115 times per minute in each cell, or about 36,000 to 160,000 per cell per day.[12] Some DNA damage may remain in any cell despite the action of repair processes. The accumulation of unrepaired DNA damage is more prevalent in certain types of cells, particularly in non-replicating or slowly replicating cells, such as cells in the brain, skeletal and cardiac muscle.[13]
^Best, BP (2009). "Nuclear DNA damage as a direct cause of aging" (PDF). Rejuvenation Research. 12 (3): 199–208. CiteSeerX 10.1.1.318.738. doi:10.1089/rej.2009.0847. PMID 19594328. Archived from the original (PDF) on 2017-11-15. Retrieved 2009-08-04.
^ abcdFreitas AA, de Magalhães JP (2011). "A review and appraisal of the DNA damage theory of ageing". Mutation Research. 728 (1–2): 12–22. doi:10.1016/j.mrrev.2011.05.001. PMID 21600302.
^Ou HL, Schumacher B (2018). "DNA damage responses and p53 in the aging process". Blood. 131 (5): 488–495. doi:10.1182/blood-2017-07-746396. PMC 6839964. PMID 29141944.
^Vijg, J. (2021). "From DNA damage to mutations: All roads lead to aging". Ageing Research Reviews. 68: 101316. doi:10.1016/j.arr.2021.101316. PMC 10018438. PMID 33711511.
^Niedernhofer, L. J.; Gurkar, A. U.; Wang, Y.; Vijg, J.; Hoeijmakers JHJ; Robbins, P. D. (2018). "Nuclear Genomic Instability and Aging". Annual Review of Biochemistry. 87: 295–322. doi:10.1146/annurev-biochem-062917-012239. PMID 29925262. S2CID 49343005.
^Hoeijmakers JH (2009). "DNA damage, aging, and cancer". N. Engl. J. Med. 361 (15): 1475–85. doi:10.1056/NEJMra0804615. PMID 19812404.
^Cho M, Suh Y (2014). "Genome maintenance and human longevity". Curr. Opin. Genet. Dev. 26: 105–15. doi:10.1016/j.gde.2014.07.002. PMC 4254320. PMID 25151201.
^Lombard DB, Chua KF, Mostoslavsky R, Franco S, Gostissa M, Alt FW (2005). "DNA repair, genome stability, and aging". Cell. 120 (4): 497–512. doi:10.1016/j.cell.2005.01.028. PMID 15734682. S2CID 18469405.
^Chevanne M, Calia C, Zampieri M, Cecchinelli B, Caldini R, Monti D, Bucci L, Franceschi C, Caiafa P (2007). "Oxidative DNA damage repair and parp 1 and parp 2 expression in Epstein-Barr virus-immortalized B lymphocyte cells from young subjects, old subjects, and centenarians". Rejuvenation Res. 10 (2): 191–204. doi:10.1089/rej.2006.0514. PMID 17518695.
^Karanjawala ZE, Lieber MR. DNA damage and aging. Mech Ageing Dev. 2004 Jun;125(6):405-16. doi: 10.1016/j.mad.2004.04.003. PMID: 15272504
^Vilenchik, MM; Knudson, AG (May 2000). "Inverse radiation dose-rate effects on somatic and germ-line mutations and DNA damage rates". Proc Natl Acad Sci U S A. 97 (10): 5381–6. Bibcode:2000PNAS...97.5381V. doi:10.1073/pnas.090099497. PMC 25837. PMID 10792040.
^Holmes GE, Bernstein C, Bernstein H (September 1992). "Oxidative and other DNA damages as the basis of aging: a review". Mutat Res. 275 (3–6): 305–15. doi:10.1016/0921-8734(92)90034-m. PMID 1383772.
and 25 Related for: DNA damage theory of aging information
mutation, accumulation of genetic material (DNA) damage (DNAdamagetheoryofaging) and dysdifferentiation. The system theories include the immunologic...
new types ofDNAdamage and mutations, and several theoriesofaging argue that DNAdamage with or without mutations causes aging. DNAdamage is distinctly...
sequences of these particular genes accumulated oxidative DNAdamage, including 8-OHdG, with age (see DNAdamagetheoryofaging). They concluded that DNA damage...
slow aging. Rejuvenation is the reversal ofaging and thus requires a different strategy, namely repair of the damage that is associated with aging or replacement...
display accelerated aging. These findings are consistent with the DNAdamagetheoryofaging. The syndrome was named after German–American physician Helmut...
adequate level ofDNA repair promotes longevity (see DNAdamagetheoryofaging and reference.). In addition, an increased incidence ofDNAdamage and/or reduced...
model of premature aging, oxidative stress induced DNAdamage in the neocortex and hippocampus was substantially higher than in normally aging control...
Accumulated DNAdamage appears to be a limiting factor in the determination of maximum life span. The theory that DNAdamage is the primary cause ofaging, and...
there is an association between age and DNAdamage in humans, a finding consistent with the DNAdamagetheoryofaging. Social gerontology is a multi-disciplinary...
The disposable soma theoryofaging states that organisms age due to an evolutionary trade-off between growth, reproduction, and DNA repair maintenance...
that regardless of the suggested mathematical models, the underlying biological mechanisms remain unknown. • DNAdamagetheoryofaging Gavrilov, Leonid...
geropsychology Death DNAdamagetheoryofaging Epigenetic clock Evolution of ageing Genetics of ageing Gerontechnology Gerontology Gerascophobia List of life extension-related...
multi-system premature aging degenerative phenotype that appears to strengthen the link between DNAdamage and aging.(see DNAdamagetheoryofaging). Cockayne syndrome...
efficient repair of H2O2 sublethal oxidative DNAdamage. Higher DNA repair is thought to contribute to longevity (see DNAdamagetheoryofaging). The high...
The stem cell theoryofaging postulates that the aging process is the result of the inability of various types of stem cells to continue to replenish...
aging (also see DNAdamagetheoryofaging). Fibroblast samples from children with progeria syndrome exhibit accelerated epigenetic aging effects according...
special attention as an aging-associated disease, but the SENS claim that nuclear DNAdamage only matters for aging because of cancer has been challenged...
Global Information