DNA damage theory of aging
[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.
[citation needed] The first person to suggest that DNA damage, as distinct from mutation, is the primary cause of aging was Alexander in 1967.
[15] 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.
[29] 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.[29]).
Increasing DNA damage with age has been reported in the brains of the mouse, rat, gerbil, rabbit, dog, and human.
[31] Sen et al.[32] showed that DNA damages which block the polymerase chain reaction in rat brain accumulate with age.
Thus Lu et al.[36] 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.
[citation needed] Muscle strength, and stamina for sustained physical effort, decline in function with age in humans and other species.
[29] Hamilton et al.[37] 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.
[38] Catalase is an enzyme that removes hydrogen peroxide, a reactive oxygen species, and thus limits oxidative DNA damage.
[citation needed] Liver hepatocytes do not ordinarily divide and appear to be terminally differentiated, but they retain the ability to proliferate when injured.
[43] 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.
In mice, deficiencies in DNA repair appear to limit the capacity of hematopoietic stem cells to proliferate and self-renew with age.
[50][51][52] 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.
[37] More recently, Wolf et al.[34] showed that dietary restriction reduced accumulation of 8-OHdG with age in rat brain, heart, skeletal muscle, and liver.
[citation needed] 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.[56]).
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.
[57] 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.
[citation needed] 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.
[citation needed] Over the past decade, a series of papers have shown that the mitochondrial DNA (mtDNA) base composition correlates with animal species maximum life span.
[citation needed] 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.
[122] In middle aged human adults, oxidative DNA damage was found to be greater among individuals who were both frail and living in poverty.
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.
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.
[139] 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.
[137] These findings link excessive unrepaired DNA damage to premature aging and early atherosclerotic plaque development.
[citation needed] Several reviews[140][141][142] summarize evidence that the methylation enzyme DNMT1 is recruited to sites of oxidative DNA damage.
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.
[citation needed] For humans, after adulthood is reached and during subsequent aging, the majority of CpG sequences slowly lose methylation (called epigenetic drift).
