DNA damage theory of aging
Protein Pathway Description
NDRG1 Direct reversal long-lived Snell dwarf , GHRKO , and PAPPA-KO mice have increased expression of NDRG1 ; higher expression of NDRG1 can promote MGMT protein stability and enhanced DNA repair
NUDT1 ( MTH1 ) Oxidized nucleotide removal degrades 8-oxodGTP ; prevents the age-dependent accumulation of DNA 8-oxoguanine A transgenic mouse in which the human hMTH1 8-oxodGTPase is expressed , giving over-expression of hMTH1 , increases the median lifespan of mice to 914 days vs. 790 days for wild-type mice . Mice with over-expressed hMTH1 have behavioral changes of reduced anxiety and enhanced investigation of environmental and social cues
PARP1 Base excision repair , Nucleotide excision repair , Microhomology-mediated end joining , Single-strand break repair PARP1 activity in blood cells of thirteen mammalian species ( rat , guinea pig , rabbit , marmoset , sheep , pig , cattle , pigmy chimpanzee , horse , donkey , gorilla , elephant and man ) correlates with maximum lifespan of the species
SIRT1 Nucleotide excision repair , Homologous recombination , Non-homologous end joining Increased expression of SIRT1 in male mice extends the lifespan of mice fed a standard diet , accompanied by improvements in health , including enhanced motor coordination , performance , bone mineral density , and insulin sensitivity
SIRT6 Base excision repair , Nucleotide excision repair , Homologous recombination , Non-homologous end joining male , but not female , transgenic mice overexpressing Sirt6 have a significantly longer lifespan than wild-type mice
Inherited defects that cause premature aging -- Increased DNA repair and extended longevity
Table 2 lists DNA repair proteins whose increased expression is connected to extended longevity .
The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damages. 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). Several review articles have shown that deficient DNA repair, allowing greater accumulation of DNA damages, causes premature aging; and that increased DNA repair facilitates greater longevity. 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. Human populations studies show that single-nucleotide polymorphisms in DNA repair genes, causing up-regulation of their expression, correlate with increases in longevity. Lombard et al. compiled a lengthy list of mouse mutational models with pathologic features of premature aging, all caused by different DNA repair defects. 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. 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. Their analysis supported the hypothesis that improved DNA repair leads to longer life span.