Genome damage, a limit to longevity?

DNA damage accumulates throughout life, because of the many factors that threaten genome stability. They include extrinsic physical, chemical, and biological agents, as well as intrinsic threats (DNA replication errors, hydrolytic reactions, and reactive oxygen species) [13]. Deficiencies in DNA repair mechanisms cause accelerated aging in mice and humans, suggesting causal links between accumulation of nuclear DNA damage and aging [13] [14] [15].

Mitochondrial DNA damage. There is evidence of the implication of mitochondrial DNA (mtDNA) mutations in aging: deterioration of mtDNA through mutations [16] or defection of mtDNA polymerase [17] [18] [19] can induce premature aging or reduced lifespan. But whether mtDNA is more or less vulnerable to damage than nuclear DNA remains controversial. Besides, the multiple copies of mtDNA in each cell probably attenuate the consequences of mtDNA damage. Interestingly, the number of mitochondria decreases with age in liver cells of mice [20], rats [21], and humans [22] [23], consistent with a decrease in mtDNA copy number [24]. This could explain why mutation accumulation in mitochondrial genome might eventually become significant in the aging process. Another explanation is that accumulation of cells that contain high levels of mutant mtDNA could be an inevitable result of the normal mechanisms that maintain cellular concentrations of mtDNA [25].

Nuclear DNA damage. Somatic mutations and chromosomal anomalies are more likely to be observed in aged than young organisms [26] [27] [28]. DNA alterations eventually affect crucial genes or transcriptional pathways. As a result, cells dysfunction and may jeopardize tissue and organismal homeostasis, if not eliminated by apoptosis or senescence. Age-associated defects in the nuclear lamina may also aggravate genomic damage [29].

Recent studies suggest that nuclear DNA repair pathways might be involved in the aging process. The NAD+-dependent (1) poly(ADP-ribose) polymerase proteins (PARP) are usually associated with DNA repair mechanism. Recent studies have also linked them to mitochondrial function (4) and oxidative metabolism [30] [31]. PARP activation influences cellular metabolism through alterations in NAD+ (1) metabolism, direct PARylation events (a PARP-dependent post-translational alteration) and transcriptional reprogramming of the cell [31]. In general, PARP inhibition enhances oxidative metabolism and mitochondrial content (4). Interestingly, enhanced PARP activity is observed in aged organisms [32]. PARP-1 is an abundant nuclear enzyme activated by DNA damage and involved in repair mechanisms. Its activation may lead to rapid depletion of the cytosolic NAD+ (1) pool, and could even induce cell apoptosis [33] in case of massive DNA damage.

Another DNA damage response pathway is directed by tumor suppressor p53 (3). Interestingly, p53 can promote longevity by preventing the development of cancer, but increased p53 activation can have deleterious effects. It could promote aspects of the aging process by challenging tissue homeostasis with excessive senescence

or apoptosis signaling [34] ( see ”Cellular senescence” and ”Telomere shortening”).

As DNA damage accumulates with chronological age, the consumption of NAD+ (1) by PARP proteins increases. Sirtuins (2) activity is likely to be disturbed by NAD+ pool depletion. As for p53 (3), its overexpression in aging cells could be induced by PARP activation [35].

One interpretation is that DNA damage accumulation might be a biological clock driven by increasing entropy. DNA damage could be exponentially growing because it eventually affects genes encoding replication and repair mechanism, which thus become less efficient in faithfully replicating the DNA. With excessive activation of PARP, PARP-induced mechanism, designed to protect the organism against DNA damaged cell, may eventually deplete the NAD+ (1) pool and undermine NAD+-dependent sirtuins (2) function [36]. Although the role of sirtuins in the aging process is not fully unraveled yet, this alteration could have multiple consequences on cell metabolism.