DNA Damage, DNA Repair, Aging, and Neurodegeneration

Abstract

Aging in mammals is accompanied by a progressive atrophy of tissues and organs, and stochastic damage accumulation to the macromolecules DNA, RNA, proteins, and lipids. The sequence of the human genome represents our genetic blueprint, and accumulating evidence suggests that loss of genomic maintenance may causally contribute to aging. Distinct evidence for a role of imperfect DNA repair in aging is that several premature aging syndromes have underlying genetic DNA repair defects. Accumulation of DNA damage may be particularly prevalent in the central nervous system owing to the low DNA repair capacity in postmitotic brain tissue. It is generally believed that the cumulative effects of the deleterious changes that occur in aging, mostly after the reproductive phase, contribute to species-specific rates of aging. In addition to nuclear DNA damage contributions to aging, there is also abundant evidence for a causative link between mitochondrial DNA damage and the major phenotypes associated with aging. Understanding the mechanistic basis for the association of DNA damage and DNA repair with aging and age-related diseases, such as neurodegeneration, would give insight into contravening age-related diseases and promoting a healthy life span.

Figure 1.

Mammalian DNA repair pathways. Various types of genotoxic agents result in specific DNA damage lesions repaired by specific DNA repair pathways. Defects in each repair pathway are associated with various diseases (shown in red). Subpathways are also referred to, which are described elsewhere (Khakhar et al. 2003; Iyama and Wilson 2013). The black arrows extending from “RecQ helicases” signify that these enzymes are involved in several DNA repair pathways (Croteau et al. 2014). SSBR, single-stand break repair; TCR, transcription coupled repair; Alt-NHEJ, alternative nonhomologous end-joining pathway; AID, activation-induced cytidine deaminase; MM, mismatch of DNA bases.

Figure 2.

Four major theories of aging. Each theory has DNA damage accumulation and DNA repair as a major component. A variety of evidence, not always consistent (Moskalev et al. 2013), indicates that DNA damage accumulation is associated with aging.

Figure 3.

Pathways involved in mitochondrial maintenance.

Figure 4.

Possible sites of intervention that may ameliorate the consequence of DNA damage. Stimulation of DNA repair may be a feasible strategy for attenuating the effect of DNA damage. Recent research suggests that hyperactivation of the DNA damage–responsive enzyme poly(ADP-ribose) polymerase 1 (PARP1) may be involved in the aging process leading to downstream loss of SIRT1 and pleiotropic mitochondrial dysfunction. PARP1 hyperactivation leads to loss of NAD⁺, and reconstitution of NAD⁺ by inhibiting PARP1 or through supplementation with NAD⁺ precursors nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN) can rescue age-associated consequences of PARP1 activation. Loss of NAD⁺ leads to downstream metabolic dysregulation and treatment with ketone bodies may ameliorate those changes.