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Epigenetic changes are how the DNA of elderly people is prone to damage. One role of DNA methylation is to prevent DNA damage. In the elderly and those with aging-associated noncommunicable diseases (NCDs), DNA shows reduced methylation; consequently, the aging genome is unstable and accumulates DNA damage. While the DNA damage response (DDR) of the direct intracellular machinery repairs DNA lesions, too much DDR halts cell proliferation, and promotes senescence. Therefore, genome-wide hypomethylation drives genomic instability, causing aging-associated disease phenotypes. However, the mechanism is unknown. Independent of DNA replication, the eukaryotic genome retains a certain amount of endogenous DNA double-strand breaks (EDSBs), called physiologic replication-independent EDSBs (Phy-RIND-EDSBs), that possess physiological function. Phy-RIND-EDSBs are reduced in aging yeast, and low levels of Phy-RIND-EDSBs decrease cell viability and increase DNA damage. Thus, Phy-RIND-EDSBs have a biological role as youth-associated genomic-stabilizing DNA gaps. In humans, Phy-RIND-EDSBs are located in the hypermethylated genome. Because the genomes of aging people are hypomethylated, the elderly should also have a low level of Phy-RIND-EDSBs. Based on this evidence, I hypothesize that in the human Phy-RIND-EDSBs, reduction is a molecular process that mediates the genome-wide hypomethylation driving genomic instability, which is a nidus pathogenesis mechanism of human body deterioration in aging-associated NCDs.

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A Hypothesis to Explain How the DNA of Elderly People Is Prone to Damage: Genome-Wide Hypomethylation Drives Genomic Instability in the Elderly by Reducing Youth-Associated Gnome-Stabilizing DNA Gaps