Do DNA double-strand breaks (DSBs) have anything to do with aging?

We have some reason to believe that they do. in yeast, longevity-enhancing mutations suppress genomic instability. Conversely, in the rodent heart, aging animals show evidence of sporadic large-scale genomic rearrangements, which could be caused by misrepair of DSBs. These rearrangements are thought to contribute to transcriptional “noise,” which in turn could explain some age-related decline in tissue function.

On the other hand, genomic rearrangements do not always occur as a concomitant of aging, even within the same organism: in mouse, the rearrangements are visible in cardiomyocytes, but are absent in actively dividing tissues like the bone marrow.

Paul Hasty has written two recent reviews, critically evaluating the role of DNA DSBs in the aging process. In the first (written with colleagues Han Li and James Mitchell), the authors argue from genetic evidence that DSB repair pathways are intimately connected with aging, but that the relationship is distinct from the well-documented connection between aging and repair of UV-type damage. (Mutants the nucleotide- and base-excision pathways involved in repair of single strand lesions are well documented to exhibit segmental progerias, in some cases entering a state somewhat resembling the response to caloric restriction in a last-ditch attempt to defend the body against accumulating DNA damage.) (link):

DNA double-strand breaks: A potential causative factor for mammalian aging?

… There are many forms of DNA damage with double-strand breaks (DSBs) being the most toxic. Here we discuss DNA DSBs as a potential causative factor for aging including factors that generate DNA DSBs, pathways that repair DNA DSBs, consequences of faulty or failed DSB repair and how these consequences may lead to age-dependent decline in fitness. At the end we compare mouse models of premature aging that are defective for repairing either DSBs or UV light-induced lesions. Based on these comparisons we believe the basic mechanisms responsible for their aging phenotypes are fundamentally different demonstrating the complex and pleiotropic nature of this process.

In the second review, Hasty (this time writing alone) argues that non-homologous end-joining NHEJ), a major pathway of DSB repair, evolved primarily as a means to slow aging — rather than to prevent cancer, as is likely the case for other DNA repair pathways. One corollary of this is that mutants in NHEJ either display no increase in cancer or a very small one (which Hasty argues is either incidental to accelerated aging or altogether artifactual). (link):

Is NHEJ a tumor suppressor or an aging suppressor?

… Nonhomologous end joining (NHEJ) is considered a caretaker since it repairs DNA double-strand breaks that would otherwise lead to gross chromosomal rearrangements (GCRs). NHEJ-mutant mice display increased GCRs, but without increased cancer. Instead these mice show early aging. This commentary focuses on the role NHEJ has on aging and cancer. I propose that NHEJ evolved to reduce GCRs and moderate gatekeeper responses that would otherwise cause early aging. Furthermore, NHEJ did not evolve to suppress tumors and any observed tumor suppression is merely circumstantial to unnatural laboratory conditions coupled with human bias that favors defining all DNA repair pathways as caretakers.

If it does turn out that NHEJ mutants have increased genomic rearrangements and also increasing transcriptional noise, it could go a long way toward bolstering the theory of aging described above.