Abstract
DNA damage accumulates with age (Lombard et al., 2005). However, whether and how robust DNA repair machinery promotes longevity is elusive. Here, we demonstrate that ATM-centered DNA damage response (DDR) progressively declines with senescence and age, while low dose of chloroquine (CQ) activates ATM, promotes DNA damage clearance, rescues age-related metabolic shift, and prolongs replicative lifespan. Molecularly, ATM phosphorylates SIRT6 deacetylase and thus prevents MDM2-mediated ubiquitination and proteasomal degradation. Extra copies of Sirt6 extend lifespan in Atm-/- mice, with restored metabolic homeostasis. Moreover, the treatment with CQ remarkably extends lifespan of Caenorhabditis elegans, but not the ATM-1 mutants. In a progeria mouse model with low DNA repair capacity, long-term administration of CQ ameliorates premature aging features and extends lifespan. Thus, our data highlights a pro-longevity role of ATM, for the first time establishing direct causal links between robust DNA repair machinery and longevity, and providing therapeutic strategy for progeria and age-related metabolic diseases.
Highlights
A variety of metabolic insults can generate DNA lesions in mammalian cells, which, if incorrectly repaired, can lead to somatic mutations and cell transformation (Vijg, 2014)
Upregulation of gH2AX, indicating accumulated DNA damage, and an increase in p16Ink4a were observed in senescent human skin fibroblasts (HSFs), Mouse embryonic fibroblasts (MEFs), and aged brain tissues (Figure 1a–c)
We demonstrate that long-term treatment with CQ activates Ataxia telangiectasia mutated (ATM), improves DNA repair, restores age-related metabolic shift, alleviates cellular senescence, and extends lifespan of nematodes and Zmpste24 null mice
Summary
A variety of metabolic insults can generate DNA lesions in mammalian cells, which, if incorrectly repaired, can lead to somatic mutations and cell transformation (Vijg, 2014) If unrepaired, such lesions can accumulate and constantly activate the DNA damage response (DDR), a unique feature and mechanism of senescence (Halliwell and Whiteman, 2004; Tanaka et al, 2006). Mice that are genetically engineered to lack ATM can survive for longer if they produce extra SIRT6 These experiments show that enhancing the DNA damage response can slow down aging, linking the DNA repair machinery to longevity. Whether and how robust DNA repair machinery promotes longevity is poorly understood Metabolic disturbance is another antagonistic hallmark of aging (Lopez-Otın et al, 2013). Long-term treatment of CQ restores metabolic reprogramming and extends the lifespan of nematodes and a progeria mouse model
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