NAD⁺ supplementation prevents STING‐induced senescence in ataxia telangiectasia by improving mitophagy

Abstract

Senescence phenotypes and mitochondrial dysfunction are implicated in aging and in premature aging diseases, including ataxia telangiectasia (A‐T). Loss of mitochondrial function can drive age‐related decline in the brain, but little is known about whether improving mitochondrial homeostasis alleviates senescence phenotypes. We demonstrate here that mitochondrial dysfunction and cellular senescence with a senescence‐associated secretory phenotype (SASP) occur in A‐T patient fibroblasts, and in ATM‐deficient cells and mice. Senescence is mediated by stimulator of interferon genes (STING) and involves ectopic cytoplasmic DNA. We further show that boosting intracellular NAD+ levels with nicotinamide riboside (NR) prevents senescence and SASP by promoting mitophagy in a PINK1‐dependent manner. NR treatment also prevents neurodegeneration, suppresses senescence and neuroinflammation, and improves motor function in Atm−/− mice. Our findings suggest a central role for mitochondrial dysfunction‐induced senescence in A‐T pathogenesis, and that enhancing mitophagy as a potential therapeutic intervention.

NAD+ augmentation with nicotinamide riboside improves lymphoid potential of Atm−/− and old mice HSCs

“…We also noted that the decline in inflammatory factors we see after short-term NR supplementation in both the aged (Fig. 3c ) and Atm −/− mice 39 overlapped with those reported (IL-6 and TNF-α) in a study of oral NR supplementation in humans 29 .…”

Nucleotide‐binding domain and leucine‐rich‐repeat‐containing protein X1 deficiency induces nicotinamide adenine dinucleotide decline, mechanistic target of rapamycin activation, and cellular senescence and accelerates aging lung‐like changes

“…There is growing evidence that NAD levels decline during chronological aging and that this decline is both a consequence of the aging process and also a contributor to the development of age‐related cellular dysfunction (Chini et al, 2017; Fang et al, 2017). Additionally, senescence phenotypes and mitochondrial dysfunction that are implicated in aging and in premature aging diseases such as ataxia telangiectasia are critically dependent on NAD + (Fang et al, 2014; Yang et al, 2021). Intriguingly, our data revealed that the levels of NAD + and NAD + /NADH ratio were significantly decreased in NLRX1 deficiency in vitro and in vivo, and our in vitro experiments implicate a causative link of endogenous NLRX1 deficiency to the decrease in NAD + in cells.…”

Targeting Mitochondrial Metabolism as a Strategy to Treat Senescence

“…NR supplementation increases NAD + levels and the NAD + /NADH ratio, which are known to be significantly reduced in senescent cells [ 82 ]. Increased NAD + levels by NR stimulate mitophagy to remove damaged mitochondria and enhance OXPHOS efficiency by upregulating basal/maximal ATP-linked oxygen consumption rates [ 83 ]. Concurrently, improved mitochondrial function by NR prevents senescence and SASP [ 83 ].…”