DNA damage

Aerospace engineering

Neuroscience

Telomere

Enzyme

Autophagy

Sting

Ataxia

Biology

Engineering

Apoptosis

Mitophagy

Ataxia-telangiectasia

NAD+ kinase

Cell biology

Cancer research

Senescence

Genetics

Biochemistry

Aging Cell

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 <sup>+</sup> supplementation prevents STING‐induced senescence in ataxia telangiectasia by improving mitophagy

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

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