BioProject

Senescence phenotypes and mitochondrial dysfunction are implicated in aging and neurodegeneration, and in the premature aging disease, including A-T. More...

Senescence phenotypes and mitochondrial dysfunction are implicated in aging and neurodegeneration, and in the premature aging disease, including 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. Here we demonstrate impaired mitochondrial function and increased senescence growth arrest with senescence-associated secretory phenotype (SASP) in A-T patient fibroblasts, and in ATM-deficient cells and mice. We find that boosting intracellular NAD+ levels with nicotinamide riboside (NR) reduces senescence, suppresses neuroinflammation, and improves motor function in Atm-/- mice. We further show that the senescence responses are mediated by stimulator of interferon genes (STING), which is activated by cytoplasmic mtDNA and that NR prevents senescence and neuroinflammation through stimulation of mitophagy. Our findings suggest a pivotal role for mitochondrial dysfunction induced senescence in A-T pathogenesis, and that enhancing mitophagy is a potential therapeutic intervention. Overall design: Six week old male B6;129S4-Atmtm1Bal/J mice from either wild-type (WT) or Atm homozygous (Atm-/-, ATM) were given 3.5 mg/ml (12 mM) nicotinamide riboside (NR) at in their drinking water while the control groups received only water (Veh) for 2 months, using four biological replicates for each of the four experimental groups. Less...