Reverse electron transfer is activated during aging and contributes to aging and age‐related disease

Abstract Mechanisms underlying the depletion of NAD + and accumulation of reactive oxygen species (ROS) in aging and age‐related disorders remain poorly defined. We show that reverse electron transfer (RET) at mitochondrial complex I, which causes increased ROS production and NAD + to NADH conversion and thus lowered NAD + /NADH ratio, is active during aging. Genetic or pharmacological inhibition of RET decreases ROS production and increases NAD + /NADH ratio, extending the lifespan of normal flies. The lifespan‐extending effect of RET inhibition is dependent on NAD + ‐dependent Sirtuin, highlighting the importance of NAD + /NADH rebalance, and on longevity‐associated Foxo and autophagy pathways. RET and RET‐induced ROS and NAD + /NADH ratio changes are prominent in human induced pluripotent stem cell (iPSC) model and fly models of Alzheimer's disease (AD). Genetic or pharmacological inhibition of RET prevents the accumulation of faulty translation products resulting from inadequate ribosome‐mediated quality control, rescues relevant disease phenotypes, and extends the lifespan of Drosophila and mouse AD models. Deregulated RET is therefore a conserved feature of aging, and inhibition of RET may open new therapeutic opportunities in the context of aging and age‐related diseases including AD.