The NAD+/Sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling

Summary

C. elegans genetic and pharmacologic study demonstrating that NAD+ augmentation — via precursor supplementation (NR, NAM) or PARP inhibition — extends lifespan through a conserved SIR-2.1/DAF-16/mitochondrial unfolded protein response (UPR-mt) axis. Raising worm NAD+ by any of the tested interventions extended mean lifespan by 12-25% in wild-type animals, with lifespan extension abolished in sir-2.1, daf-16/FOXO, or ubl-5 (UPR-mt) loss-of-function backgrounds. Transcriptomic profiling showed activation of mitochondrial chaperones (hsp-6, hsp-60) and canonical FOXO targets. Parallel experiments in mammalian cells and mouse muscle confirmed conservation of the NAD+ → SIRT1 → UPR-mt program. This paper is central to the mechanistic rationale for NAD+ boosters as geroprotectors: it ties together three disparate literatures (NAD+ metabolism, sirtuin signaling, mitochondrial proteostasis) into a single longevity-regulating pathway and provides the first unambiguous genetic demonstration that NAD+ repletion extends lifespan in a metazoan.

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