Methyl Nicotinate Is a Novel Geroprotective Compound That Promotes Mitochondria Dependent Lifespan Extension

Abstract Aging involves cellular decline and reduced stress resilience. We investigated geroprotective interventions using the yeast chronological aging model and identified methyl nicotinate (MN) as a potent lifespan-extending compound. MN enhanced cellular lifespan and stress resistance through mitochondria-dependent mechanisms, including AMPK/SNF1 signaling and HAP4 -mediated mitochondrial biogenesis. These benefits extended to human cells, improving their survival and mitochondrial function under aging conditions. Importantly, the effects of MN are linked to the NAD⁺ biosynthetic pathway, with its conversion to nicotinic acid (NA) and subsequent entry into the NAD⁺ salvage pathway being essential. We also identified the esterase IAH1 as a key enzyme for converting MN to NA in yeast. Our findings reveal MN as a conserved longevity compound, offering a new avenue for NAD + modulating anti-aging strategies.