Effect of NAMPT modulation in OIS-senescent IMR90 cells

Here, we identify senescence as one such context. Senescent cells retained elevated levels of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAM salvage pathway yet exhibited a paradoxical reduction in NAD+ turnover, suggesting a disconnect between protein abundance and enzymatic output.

Treatment with SBI-0802162 engaged the spare enzymatic capacity of NAMPT in senescent cells and produced a marked rise in intracellular NAD+ that, when sustained, reinforced their existing stress-associated transcriptional program and selectively reduced senescent cell viability while sparing proliferating cells. Together, these findings identify elevated NAMPT coupled with reduced NAD+ turnover as a metabolic vulnerability in senescent cells and support combined NAMPT activation with dietary NAM as a novel strategy to restore NAD+ homeostasis and improve age-associated inflammation.