Blocking one aging enzyme extended lifespan in mice — in mice, through an NAD+ pathway tied to mitochondria

Edited by Samael A. Tejada, Founder & Editor-in-Chief

Most longevity drugs chase one symptom of aging at a time. This study chased an enzyme that sits upstream of several of them at once — and its clearest molecular thread leads to NAD+, the coenzyme mitochondria cannot make energy without. The lifespan number is real, in mice. So is every caveat the authors attach to it, and this page keeps both in view.

What did the AEP inhibitor study actually do?

Yang and colleagues fed naturally aged C57BL/6 mice a standard diet or food supplemented with the optimized AEP inhibitor #11a (0.056 grams per kilogram of feed, roughly 7.5 mg/kg/day in the published study design), starting at about 18 months of age — late middle age for a mouse. Mean survival was 28 months on treatment versus 24 months in controls, with a hazard ratio of 2.08 for death in the control group. Blinded frailty scoring across 29 phenotypes, repeated every four weeks, showed slower accumulation of age-related deficits in both sexes, and at 23 months treated mice performed better on treadmill, wire-hang, open-field and memory tests. After five months, blood counts, serum chemistry and histopathology of heart, liver, spleen, lung and kidney showed no overt abnormalities — reassuring within the study's duration, and not a long-term safety verdict.

Where do mitochondria and NAD+ fit in?

Directly, in the authors' model. The transcription factor C/EBPbeta drives AEP expression with age; AEP then cleaves NAMPT at position N136, and because NAMPT is the rate-limiting step in NAD+ production, NAD+ falls. In the treated aged mice, #11a reduced active AEP in the hippocampus, reduced NAMPT fragmentation, raised the NAD+/NADH ratio significantly in brain, muscle, liver and kidney, and raised levels of the NAD+-dependent enzyme SIRT1 and of PGC-1alpha — the master regulator of mitochondrial biogenesis — in hippocampus and quadriceps muscle. Senescence markers and the inflammatory cytokines IL-1beta, IL-6 and TNF-alpha fell across organs, and insulin sensitivity improved. The authors state plainly that in naturally aged mice this chain is largely correlative: they have not yet proven the AEP-NAMPT-NAD+ pathway is necessary for the survival benefit.

What could make this result smaller than it looks?

Three things, all named by the authors themselves. First, food intake was measured only at the cage level and ran numerically lower in treated cages at several time points — and eating less is itself one of the most reliable ways to extend mouse lifespan, so a pair-feeding study is needed to separate a drug effect from a calorie effect. Second, the cohort was not powered to detect sex-specific effects for most endpoints, and females unexpectedly lived shorter lives than males in both groups. Third, AEP is not a free target: it has normal jobs in the endo-lysosomal system, mice lacking AEP specifically in kidney tubules develop spontaneous renal fibrosis, and AEP inhibition accelerated diabetic kidney disease in another model — so chronic blocking will need careful kidney monitoring in any future work. There is no human AEP-inhibitor aging trial, no human dose, and no approved product.

Where the evidence stands

• Established: NAD+ declines with age in multiple tissues; NAMPT is the rate-limiting enzyme in NAD+ biosynthesis; SIRT1 and PGC-1alpha link NAD+ status to mitochondrial biogenesis and function; and AEP/legumain activity rises with age and cleaves substrates including Tau and NAMPT.
• Preliminary: In naturally aged C57BL/6 mice (iScience, 2026; DOI 10.1016/j.isci.2026.117990), dietary AEP inhibitor #11a from about 18 months extended mean lifespan 24 to 28 months, reduced frailty, improved function and insulin sensitivity, and raised NAD+/NADH, SIRT1 and PGC-1alpha — with food intake measured only per cage and the mechanism described by the authors as largely correlative.
• Absent: Any human evidence, dose-response and pair-feeding controls, long-term safety data, and proof that the NAD+ pathway causes the survival benefit.