Blocking an ageing enzyme extended life in old mice, but only just

The mice started on the experimental diet at about 18 months of age. Those whose food contained a compound coded #11a lived on average to 28 months; untreated mice lived to 24. The compound blocks asparagine endopeptidase (AEP), also called legumain, a protein-cutting enzyme inside lysosomes whose activity, the authors write, rises with age in mice. The study appeared on 23 October 2026 in iScience. Its first author is Menghan Yang of the Shenzhen Institutes of Advanced Technology; the work was supervised by Keqiang Ye of the Shenzhen University of Advanced Technology.

Twenty-six mice per group, a death-risk ratio of about two

The authors randomised C57BL/6 mice of both sexes into two groups of 26: standard chow or chow with #11a. In the control group the risk of death was about twice as high as in the treated group: hazard ratio 2.08 (95% CI 1.02 to 4.27, p = 0.045). The lower end of that interval sits almost on 1, so the survival result clears statistical significance by a thin margin.

Alongside survival, the team scored a frailty index every month: 29 signs of age-related decline, from gait and balance to vision and coat condition, each rated blind. Treated mice accumulated these signs more slowly, in females and in males; vision loss and coat condition improved most. At 23 months the treated animals did better on treadmill, wire-hang and memory tests (12 mice per group): in a novel-object recognition test their discrimination index was 48% against 32% in the controls.

Why the result touches NAD+

The authors link the effect to NAD+, a molecule cells need for energy metabolism. In earlier work the same lab reported that AEP cuts NAMPT, a key enzyme for making NAD+ in cells. In the old treated mice, NAMPT cleavage was lower, the NAD+/NADH ratio in brain, muscle, liver and kidney was higher, and SIRT1 levels rose; markers of senescent cells and inflammation in several organs were reduced. The authors themselves call this mechanistic evidence largely correlative: it does not show that the NAMPT pathway is required for the longer life.

The hypothesis has a history in this lab. In 2022 it reported in Science Advances that raising neuronal C/EBPβ, the factor that switches AEP on, shortened lifespan in mice and in worms. In 2024 it showed that #11a eased Alzheimer-like changes in a mouse model of the disease.

Three gaps between this and a drug for people

The first is food. Intake was measured per cage, not per mouse, and was numerically lower in the treated cages at several points, although the difference was not significant over the first five months. Because of this, the study cannot separate a possible effect of eating less from the effect of the compound. The authors write that a pair-feeding study, where control mice get exactly as much food, is needed. Body weight did not differ.

The second is scale and design. This is a single study with one inbred strain and 26 mice per group. Males and females were pooled, and the study was not powered to test the sexes separately. Animals taken out for planned tissue collection were not counted as deaths. For comparison, rapamycin's lifespan extension in 2009 was tested by the US Interventions Testing Program at three independent sites in genetically mixed mice: started at 600 days of age, it raised the age at 90% mortality by 14% in females and 9% in males.

The third is safety and independence. Blood counts in the treated mice showed no major abnormalities within the study period, which the authors say does not establish long-term safety. A 2009 study reported that mice lacking AEP altogether developed signs resembling haemophagocytic syndrome, a severe immune disorder. That does not mean #11a causes it, but it makes blocking the enzyme for years a safety question. Keqiang Ye is named as an inventor on patent applications for AEP inhibitors. The work was funded by the National Natural Science Foundation of China and national and Shenzhen research programmes.

A search of ClinicalTrials.gov on 3 November 2026 found no study of #11a in people. This is a target to follow, not something to try: the result comes from mice only, and any supplement taken in the hope of slowing ageing is worth discussing with a doctor. This article is for information and does not replace medical advice. The result will become more convincing if another laboratory repeats it with controlled feeding.

Sources

• Yang M, Meng X, Xie Z, Wang M, Qian Z, Ye K. Inhibition of asparagine endopeptidase extends the lifespan and improves health span during aging. iScience, 23 October 2026. PubMed 42964811 · Full text

• Xia Y, et al. Neuronal C/EBPβ/AEP pathway shortens life span via selective GABAnergic neuronal degeneration by FOXO repression. Science Advances, 2022. PubMed 35353567

• Qian Z, et al. Inhibition of asparagine endopeptidase (AEP) effectively treats sporadic Alzheimer's disease in mice. Neuropsychopharmacology, 2024. PubMed 38030711

• Chan CB, et al. Mice lacking asparaginyl endopeptidase develop disorders resembling hemophagocytic syndrome. PNAS, 2009. PubMed 19106291

• Harrison DE, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature, 2009. PubMed 19587680