Mice given the AEP enzyme inhibitor in their food from 18 months of age lived an average of 28 months, compared with 24 months for mice without the inhibitor
Mice given the AEP enzyme inhibitor in their food from 18 months of age lived an average of 28 months, compared with 24 months for mice without the inhibitor
On October 23, iScience published a paper by Keqiang Ye’s group in Shenzhen. AEP is an enzyme that cleaves proteins. The authors describe its activity as increasing with age and identify compound #11a as an inhibitor.
The experiment used male and female C57BL/6 laboratory mice, with 26 mice per group. Starting at about 18 months of age, one group received #11a in their food, while the other received regular food. According to the authors, #11a is well absorbed when taken orally. The mean age at death was 24 months in the control group and 28 months in the #11a group. Thus, after the experiment began, the mice lived for an average of about ten months rather than six. The risk of death in the control group was 2,08 times higher (with a range of plausible values from 1,02 to 4,27). The authors report that the inhibitor extended lifespan in both sexes. Some animals were euthanized at 23 months for tissue analysis and were excluded from the death count.
Keqiang Ye’s group previously studied AEP in Alzheimer’s disease: the enzyme cleaves tau protein, and the resulting fragments clump together. The group then identified another AEP target, NAMPT, an enzyme that produces NAD+. Cells need NAD+ for metabolism and for the activity of sirtuins, proteins that influence aging, including SIRT1. NAD+ levels decline with age, and cleaved NAMPT cannot produce it. In a 2025 study in Advanced Science, the group used mice with increased neuronal expression of C/EBPβ, a protein that induces AEP production. Deleting the AEP gene or protecting NAMPT from cleavage extended their lifespan. Both #11a and NMN, a precursor of NAD+, also extended their lifespan, although #11a was more effective at reducing accelerated aging. In September, the same group reported in Science Advances that increasing C/EBPβ or AEP in the cells lining blood vessels shortened the mice’s lifespan. Both earlier studies used genetically modified mice; the new paper tests the compound in normally aging mice.
The mice’s condition was assessed using a frailty index, a composite score covering 29 signs of aging, from hearing and gait to cataracts. The researchers assigning the scores did not know whether a mouse had received #11a. The frailty index was lower in both female and male mice given #11a. At 23 months, after five months of treatment, mice receiving #11a ran longer on a treadmill before falling and hung longer from an inverted grid. In a memory test, mice were shown two identical objects; one hour later, one object was replaced with a new one. Mice given #11a spent 48% of their total object exploration time on the new object, compared with 32% in the control group. Insulin sensitivity was also higher, and levels of three inflammatory signaling proteins were lower in five organs.
To test whether #11a acts by preserving NAMPT, the authors examined brain and quadriceps muscle tissue. They found less active AEP and cleaved NAMPT, along with more SIRT1. The ratio of NAD+ to NADH, another form of the same molecule, increased in the brain, muscle, liver and kidney. The authors examined whether this increase could reflect reduced activity of CD38 and PARP, other enzymes that consume NAD+. Indicators of their activity in the brain and muscle were unchanged. In the authors’ model, #11a prevents AEP from cleaving NAMPT, preserving NAD+ and supplying sirtuins with a molecule they need to function.
Food intake was measured per cage, and #11a had no effect on body weight. During the first five months, the difference in food intake was not statistically significant. However, some measurements showed lower intake in cages receiving #11a, and the authors acknowledge that reduced food intake may have contributed to the lifespan extension. Keqiang Ye disclosed in the paper that he is a named inventor on patent applications for AEP inhibitors.