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Peer-reviewedCC BY 4.0iScience

Inhibition of asparagine endopeptidase extends the lifespan and improves health span during aging

  • Menghan Yang
  • Xin Meng
  • Zhongyun Xie
  • Mengmeng Wang
  • Zhengjiang Qian
  • Keqiang Ye
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Abstract

Asparagine endopeptidase (AEP), also known as legumain, is a lysosomal cysteine protease whose activity increases with age and contributes to age-related tissue dysfunction. We tested whether chronic AEP inhibition could slow aging phenotypes in naturally aged mice. Here, we show that chronic treatment with the AEP inhibitor #11a extended lifespan and improved health span in aged C57BL/6 mice, together with reduced frailty and improved physical and cognitive performance. #11a treatment also attenuated several senescence- and inflammation-associated readouts in multiple organs. Mechanistically, #11a treatment suppressed AEP-dependent cleavage of nicotinamide phosphoribosyltransferase (NAMPT), accompanied by an increased NAD+/NADH ratio and higher SIRT1 levels. These findings support further investigation of pharmacological AEP inhibition as a strategy to promote healthy aging.

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Cite

BibTeXRIS
BibTeX
@article{yang2026inhibition,
  title = {{Inhibition of asparagine endopeptidase extends the lifespan and improves health span during aging}},
  author = {Menghan Yang and Xin Meng and Zhongyun Xie and Mengmeng Wang and Zhengjiang Qian and Keqiang Ye},
  journal = {iScience},
  year = {2026},
  month = oct,
  doi = {10.1016/j.isci.2026.117990},
  url = {https://www.cell.com/iscience/fulltext/S2589-0042(26)03373-0},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Inhibition of asparagine endopeptidase extends the lifespan and improves health span during aging
AU  - Menghan Yang
AU  - Xin Meng
AU  - Zhongyun Xie
AU  - Mengmeng Wang
AU  - Zhengjiang Qian
AU  - Keqiang Ye
PY  - 2026
DA  - 2026/10/23
JO  - iScience
DO  - 10.1016/j.isci.2026.117990
UR  - https://www.cell.com/iscience/fulltext/S2589-0042(26)03373-0
AB  - Asparagine endopeptidase (AEP), also known as legumain, is a lysosomal cysteine protease whose activity increases with age and contributes to age-related tissue dysfunction. We tested whether chronic AEP inhibition could slow aging phenotypes in naturally aged mice. Here, we show that chronic treatment with the AEP inhibitor #11a extended lifespan and improved health span in aged C57BL/6 mice, together with reduced frailty and improved physical and cognitive performance. #11a treatment also attenuated several senescence- and inflammation-associated readouts in multiple organs. Mechanistically, #11a treatment suppressed AEP-dependent cleavage of nicotinamide phosphoribosyltransferase (NAMPT), accompanied by an increased NAD+/NADH ratio and higher SIRT1 levels. These findings support further investigation of pharmacological AEP inhibition as a strategy to promote healthy aging.
SN  - 2589-0042
ER  -