Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice

Masayoshi Suda, Ippei Shimizu, Goro Katsuumi, Yohko Yoshida, Yuka Hayashi, Ryutaro Ikegami, Naomi Matsumoto, Yutaka Yoshida, Ryuta Mikawa, Akihiro Katayama, Jun Wada, Masahide Seki, Yutaka Suzuki, Atsushi Iwama, Hironori Nakagami, Ayako Nagasawa, Ryuichi Morishita, Masataka Sugimoto, Shujiro Okuda, Masanori TsuchidaKazuyuki Ozaki, Mayumi Nakanishi-Matsui, Tohru Minamino

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

Elimination of senescent cells (senolysis) was recently reported to improve normal and pathological changes associated with aging in mice1,2. However, most senolytic agents inhibit antiapoptotic pathways3, raising the possibility of off-target effects in normal tissues. Identification of alternative senolytic approaches is therefore warranted. Here we identify glycoprotein nonmetastatic melanoma protein B (GPNMB) as a molecular target for senolytic therapy. Analysis of transcriptome data from senescent vascular endothelial cells revealed that GPNMB was a molecule with a transmembrane domain that was enriched in senescent cells (seno-antigen). GPNMB expression was upregulated in vascular endothelial cells and/or leukocytes of patients and mice with atherosclerosis. Genetic ablation of Gpnmb-positive cells attenuated senescence in adipose tissue and improved systemic metabolic abnormalities in mice fed a high-fat diet, and reduced atherosclerotic burden in apolipoprotein E knockout mice on a high-fat diet. We then immunized mice against Gpnmb and found a reduction in Gpnmb-positive cells. Senolytic vaccination also improved normal and pathological phenotypes associated with aging, and extended the male lifespan of progeroid mice. Our results suggest that vaccination targeting seno-antigens could be a potential strategy for new senolytic therapies.

Original languageEnglish
Pages (from-to)1117-1126
Number of pages10
JournalNature Aging
Volume1
Issue number12
DOIs
Publication statusPublished - Dec 2021
Externally publishedYes

ASJC Scopus subject areas

  • Ageing
  • Geriatrics and Gerontology
  • Neuroscience (miscellaneous)

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