The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice.

Abstract

Ageing-associated functional decline of organs and increased risk for age-related chronic pathologies is driven in part by the accumulation of senescent cells, which develop the senescence-associated secretory phenotype (SASP). Here we show that procyanidin C1 (PCC1), a polyphenolic component of grape seed extract (GSE), increases the healthspan and lifespan of mice through its action on senescent cells. By screening a library of natural products, we find that GSE, and PCC1 as one of its active components, have specific effects on senescent cells. At low concentrations, PCC1 appears to inhibit SASP formation, whereas it selectively kills senescent cells at higher concentrations, possibly by promoting production of reactive oxygen species and mitochondrial dysfunction. In rodent models, PCC1 depletes senescent cells in a treatment-damaged tumour microenvironment and enhances therapeutic efficacy when co-administered with chemotherapy. Intermittent administration of PCC1 to either irradiated, senescent cell-implanted or naturally aged old mice alleviates physical dysfunction and prolongs survival. We identify PCC1 as a natural senotherapeutic agent with in vivo activity and high potential for further development as a clinical intervention to delay, alleviate or prevent age-related pathologies.

• Authors: Qixia Xu, Qiang Fu, Zi Li, Hanxin Liu, Ying Wang, Xu Lin, Ruikun He, Xuguang Zhang, Zhenyu Ju, Judith Campisi, James L Kirkland, Yu Sun
• Journal: Nature metabolism (Nat Metab) Vol. 3 Issue 12 Pg. 1706-1726 (12 2021) ISSN: 2522-5812 [Electronic] Germany
• PMID: 34873338 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Flavonoids
• Senotherapeutics
• procyanidin trimer C1

Topics

• Animals
• Apoptosis
• Cell Line
• Cellular Senescence (drug effects, genetics)
• Computational Biology (methods)
• Drug Development
• Energy Metabolism (drug effects)
• Flavonoids (chemistry, pharmacology)
• Gene Expression Profiling
• Gene Expression Regulation (drug effects)
• Humans
• Longevity (drug effects)
• Mice
• Mitochondria (drug effects, genetics)
• Oxidative Stress
• Senescence-Associated Secretory Phenotype (genetics)
• Senotherapeutics (chemistry, pharmacology)