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.

Antiaging agents: safe interventions to slow aging and healthy life span extension

“…PCC1 is considered as a natural senotherapeutic agent which exhibits activity in vivo. It has great potential to be further developed as an effective intervention in clinics to delay, reduce or prevent age-related pathology [ 116 ].…”

Senolytics: Eliminating Senescent Cells and Alleviating Intervertebral Disc Degeneration

“…As for natural extracts, compounds with senolytic features mainly include quercetin, fisetin, curcumin, and its derivative o-Vanillin ( Di Micco et al, 2021 ). The latest study has found that the grape seed extract PCC1 also has senolytic properties, which may be stronger than existing compounds ( Xu Q. et al, 2021 ). Among them, curcumin and its metabolite o-Vanillin have been proven to eliminate senescent cells in the intervertebral disc, reducing SASP secretion and alleviating IVDD ( Cherif et al, 2019 ; Mannarino et al, 2021 ).…”

Senescence: Pathogenic Driver in Chronic Obstructive Pulmonary Disease

“…The following candidates for future senolytic therapies based on early-stage research were conducted in human cell lines in vitro: FOXO4-related peptides [195], previous mentioned BCL-2 inhibitors [196,197], USP7 inhibitors [198], Quercetin plus Dasatinib [199], Fisetin, [200,201] Piperlonguimine [200,202], BIRC5 gene knockout [203], GLS1 inhibitors [204], procyanidin C1 [205], and EF-24 [196]. Medications or potential therapeutic targets studied in either mice or xenograft models include src inhibitors/dasatinib [206], Navitoclax [207], senescence-specific killing compound 1 (SSK1)/gemcitabine [208], and anti-glycoprotein nonmetastatic melanoma protein B (anti-GPNMD) [209].…”