Procyanidin C1 as a Senotherapeutic
This open access paper runs through a range of data for the assessment of procyanidin C1 as a senolytic compound capable of selectively destroying senescent cells, both in cell studies and in animal studies. Procyanidin C1 clearly isn't as good as dasatinib and quercetin (or fisetin alone) in mice, but it does extend mouse life span by a little under 10%. The mechanism of action appears to involve induction of mitochondrial dysfunction in senescent cells, leading to programmed cell death, but there is a good deal of work remaining in order to fully understand how procyanidin C1 achieves this outcome, and whether or not it is synergistic with other senolytics.
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.