Cell Survival, Death, and Proliferation in Senescent and Cancer Cells: the Role of (Poly)phenols

Abstract

ABSTRACT Cellular senescence has long been considered a permanent state of cell cycle arrest occurring in proliferating cells subject to different stressors, used as a cellular defense mechanism from acquiring potentially harmful genetic faults. However, recent studies highlight that senescent cells might also alter the local tissue environment and concur to chronic inflammation and cancer risk by secreting inflammatory and matrix remodeling factors, acquiring a senescence-associated secretory phenotype (SASP). Indeed, during aging and age-related diseases, senescent cells amass in mammalian tissues, likely contributing to the inevitable loss of tissue function as we age. Cellular senescence has thus become one potential target to tackle age-associated diseases as well as cancer development. One important aspect characterizing senescent cells is their telomere length. Telomeres shorten as a consequence of multiple cellular replications, gradually leading to permanent cell cycle arrest, known as replicative senescence. Interestingly, in the large majority of cancer cells, a senescence escape strategy is used and telomere length is maintained by telomerase, thus favoring cancer initiation and tumor survival. There is growing evidence showing how (poly)phenols can impact telomere maintenance through different molecular mechanisms depending on dose and cell phenotypes. Although normally, (poly)phenols maintain telomere length and support telomerase activity, in cancer cells this activity is negatively modulated, thus accelerating telomere attrition and promoting cancer cell death. Some (poly)phenols have also been shown to exert senolytic activity, thus suggesting both antiaging (directly eliminating senescent cells) and anticancer (indirectly, via SASP inhibition) potentials. In this review, we analyze selective (poly)phenol mechanisms in senescent and cancer cells to discriminate between in vitro and in vivo evidence and human applications considering (poly)phenol bioavailability, the influence of the gut microbiota, and their dose-response effects. Keywords: polyphenols, telomere, telomerase, antiaging, senolytics, anticancer, longevity