Senescent cells are aged or damaged cells with significantly decreased functionality and resistance to normal programmed cell death. Their existence is thought to represent a metabolic compromise: until cell death occurs, in the form of apoptosis (programmed death) or autophagy (immune-mediated cell clearance), senescence decreases the likelihood of these proinflammatory cells transforming into cancer cells. While this protective strategy is generally effective, senescent cells are often far from quiescent, and may even create microenvironments that promote certain forms of cancer.
The Nrf2 antioxidant response pathway is able to upregulate the coordinated activities of over 200 genes related to detoxification and antioxidant protection as part of the cellular reaction to injury, inflammation, and oxidative stress. Key enzymes involved include glutathione transferases and peroxidases, hemeoxygenases, and superoxide dismutase. What’s the connection? This research team proposes that the Nrf2 pathway may, in cells with irreparable damage, like cancer cells, help trigger senescence or cell death as a means of mitigating damage and protecting normal cells.
According to the authors, “several natural compounds that activate [the] Nrf2 pathway, which is involved in complex cytoprotective responses, have been paradoxically shown to induce cell death or senescence in cancer.” The fifteen phytonutrients profiled in this review article for their dual impacts on cell senescence and the Nrf2 response include:
● The polyphenols quercetin, fisetin, epigallocatechin gallate (EGCG), resveratrol, genistein, curcumin, silybin (from milk thistle seed), and phloretin (found in apple leaves)
● The organosulfur compounds sulforaphane (a human metabolite of cruciferous vegetable phytonutrients), phenylethyl isothiocyanate (PEITC) (found in cruciferous vegetables), and allicin (found in garlic)
● The alkaloids piperlongumine (found in black pepper) and berberine
● The diterpene triptolide, a somewhat toxic component of the TCM herb thunder god vine
Certain Senolytic Phytonutrients May Also Trigger the Antioxidant Response
Phytonutrients have unique and varying influences on cells of different types and in different states of function or dysfunction. In addition, high tissue concentrations of these phytonutrients may produce effects quite distinct from those at lower tissue levels. This review documents 15 phytonutrients that have, individually, shown a spectrum of cell- and tissue-regulating activities, ranging from protecting normal cells to encouraging senescence or cell death in dysfunctional cells.