Fight Aging!

Senescent cells accumulate with age, largely due to cells reaching the Hayflick limit, but a range of cell stresses can also induce senescence. Senescent cells are rapidly cleared by the immune system in youth, but the balance between creation and destruction shifts with advancing age. The immune system becomes less capable, but it is also likely that the aged environment inflicts greater stress that leads to more cells becoming senescent.

Clearance of senescent cells via senolytic compounds that provoke these cells into self-destruction is presently a well funded and promising area of development. Fisetin is one such senolytic, interesting for being a cheap, safe, and widely used plant-derived supplement, but only animal data has so far been published on its ability to rapidly clear senescent cells. As noted in this paper, it may be that fisetin can to some degree also prevent cells from becoming senescent in response to stress, which might slow the accumulation of senescent cells over time. As is always the case, it is worth remembering that just because a mechanism is demonstrated to exist in cell cultures doesn't mean that it does provide a meaningfully large contribution to the balance of creation and destruction of senescent cells in living animals, however. That remains to be shown.

Reactive oxygen species (ROS) are a key risk factor of cellular senescence and age-related diseases, and protein kinase C (PKC) has been shown to activate NADPH oxidases (NOXs), which generate ROS. Although PKC activation induces oxidative stress, leading to the cellular dysfunction in various cell types, the correlation between PKC and senescence has not been reported in vascular smooth muscle cell (VSMC). Several studies have indicated cellular senescence is accompanied by phosphatase and tensin homolog (PTEN) loss and that an interaction exists between PTEN and PKC. Therefore, we aimed to determine whether PTEN and PKC are associated with VSMC senescence and to investigate the mechanism involved.

We found hydrogen peroxide (H2O2) decreased PTEN expression and increased PKCδ phosphorylation. Moreover, H2O2 upregulated the NOX1 subunits, p22phox and p47phox, and induced VSMC senescence via p53-p21 signaling pathway. We identified PKCδ activation contributed to VSMC senescence through activation of NOX1 and ROS production. However, fisetin inhibited cellular senescence induced by the PTEN-PKCδ-NOX1-ROS signaling pathway, and this anti-aging effect was attributed to reduced ROS production caused by suppressing NOX1 activation. These results suggest that the PTEN-PCKδ signaling pathway is directly related to senescence via NOX1 activation and that the downregulation of PKCδ by flavonoids such as fisetin provides a potential means of treating age-associated diseases.

Link: https://doi.org/10.1016/j.archger.2023.104927