Potential Role of Polyphenolic Flavonoids as Senotherapeutic Agents in Degenerative Diseases and Geroprotection

Abstract

Cellular senescence, a hallmark of ageing, contributes to tissue or organ dysfunction and the pathophysiology of diverse age-related diseases (ARD) by various mechanisms. Targeting it by selective elimination of senescent cells (SCs) or blocking senescence-associated secretory phenotypes (SASP) with natural or synthetic compounds has been suggested to improve lifespan. Dietary phytochemicals possess a broad spectrum of biochemical and pharmacological effects that are beneficial to human health. Flavonoids, which are widely consumed in fruits and vegetables worldwide, are emerging as potential therapeutic agents to mitigate senescence. Naringenin, hesperetin, hesperidin, quercetin, fisetin, kaempferol, rutin, apigenin, luteolin, nobiletin, tangeretin, genistein, wogonin, epigallocatechin gallate (EGCG), theaflavin-3-gallate (TF2A), and procyanidin C1 possess potent antisenescence effects. A single biochemical process may not explain their pleiotropic pharmacological impact. Flavonoids directly modulate underlying cellular senescence processes or interact with molecular targets that regulate ageing-related pathways. This review discusses the potential use of flavonoids to mitigate senescence and consequently delay the onset of ageing-related diseases. We also highlight the underlying mechanisms of action of flavonoids as potential senotherapeutics and reflect on future perspectives and possible strategies to optimize and increase the translatability from bench to bedside in senotherapy.

A Fisetin Delivery System for Neuroprotection: A Co-Amorphous Dispersion Prepared in Supercritical Carbon Dioxide

“…It has a remarkable potential to selectively induce apoptosis (cell death) in senescent cells while leaving healthy cells unaffected [5]. Research has shown that FIS is considered one of the most potent senolytic compounds, exhibiting strong anti-senescence effects in preclinical studies across different tissues and animal models [6][7][8]. Its unique ability to promote the clearance of senescent cells has sparked interest in exploring FIS's therapeutic applications for extending health span and potentially addressing age-related ailments [9].…”

Protection of C2C12 skeletal muscle cells toward oxidation by a polyphenol-rich plant extract

“…These two cholesterol oxidative derivatives, mainly formed by cholesterol autoxidation, were identified at enhanced levels in the plasma of sarcopenic patients (Ghzaiel et al, 2021), and are often increased in patients with age-related diseases (Zarrouk et al, 2014) , A nutraceutical approach to the treatment of age-related diseases, including sarcopenia, has been favored for several years by our team and it is this guideline that led us to have an interest in PRPE. In addition, several polyphenols present in PRPE, such as resveratrol and quercetin, are now recognized for their senolytic properties which are attractive to fight aging and age-related diseases (Mbara et al, 2022). This aspect constituted an additional reason which motivated the evaluation of the cytoprotective and antioxidant activities of PRPE on AAPH-treated C2C12 cells.…”

Nanocarriers for natural polyphenol senotherapeutics

“…Among other agents presented in Table 1, the following also merit a mention. Luteolin plays a significant role as an antioxidant, antiinflammatory, and anticancer agent, scavenging free radicals and suppressing neuroinflammation (Mbara et al, 2022;Shi et al, 2004).…”