Pre-clinical evidence suggests that polyphenols have a positive effect on cellular senescence, indicating their potential as senotherapeutics, according to a new review published in Nutrients.

Polyphenol compounds may modulate the processes that drive age-related diseases and promote tissue homeostasis. However, largeclinical trials are needed to confirm their efficacy and safety and shedmore light on their physiological effects on aging.

Researchers at the National Institute of Gastroenterology Saverio deBellis in Italy conducted a literature search to summarize the currentevidence on the effects of polyphenols on aging and cellularsenescence, exploring the mechanisms involved and the potential fornutritional strategies.

The senescence-associated secretoryphenotype

Cellular senescence is a process in which cells stop dividing inresponse to stress or damage, but instead of dying, they remain as dysfunctional yet metabolically active cells.

Transient senescence can play a crucial physiological role in woundhealing and tissue homeostasis; however, the chronic accumulation ofsenescent cells that occurs in aging causes detrimental, inflammatoryeffects and contributes to the development of age-related diseases.

The senescence-associated secretory phenotype (SASP) can developas a result of cellular senescence. This involves bioactive molecules,such as cytokines,chemokines, and growth factors that can drive diseases like cancer.

“This secretory phenotype is considered a key link between cellular senescence and the chronic, low-grade inflammation observed with aging, often referred to as ‘inflammaging,” the study noted.

Development of senotherapeutics

The SASP presents a potential target for enhancing health and lifespanthrough natural or synthetic supplements, referred to as senotherapeutics.

There are two categories of senotherapeutics: senolytics, which selectively induce apoptosis (cell death), and senomorphics, which suppress the SASP without inducing cell death.

However, the researchers noted that studies on senolytic and senomorphic therapies have demonstrated “dose-dependent sideeffects and potential toxicity,” which has spurred interest in naturalalternatives with fewer adverse effects.

Polyphenols may modulate cellular senescence by downregulating andinhibiting inflammatory pathways, as well as influencing the regulation of cell death.

The review mentions multiple polyphenol compounds that may have potential in cellular senescence, including curcumin, genistein,resveratrol, epigallocatechin gallate, hesperidin, naringenin, luteolin,quercetin, kaempferol, rutin, fisetin, procyanidin and gingerenone.

“Intriguingly, these compounds have been shown not only to alleviatecellular senescence in vitro and in vivo but also to extend the lifespan ofvarious model organisms,” the researchers wrote.

They noted that despite the promising findings, several challenges arisewhen translating flavonoid-based senotherapeutics into clinical practice.

These include the low bioavailability of polyphenolic flavonoids andtheir “extensive first-pass metabolism into inactive glucuronide andsulphate conjugates”. Additionally, genetic polymorphisms may influence how individuals absorb flavonoids, resulting in inconsistenttreatment outcomes.

Therefore, the researchers said that “innovative strategies are urgentlyneeded to overcome these pharmacokinetic limitations,” mentioningnanoparticle encapsulation, liposomal carriers and co-crystallization aspotential solutions.

Addressing safety

While dietary polyphenols are generally considered safe for healthyindividuals, the researchers added a word of caution about consumingsupplements or concentrated plant extracts, noting that the unnaturallylarge quantities of polyphenols may be “in the form of purifiedaglycones rather than the glycosylated forms typically found in wholefoods-levels that may pose health risks.”

They concluded that large-scale, randomized clinical trials are essentialfor determining the efficacy and safety of these compounds and forpaving the way for the development of next-generation senotherapeutics.