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, large clinical trials are needed to confirm their efficacy and safety and shed more light on their physiological effects on aging.
Researchers at the National Institute of Gastroenterology Saverio de Bellis in Italy conducted a literature search to summarize the current evidence on the effects of polyphenols on aging and cellular senescence, exploring the mechanisms involved and the potential for nutritional strategies.
Cellular senescence is a process in which cells stop dividing in response 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 wound healing and tissue homeostasis; however, the chronic accumulation of senescent cells that occurs in aging causes detrimental, inflammatory effects and contributes to the development of age-related diseases.
The senescence-associated secretory phenotype (SASP) can develop as 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.
The SASP presents a potential target for enhancing health and lifespan through 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 side effects and potential toxicity," which has spurred interest in natural alternatives with fewer adverse effects.
Polyphenols may modulate cellular senescence by downregulating and inhibiting 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 alleviate cellular senescence in vitro and in vivo but also to extend the lifespan of various model organisms," the researchers wrote.
They noted that despite the promising findings, several challenges arise when translating flavonoid-based senotherapeutics into clinical practice.
These include the low bioavailability of polyphenolic flavonoids and their "extensive first-pass metabolism into inactive glucuronide and sulphate conjugates". Additionally, genetic polymorphisms may influence how individuals absorb flavonoids, resulting in inconsistent treatment outcomes.
Therefore, the researchers said that "innovative strategies are urgently needed to overcome these pharmacokinetic limitations," mentioning nanoparticle encapsulation, liposomal carriers and co-crystallization as potential solutions.
While dietary polyphenols are generally considered safe for healthy individuals, the researchers added a word of caution about consuming supplements or concentrated plant extracts, noting that the unnaturally large quantities of polyphenols may be "in the form of purified aglycones rather than the glycosylated forms typically found in whole foods -- levels that may pose health risks."
They concluded that large-scale, randomized clinical trials are essential for determining the efficacy and safety of these compounds and for paving the way for the development of next-generation senotherapeutics.