Can Polyphenol Senotherapeutics be Improved with the Use of Nanocarriers?

If you've ever wondered why so much effort goes towards the development of supplements and other only marginally effective interventions based on the use of plant extracts, the answer is quite simple: it is usually far cheaper to gain regulatory approval for commercial sale via this approach. From the point of view of many developers, it doesn't much matter how good the result is, as sales in the supplement space are driven by marketing, not efficacy. Thus keep the costs low. So much of this industry is trapped in a cycle in which the search for the lowest regulatory cost produces a market packed with marginal interventions, where competition is driven by branding and marketing rather than product efficacy, and that in turn educates developers and consumers to work towards more of the same.

That said, there are a few plant extracts that might actually be useful enough to pay attention to. Clearance of senescent cells in aged tissues is an important goal, as these cells actively harm tissue function and promote chronic inflammation. A few plant extracts appear to be able to selectively kill senescent cells, most notably piperlongumine and fisetin when used on their own. Quercetin is more widely known, but only because it is a part of the well studied dasatinib and quercetin combination; on its own quercetin isn't meaningfully senolytic. For piperlongumine and fisetin there is an absence of published human data (despite the existence of a clinical trial in the case of fisetin).

Still, all of these compounds are comparatively poorly bioavailable, which has led to groups attempting formulations with varieties of nanocarrier, such as encapsulation in liposomes, that will enable better distribution into the desired target cells. Time will tell as to whether this is a useful line of research and development that will lead to senolytic therapies that are both cheaper and comparably effective to the more sophisticated therapies under development in the longevity industry.

Nanocarriers for natural polyphenol senotherapeutics

Senescence is a heterogenous and dynamic process in which various cell types undergo cell-cycle arrest due to cellular stressors. While senescence has been implicated in aging and many human pathologies, therapeutic interventions remain inadequate due to the absence of a comprehensive set of biomarkers in a context-dependent manner. Polyphenols have been investigated as senotherapeutics in both preclinical and clinical settings. However, their use is hindered by limited stability, toxicity, modest bioavailability, and often inadequate concentration at target sites.

To address these limitations, nanocarriers such as polymer nanoparticles and lipid vesicles can be utilized to enhance the efficacy of senolytic polyphenols. Focusing on widely studied senolytic agents - specifically fisetin, quercetin, and resveratrol - we provide concise summaries of their physical and chemical properties, along with an overview of preclinical and clinical findings. We also highlight common signaling pathways and potential toxicities associated with these agents. Addressing challenges linked to nanocarriers, we present examples of senotherapeutic delivery to various cell types, both with and without nanocarriers. Finally, continued research and development of senolytic agents and nanocarriers are encouraged to reduce the undesirable effects of senescence on different cell types and organs.

This review underscores the need for establishing reliable sets of senescence biomarkers that could assist in evaluating the effectiveness of current and future senotherapeutic candidates and nanocarriers.

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