Nutraceuticals are compounds derived from foods, usually plants. In principle one can find useful therapies in the natural world, taking the approach of identifying interesting molecules and refining them to a greater potency than naturally occurs in order to produce a usefully large therapeutic effect. Unfortunately, in practice the nutraceutical industry is a largely a lazy one, in which entrepreneurs take advantage of a short path to market, and a lack of interest among consumers in whether or not products actually work, in order to repackage cheap ingredients into expensive brands that have minimal, unreliable, or even no beneficial effects.
In today’s open access paper, researchers discuss the potential for nutraceutical research and development to produce useful senolytic compounds. A senolytic therapy is one that selectively kills senescent cells in aged tissues, thus reversing aspects of aging by removing the inflammatory, harmful signaling of these cells. This class of therapy has performed well in animal models, and early human trials continue to produce promising outcomes.
Any survey of nutraceutical development is, as noted above, going to include a lot of useless, overhyped lines of work. Just because a mechanism exists doesn’t mean that the mechanism produces a large enough benefit to be therapeutic, and tiny to nonexistent effect sizes are characteristic of nutraceutical development. It is safe to tune out any time compounds in green tea are mentioned, for example. Still, some plant extract senolytics, such as fisetin and piperlongumine, do appear to have interestingly large effects in animal studies – even similarly sized to the small molecule chemotherapeutic senolytics. Whether they do as well in human trials remains to be seen, but making the attempt is not unreasonable based on the animal data.
Recent studies argue for a pathogenic role of senescent cells, which contribute to a range of aging related diseases, such as osteoarthritis, cardiovascular disease, and cataract. Senescent cells are found in aging related cognitive decline but also in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Therefore, the possible application of senolytics in a wide range of clinical scenarios is becoming an attractive concept. Senolytics could be used as a preventative in the elderly, as a supplement to clear senescent cells to thus improve or maintain tissue and organ health. They are also being looked at as an adjuvant cancer therapy, with the aim of clearing treatment-induced senescent cells and thus reducing the probability of relapse.
Synthetic compounds with senolytic or senostatic properties can be effective, however, they are not specific, and systemic side effects can be severe and deleterious to healthy cells. Hence, a movement toward the research of natural based compounds (nutraceuticals) with potential anti-senescence properties has begun. Nutraceuticals are bioactive compounds derived from food, including plant material, with physiological benefits in the prevention or treatment of disease. For instance, polyphenols, found in high abundance in plants, are bio-active compounds with anti-oxidant and anti-inflammatory properties making them potential senostatics by negating the pro-oxidant and pro-inflammatory signaling of senescent cells. The aim remains to find potential anti-aging therapies that are effective but exhibit minimal side effects, and some natural plant-based compounds could fit this criterion.
In vitro, two olive phenols called hydroxytyrosol (HT) and oleuropein aglycone (OLE) have shown to counteract senescence via significant reductions in SA-β-Gal staining, p16 levels, and senescence-associated secretory phenotype (SASP) levels in human lung fibroblasts and neonatal human dermal fibroblasts. Catechin is a tannin found in green tea that exists in multiple forms, including Epigallocatechin gallate (EGCG). Research investigating the effects of EGCG against replicative senescence in cells has shown the potential senostatics effects of the nutraceutical. Fisetin is bioactive flavonol molecule. Naturally aged C57BL/6 mice treated orally at 22-24 months with 100 mg/kg fisetin for 5 days showed a reduction in senescent cells in white adipose tissue. Additionally, fisetin treatment at 85 weeks of age significantly prolonged life-span of these mice by an additional 3 months. Resveratrol treatment in endothelial progenitor cells (EPCs) also showed prevention of replicative senescence. However, when a large-scale in vivo study of resveratrol in genetically heterogenous (outbred) mice was conducted in parallel with rapamycin treatment, analysis of activity showed that there was no significant difference between control and resveratrol-treated mice.
For senolytics to be widely used in aged but otherwise healthy populations to prevent tissue dysfunction, unwanted side effects have to be kept to the minimum. The use of nutraceutical based senolytics could result in fewer complications, while retaining anti-senescent effects. Despite promising in vitro reports, the data on the in vivo efficacy of nutraceutical senolytics is still sparse and, in some cases, contradictory. Thus, more research is still needed to determine whether they could be an attractive alternative to the most used chemical senolytics, such as dasatinib + quercetin, which have shown promising results in preliminary short-term clinical trials.