As part of my preparations for signing off for a while — and for even longer than usual (it’s spring and there are whole lot of things outside that now need doing), I want to first cap off that last piece about the historical cases of fortuitous self-medication with quercetin. I’ll do this by providing a quick look at the current dearth of clinical testing of this non-proprietary senolytic found in very many human plant foods.
The James Kirkland research group based in the Mayo Clinic in Rochester, Minnesota, is currently the most publication-prolific on the subject of senolytic compounds. The Kirkland group’s working hypothesis/theory with regard to the health potential of small molecule senolytics like quercetin is depicted nicely in the graphic below from one of their recent review articles on the subject.
A potentially crucial idea of theirs, emphasized in italics below, with regard to the function of senolytic compounds is mentioned in this same Kirkland group review article:
“According to the threshold theory of cellular senescence, senescent cells can be present without clinical manifestations but, if their abundance exceeds a threshold, senescent cell burden can increase further and contribute to development of local and systemic dysfunction and multiple diseases (Fig. 2 [above]). Senescent cells can spread even to distant sites because of their SASP [senescence-associated secretory phenotype]; therefore, systemic, intermittent administration of senolytics for senescence-associated diseases is potentially more promising than local administration, with the exception of perhaps eye, skin or dental topical or other local applications. Perhaps there may not need to be strict cell type specificity of senolytics administered in vivo. Arguably, once systemic senolytic treatment has reduced overall senescent cell burden to below a threshold, the immune system might clear remaining senescent cells, including those resistant to that particular senolytic. This could be especially important for older individuals or those with chronic diseases, who already have a high systemic senescent cell burden.”
Given the Kirkland group’s suspicion that strict cell specificity of senolytics may not be necessary for reducing the total senescent cell burden back down below the threshold where health can start to be restored, it is puzzling to me to see that the team has concentrated on using a combination of quercetin and the cancer drug dasatinib in its human clinical trials. The Kirkland group has, after all, itself shown that quercetin alone is quite effective in reducing senolytic cell burden for endothelial cells as represented by human umbilical vein endothelial cells (HUVEC) at quite low concentrations not toxic to non-senescent (i.e., proliferating) cells. See center graph below.
Table I below from the another recent (August 2022) paper from the Mayo Clinic group tallies the different senolytics being used in ongoing or planned clinical trials. Note in the Table that there is only one ongoing clinical trial employing quercetin alone.
Fisetin (“F”) is another plant-derived senolytic that is also found in human food stuffs, but at much lower concentrations than quercetin. Reportedly, its senolytic potency is only about double that of quercetin, however. This compound appears to target the same sort of senescent endothelial cells as quercetin. The UBX series of senolytics at the end of the table are proprietary, man-made pharmaceuticals.
In any case, the Kirkland research group’s suggestion above, that “strict cell type specificity” for senolytics is arguably not as important a matter as just reducing the overall senolytic cell burden, may well explain why the fortuitous consumption of very high amounts of quercetin in various everyday foodstuffs appears to be associated with remarkable longevity and good health in old age.