Yet More Mouse Data on Fisetin as a Senotherapeutic
Mouse data has consistently shown fisetin to be senolytic, capable of selectively destroying the senescent cells that accumulate in tissues with age. Doses most often used are equivalent to around 20 mg/kg in humans, but dosing strategies range from a one-time course of treatment of a few days to intermittent doses provided over months. Unfortunately, despite planned and actually undertaken human trials of fisetin supplementation, there is still no published data of its senolytic capacity in humans. The dasatinib and quercertin combination and the locally delivered senolytic developed by UNITY Biotechnology before they ran out of funds remain the only senolytics with human data for clearance of senescent cells.
Advancing age is the strongest risk factor for cardiovascular diseases (CVDs), primarily due to progressive vascular endothelial dysfunction. Cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to age-related endothelial dysfunction by promoting mitochondrial oxidative stress and inflammation, which reduce nitric oxide (NO) bioavailability. However, the molecular changes in senescent endothelial cells and their role in endothelial dysfunction with aging remain incompletely unclear. As such, in this study we sought to identify the endothelial cell senescence-related signalling pathways, endothelial-derived SASP factors, and their impact on endothelial function with aging.
Single-cell transcriptomics was performed on aortas from young (6 months) and old (27 months) mice with and without in vivo senolytic treatment with fisetin (100 mg/kg/day administered in an intermittent dosing paradigm) to characterize endothelial cell senescence and transcript expression changes. Senescent endothelial cells exhibited elevated expression of SASP factors, particularly Cxcl12, which was reversed by fisetin supplementation, with responses also reflected in circulating CXCL12 concentrations. Plasma from old mice impaired endothelial function by inducing vascular cell senescence, reducing NO, increasing mitochondrial oxidative stress, and promoting endothelial-to-mesenchymal transition-effects partially driven by CXCL12 and prevented by fisetin.
It would seem to be a no-brainer (pun intentional) to do 'omic assessment via OLINK to discern the effects on signal transduction pathways BEFORE and AFTER various doses of fisetin in humans. If there is any causality, I would feel confident that a change in signal transduction pathways would be observed. Perhaps this has been done and published.
• Suh Y, Afaq F, Khan N, Johnson JJ, Khusro FH, Mukhtar H: Fisetin induces autophagic cell death through suppression of mTOR signaling pathway in prostate cancer cells. Carcinogenesis 2010, 31(8):1424-1433. 10.1093/carcin/bgq115
• Khan N, Afaq F, Khusro FH, Mustafa Adhami V, Suh Y, Mukhtar H: Dual inhibition of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin signaling in human nonsmall cell lung cancer cells by a dietary flavonoid fisetin. Int J Cancer 2012, 130(7):1695-1705. 10.1002/ijc.26178
• Khan N, Afaq F, Syed DN, Mukhtar H: Fisetin, a novel dietary flavonoid, causes apoptosis and cell cycle arrest in human prostate cancer LNCaP cells. Carcinogenesis 2008, 29(5):1049-1056. 10.1093/carcin/bgn078
It is no surprise that the same pathways routinely upregulated in diseases of the older to aged population are also found in clinical diseases associated with advanced age (e.g., COVID-19). So, it is not a giant leap of a hypothesis to consider the senescence-associated secretory phenotype (SASP) as a significant factor in all things that are negatively associated with aging. Reversing or down-regulating these pathways with natural compounds is certainly worth trials in the human population, primarily if natural compounds with negligible toxicity are employed. A publication that brings all this to mind is:
Feng T, Zhang M, Xu Q et al: Exploration of molecular targets and mechanisms of Chinese medicinal formula Acacia Catechu -Scutellariae Radix in the treatment of COVID-19 by a systems pharmacology strategy. Phytother Res 2022, 36(11):4210-4229. 10.1002/ptr.7554
follow-up comment: I read the referenced article per the DOI:
Mahoney SA, Mazan-Mamczarz K, Tsitsipatis D et al: Senolytic treatment with fisetin reverses age-related endothelial dysfunction partially mediated by SASP factor CXCL12. bioRxiv 2025. 10.1101/2025.08.13.670216
The authors studied young (six-month-old) wildtype mice versus old (27-month-old) mice. Using an Excel program, and speculating that the average weight of the young mouse was 0.025 kg (25 grams), the Human Equivalent Dose (HED) for a 70 kg man would be 510 mg/d. I was able to find some fisetin products on Amazon that were 500 mg of fisetin per capsule. I need to explore further because that product also contained quercetin at a dose of 200 mg per capsule. This was a liposomal product called Sharoaid, apparently manufactured according to the label in the UK. I'm just checking now, but the same company makes a Fisetin liposomal product only at 1500 mg per 2 capsules. The pricing is reasonable. I cannot see what the big deal would be in doing baseline triptomics on 20 older humans, treating them based on the Human Equivalent Dose (HED) Excel program, and then repeating the triptomics and related clinical data at 1 month, 2 months, 3 months, and 6 months. I will make this suggestion to those at Life Extension in Florida as a possible clinical trial. I did discover that Life Extension (LE) makes a fisetin supplement, but it contains 44.5 mg per capsule. At a dose of 500 mg/d, that would amount to 11 capsules per day for a 70 kg person. What appears to be needed are fisetin assays to determine first what the true amount of fisetin is per capsule.
It is almost impossible to determine the actual dosages per capsule by simply buying a product. To do so without risking objections from the manufacturere on negative findings, would require their cooperation in a trial, with nothing to stop them from producing "special" versions for the trial.
To do what seems like a simple human senolytics study would run to several million dollars to exert proper controls and appropriate followups, and then would only be credible if using the right metrics from the Mayo Clinic or the Buck institute. Easy to understand why the current senolytics literature is such a confused mess.