Fisetin and the Search for Natural Senotherapeutics that can Improve Health and Extend Lifespan by Regulating mTOR, AMPK, and MAPK

Research suggests that fisetin has strong senolytic activity, which means it can selectively induce the death of senescent cells. Senescent cells are damaged cells that cease to divide but do not die as they should. They release inflammatory factors that lead to tissue dysfunction and age-related diseases, and subsequently, play a major role in the aging process. By clearing these cells, clearing these cells reduced inflammation and improved tissue function in animal models, with effects on lifespan reported in mice.

A 2018 study [1] set out to test ten flavonoids for their senolytic properties. The study acknowledged that the combination of Dasatinib, (when combined with the flavonoid quercetin) is a potent senolytic, improving numerous age-related conditions including frailty, osteoporosis, and cardiovascular disease. However, the goal of this study was to identify natural flavinoids with even more potent senolytic activity.

The study examined critical connectivity tissue (human fibroblasts) that had become senescent from oxidative and genotoxic stress. They further tested the flavinoids on mice, evaluating age-related histopathology, disease markers, health span and lifespan.

Of the 10 flavonoids tested, fisetin was the most potent senolytic. When they treated the old mice. Fisetin reduced senescent markers in multiple tissues, consistent with a hit-and-run senolytic treatment like Dasatinib + Quercetin. It was determined that fisetin demonstrates senotherapeutic activity in both human and mice tissue. In mice, it was found that fisetin restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan.

Additionally, fisetin is known for its antioxidant properties. It combats oxidative stress, a key contributor to aging and chronic disease, by neutralizing free radicals and reducing oxidative damage. Antioxidant activity of this kind has been studied in relation to aging and cognitive function, though these remain preclinical findings.

Fisetin has been reported to act on AMPK, MAPK and mTOR signalling while also inhibiting CDK1, and CDK4 kinase enzymes. [4] A 2015 study indicated that AMPK activation can delay aging [2], while a 2019 study demonstrated mTOR inhibition has profound effects on life span and age-associated phenotypes across a wide array of organisms. [3]

Natural senolytic supplements are widely available, but notably, NEUROmergence®, which contains fisetin, is formulated with seven additional compounds thought to have the ability to affect similar pathways as Dasatinib. NEUROmergence® also contains quercetin to further align the formulation to D+Q.

1. Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, Ling YY, Melos KI, Pirtskhalava T, Inman CL, McGuckian C, Wade EA, Kato JI, Grassi D, Wentworth M, Burd CE, Arriaga EA, Ladiges WL, Tchkonia T, Kirkland JL, Robbins PD, Niedernhofer LJ. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018 Oct;36:18-28. doi: 10.1016/j.ebiom.2018.09.015. Epub 2018 Sep 29. PMID: 30279143; PMCID: PMC6197652. https://pubmed.ncbi.nlm.nih.gov/30279143/

2. Stancu AL. AMPK activation can delay aging. Discoveries (Craiova). 2015 Dec 31;3(4):e53. doi: 10.15190/d.2015.45. PMID: 32309575; PMCID: PMC6941559. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941559/

3. Papadopoli D, Boulay K, Kazak L, Pollak M, Mallette FA, Topisirovic I, Hulea L. mTOR as a central regulator of lifespan and aging. F1000Res. 2019 Jul 2;8:F1000 Faculty Rev-998. doi: 10.12688/f1000research.17196.1. PMID: 31316753; PMCID: PMC6611156.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611156/

4. Baier A, Szyszka R. Compounds from Natural Sources as Protein Kinase Inhibitors. Biomolecules. 2020 Nov 12;10(11):1546. doi: 10.3390/biom10111546. PMID: 33198400; PMCID: PMC7698043. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698043/

Update, November 2026

Two things have changed since this article was written, and they point in opposite directions.

The rodent evidence has strengthened. A 2025 study in Aging Cell tested intermittent oral fisetin, one week on and two weeks off, in old mice and reported improved frailty scores and grip strength, with RNA sequencing of skeletal muscle identifying the senescence-related pathways involved. The study benchmarked fisetin against two established methods of removing senescent cells, including genetic clearance in a transgenic model, which is a more demanding comparison than most natural-compound work attempts (Murray et al., 2025).

Human efficacy evidence remains absent. Randomized trials in people are underway rather than reported. One registered triple-blind placebo-controlled trial is giving 100 mg of fisetin daily for seven weeks to adults aged 50 and over, with a circulating inflammation marker as its primary endpoint, and its protocol was published in 2026 (Tavenier et al., 2026). Notably, that trial uses 100 mg daily, far below the intermittent high-dose regimens discussed in the senolytic literature.

The accurate position is therefore narrower than this article originally implied. Fisetin has replicated, mechanistically characterized senolytic activity in mice, benchmarked against genetic controls. Whether any of that transfers to humans is an open question that the running trials are designed to answer, and no published randomized trial has yet demonstrated a clinical benefit in people.