Tier 3 — preclinical

Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used

Harrison DE, Strong R, Reifsnyder P, Rosenthal N, Korstanje R, Fernandez E, Flurkey K, Ginsburg BC, Murrell MD, Javors MA, Lopez-Cruzan M, Nelson JF, Willcox BJ, Allsopp R, Watumull DM, Watumull DG, Cortopassi G, Kirkland JL, Tchkonia T, Choi YG, Yousefzadeh MJ, Robbins PD, Mitchell JR, Acar M, Sarnoski EA, Bene MR, Salmon A, Kumar N, Miller RA
GeroScience 2024 46(1):795-816

Bibliography

PubMed
PMID 38041783
PubMed Central
PMC10828146
DOI
10.1007/s11357-023-01011-0
Funding
NIH-funded National Institute on Aging Interventions Testing Program (ITP). Full acknowledgement: NIA grants AG022308 (D.E. Harrison), AG022303 (R.A. Miller), AG022307 (R. Strong), AG013319 (R. Strong); UM site work also supported by the Glenn Foundation for Medical Research; R. Strong supported by a Senior Career Research Scientist Award, Dept. of Veterans Affairs Office of Research and Development.
Competing interests
Per the published Declarations: the PIs and technicians running the lifespan studies at all three sites had no conflicts of interest. Two co-authors (D.M. Watumull, D.G. Watumull) run Cardax, the company that supplied astaxanthin for this study in a proprietary formulation -- a conflict specific to the astaxanthin arm, not fisetin. Mayo Clinic (co-authors J.L. Kirkland, T. Tchkonia) holds patents on unspecified senolytic compounds, none currently licensed; T. Tchkonia holds shares in Unity Biotechnology and P.D. Robbins co-founded Itasca Therapeutics, both senolytic-drug developers -- general senolytics-field financial interests, not fisetin-specific and not disclosed as bearing on the fisetin arm's null result.

Study snapshot

DesignRandomised, controlled, genetically heterogeneous (UM-HET3) mouse lifespan study conducted in parallel across three independently NIA-funded testing sites (The Jackson Laboratory; University of Texas Health Science Center, San Antonio; University of Michigan), as part of the NIA Interventions Testing Program (ITP).
ModelUM-HET3 mice (CByB6F1 x C3D2F1 four-way cross), genetically heterogeneous, both sexes, treatment starting at approximately 12 months of age.
SampleCohort 2018, pooled across three independently NIA-funded ITP sites (Jackson Laboratory; University of Michigan; UT Health Science Center San Antonio). Males: Fis_Cyc n=150, Fis_On n=142, pooled matched control n=292. Females: Fis_Cyc n=134, Fis_On n=144, pooled matched control n=286.
InterventionFisetin fed at a target dose of 600 ppm in the diet (actual measured amount 99±9% of target across diet preparations, i.e. approximately 594 ppm), started at 20 months of age, administered on one of two schedules: continuously (Fis_On) or pulsed 3 days on/11 days off (Fis_Cyc) -- alongside four other novel ITP agents tested in the same round (SG1002, dimethyl fumarate, mycophenolic acid, 4-phenylbutyrate). Plasma fisetin levels could not be reliably quantified in treated mice with the assay methods available, so systemic drug exposure could not be independently confirmed.
DurationLifespan study — mice followed from approximately 12 months of age until natural death, per standard ITP protocol.
EndpointsMedian lifespan (log-rank test); 90th percentile lifespan (Wang-Allison test); Body weight

What the study showed, in plain terms

This is the most rigorous mouse-lifespan test of fisetin conducted to date. The National Institute on Aging's Interventions Testing Program (ITP) exists specifically to stress-test promising longevity compounds: the same intervention is run simultaneously at three independent laboratories, in a genetically heterogeneous mouse population rather than an inbred strain, and a result only counts if it replicates. That is a materially higher bar than the single-site, often more genetically uniform mouse studies that produced fisetin's headline senolytic findings.

In this ITP round, fisetin was one of five new agents tested. Two others — astaxanthin and meclizine — significantly extended male median lifespan (12% and 8% respectively). Fisetin did not extend lifespan, in either sex, at the dose and schedule used.

This does not overturn fisetin's senolytic biology — this study measured lifespan, not senescent cell clearance, frailty, or physical function, which is what most other fisetin mouse studies measure. But it is an honest, necessary data point: the compound with the most attention as a longevity intervention has not, in the field's most rigorous lifespan test to date, extended lifespan in normal ageing mice.

Key findings

  • Continuous fisetin (Fis_On, males): median lifespan 715 days vs 750 control (-5%, log-rank p=0.85); 90th percentile 1016 days (0%, Wang-Allison p=1.00).
  • Pulsed fisetin, 3 days on/11 off (Fis_Cyc, males): median lifespan 799 days vs 750 control (+7%, p=0.54, not significant); 90th percentile 1011 days (-1%, p=0.74).
  • Females: Fis_Cyc median 871 vs 876 control (-1%, p=0.75); Fis_On median 883 vs 876 control (+1%, p=0.37). Neither schedule extended female lifespan.
  • Critical biomarker result: p16(Ink4a) senescent-cell marker mRNA was measured in liver, kidney, and brain of mice fed fisetin (both schedules) from 20 months of age for 2-4 months. Neither fisetin regimen significantly lowered p16(Ink4a) levels versus age-matched untreated controls in any of the three tissues -- the hoped-for senescent-cell-clearing effect was not detected biomarker-wise in this cohort, despite fisetin's senolytic activity shown in other published mouse and cell models.
  • By contrast, two other agents tested in the same round, astaxanthin and meclizine, significantly extended male median lifespan (12%, p=0.003; and 8%, p=0.03).

What this study can and cannot tell us

  • Both a continuous-feeding schedule and a pulsed 3-days-on/11-days-off schedule (closer to human senolytic 'hit-and-run' dosing) were tested; neither extended lifespan in either sex, which weakens the argument that pulsed dosing specifically was the missing variable.
  • The p16(Ink4a) senescence-marker result is a genuine negative finding, not just an untested hypothesis -- fisetin did not measurably reduce this senescent-cell marker in liver, kidney, or brain at the dose, schedule, and age window used.
  • Plasma fisetin was not reliably detected in treated mice with the assay used, so it cannot be fully confirmed the compound achieved adequate systemic exposure at this dietary dose -- though the same dietary dosing approach has shown detectable senolytic activity in other published studies.
  • This is a lifespan and p16-marker null result specifically. It does not directly contradict fisetin's senolytic activity shown in other mouse studies that measured different endpoints (frailty, physical function, targeted organ senescence under different dosing regimens) rather than survival and whole-tissue p16 mRNA.
  • A null lifespan and p16 result does not rule out benefits on other ageing biomarkers, frailty, or organ-level senescence -- Murray 2025 and Mahoney 2023, using different (intermittent, targeted) dosing regimens, found significant improvements in frailty index, grip strength, and arterial function in old mice.

Related papers in the corpus

Tier 3
Fisetin is a senotherapeutic that extends health and lifespan
Yousefzadeh MJ et al. · EBioMedicine · 2018
Tier 3
Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches
Kevin O. Murray et al. · Aging Cell · 2025
Tier 3
Intermittent supplementation with fisetin improves arterial function in old mice by decreasing cellular senescence
Mahoney SA et al. · Aging Cell · 2023

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology