Tier 4 — mechanistic

REPROGRAM: REsilience PROmotion with GeRoprotectors: AssessMent of biological effect: Rationale and protocol for a trial of biological effect

Daisy Wilson, Animesh Acharjee, Niharika A. Duggal, Jose R. Hombrebueno, Simon W. Jones, Jonathan W. Lewis, João Pedro de Magalhães, Yessica Martinez-Serrato, Ali Mazaheri, Helen M. McGettrick, Sudip Mondal, Amy J. Naylor, Aline Nixon, Thomas Nicholson, Judith Partridge, Thomas Pinkney, Nicholas J. W. Rattray, Claire Steves, Kristina Tomkova, Carly Welch, Thomas Jackson
PLOS ONE 2026 21(6):e0346347

Bibliography

PubMed
PMID 42308222
PubMed Central
PMC13274875
DOI
10.1371/journal.pone.0346347
Trial registry
View on ClinicalTrials.gov Registered trial — results not yet published in a peer-reviewed journal.
Funding
Funded by a Wellcome Leap Dynamic Resilience Award, co-funded by Temasek Trust. The paper states that the funders had no role in study design, data collection and analysis, publication decisions, or manuscript preparation.
Competing interests
The authors declared no competing interests.

Study snapshot

DesignPhase IIa randomized, three-arm mechanistic clinical trial protocol without a placebo arm.
ModelHealthy adults aged 70 years and older.
SamplePlanned n=60: 20 participants per intervention arm, balanced by sex.
InterventionThree intervention arms: metformin MR 1500 mg/day, fisetin 100 mg/day, or spermidine 15 mg/day. The fisetin and spermidine interventions are given for 3 weeks.
Duration3-week treatment period for fisetin, with post-intervention biological assessments after a rest week.
EndpointsPrimary: senescent-cell burden in adipose tissue measured by SA-β-gal; Additional senescence markers; Epigenetic age; Autophagy and nutrient-sensing readouts; Inflammation; Immune-cell phenotypes; Bioenergetics; Stem-cell function; Gut microbiome; EEG-related neural measures

What the study showed, in plain terms

REPROGRAM is a peer-reviewed protocol testing three geroprotective interventions in healthy adults aged 70 years or older. The fisetin arm uses 100 mg once daily for three weeks, a much lower continuous dose than the commonly cited 20 mg/kg intermittent senolytic schedules.

The trial is designed to measure biological effects, including senescent-cell burden in adipose tissue. It has no placebo arm and this publication reports the protocol only, so it cannot establish that fisetin reduces senescent cells or improves health outcomes in people.

Key findings

  • The fisetin arm uses 100 mg/day for three weeks in older adults.
  • The target sample is 60 participants, with 20 assigned to each of metformin, fisetin and spermidine.
  • The primary biological question is whether the interventions change adipose-tissue senescent-cell burden measured by SA-β-gal.
  • This protocol demonstrates that current human fisetin research includes continuous low-dose regimens as well as intermittent high-dose schedules.

What this study can and cannot tell us

  • Protocol only: no fisetin efficacy or safety outcome data are reported.
  • There is no placebo arm, so any future within-group biological changes will require cautious interpretation.
  • The intervention lasts only three weeks and focuses on mechanistic biomarkers rather than clinical longevity outcomes.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology