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; Alejandro Torrado Pacheco

doi:10.1371/journal.pone.0346347

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, Alejandro Torrado Pacheco (Editor)

^*Corresponding author for this work

Strathclyde Institute Of Pharmacy And Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

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Abstract

Background
Ageing is associated with reduced resilience to physiological stressors such as infection and surgery. This reduced resilience is believed to be underpinned by the hallmarks of ageing, the key biological mechanisms driving the aged phenotype. Geroprotectors are drugs that are proposed to slow down the ageing process and promote longevity and healthspan. Despite this, mechanistic studies in healthy older adults are lacking.

Methods and analysis
This trial will test the hypothesis that geroprotectors targeted towards biological mechanisms associated with poor resilience can reverse these pathways within a three-week period. Three geroprotectors with a good safety profile in older adults and evidence of effect on the hallmarks of ageing will be administered to 60 (30 female; 30 male) adults 70 + . Participants will be randomised to one of three arms (Metformin MR 1500 mg, Fisetin 100 mg or Spermidine 15 mg). Participants will be extensively clinically characterised at baseline. Blood, abdominal adipose tissue and stool samples will be taken at baseline and following the three-week intervention. The primary research question will answer whether a three-week course of Metformin, Spermidine, or Fisetin reduce the number of senescent cells as measured by SA-β-GAL in adipose biopsies in healthy older volunteers. Additionally, there will be assessment of the effect of the geroprotectors on other hallmarks of ageing, including autophagy, immunosenescence, chronic inflammation, dysregulated mTOR signalling, epigenetic age, DNA damage, dysregulated metabolism, stem cell exhaustion and microbial composition.

Ethics and dissemination
Ethical approval is in place (24/LO/0549). The main trial report and any sub-studies will be published in high impact peer-reviewed gerontology journals, presented at academic conferences and through a series of public engagement events. Participants enrolled in the study will be informed of the results by a written summary.

Trial registration
REPROGRAM was registered with ISRCTN on 10/09/24. ISRCTN47919839. Available at https://www.isrctn.com/search?q=47919839.

Original language	English
Article number	e0346347
Number of pages	20
Journal	PLoS ONE
Volume	21
Issue number	6
DOIs	https://doi.org/10.1371/journal.pone.0346347
Publication status	Published - 17 Jun 2026

Funding

This research is funded by a Wellcome Leap Dynamic Resilience Award (co-funded by Temasek Trust). TJ is the Principle Investigator for the funding received from Wellcome Leap Dynamic Resilience Award - https://wellcomeleap.org/dr/. CW and HMM are Co-Principal Investigators. AA, ND, JPdM, SJ, AM, DW, JH, TP, JP and CS are all Co-Investigators.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

ageing
resilience
geroprotectors

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Wilson, D., Acharjee, A., Duggal, N. A., Hombrebueno, J. R., Jones, S. W., Lewis, J. W., de Magalhães, J. P., Martinez-Serrato, Y., Mazaheri, A., McGettrick, H. M., Mondal, S., Naylor, A. J., Nixon, A., Nicholson, T., Partridge, J., Pinkney, T., Rattray, N. J. W., Steves, C., Tomkova, K., ... Torrado Pacheco, A. (Ed.) (2026). REPROGRAM: REsilience PROmotion with GeRoprotectors: AssessMent of biological effect: Rationale and protocol for a trial of biological effect. PLoS ONE, 21(6), Article e0346347. https://doi.org/10.1371/journal.pone.0346347

@article{f3bbcf352009479baa8175c854c3e78e,

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

abstract = "Background Ageing is associated with reduced resilience to physiological stressors such as infection and surgery. This reduced resilience is believed to be underpinned by the hallmarks of ageing, the key biological mechanisms driving the aged phenotype. Geroprotectors are drugs that are proposed to slow down the ageing process and promote longevity and healthspan. Despite this, mechanistic studies in healthy older adults are lacking. Methods and analysis This trial will test the hypothesis that geroprotectors targeted towards biological mechanisms associated with poor resilience can reverse these pathways within a three-week period. Three geroprotectors with a good safety profile in older adults and evidence of effect on the hallmarks of ageing will be administered to 60 (30 female; 30 male) adults 70 + . Participants will be randomised to one of three arms (Metformin MR 1500 mg, Fisetin 100 mg or Spermidine 15 mg). Participants will be extensively clinically characterised at baseline. Blood, abdominal adipose tissue and stool samples will be taken at baseline and following the three-week intervention. The primary research question will answer whether a three-week course of Metformin, Spermidine, or Fisetin reduce the number of senescent cells as measured by SA-β-GAL in adipose biopsies in healthy older volunteers. Additionally, there will be assessment of the effect of the geroprotectors on other hallmarks of ageing, including autophagy, immunosenescence, chronic inflammation, dysregulated mTOR signalling, epigenetic age, DNA damage, dysregulated metabolism, stem cell exhaustion and microbial composition. Ethics and dissemination Ethical approval is in place (24/LO/0549). The main trial report and any sub-studies will be published in high impact peer-reviewed gerontology journals, presented at academic conferences and through a series of public engagement events. Participants enrolled in the study will be informed of the results by a written summary. Trial registration REPROGRAM was registered with ISRCTN on 10/09/24. ISRCTN47919839. Available at https://www.isrctn.com/search?q=47919839.",

keywords = "ageing, resilience, geroprotectors",

author = "Daisy Wilson and Animesh Acharjee and Duggal, \{Niharika A.\} and Hombrebueno, \{Jose R.\} and Jones, \{Simon W.\} and Lewis, \{Jonathan W.\} and \{de Magalh{\~a}es\}, \{Jo{\~a}o Pedro\} and Yessica Martinez-Serrato and Ali Mazaheri and McGettrick, \{Helen M.\} and Sudip Mondal and Naylor, \{Amy J.\} and Aline Nixon and Thomas Nicholson and Judith Partridge and Thomas Pinkney and Rattray, \{Nicholas J. W.\} and Claire Steves and Kristina Tomkova and Carly Welch and Thomas Jackson and \{Torrado Pacheco\}, Alejandro",

year = "2026",

month = jun,

day = "17",

doi = "10.1371/journal.pone.0346347",

language = "English",

volume = "21",

journal = "PLoS ONE",

issn = "1932-6203",

number = "6",

}

Wilson, D, Acharjee, A, Duggal, NA, Hombrebueno, JR, Jones, SW, Lewis, JW, de Magalhães, JP, Martinez-Serrato, Y, Mazaheri, A, McGettrick, HM, Mondal, S, Naylor, AJ, Nixon, A, Nicholson, T, Partridge, J, Pinkney, T, Rattray, NJW, Steves, C, Tomkova, K, Welch, C, Jackson, T & Torrado Pacheco, A (ed.) 2026, 'REPROGRAM: REsilience PROmotion with GeRoprotectors: AssessMent of biological effect: Rationale and protocol for a trial of biological effect', PLoS ONE, vol. 21, no. 6, e0346347. https://doi.org/10.1371/journal.pone.0346347

TY - JOUR

T1 - REPROGRAM: REsilience PROmotion with GeRoprotectors: AssessMent of biological effect

T2 - Rationale and protocol for a trial of biological effect

AU - Wilson, Daisy

AU - Acharjee, Animesh

AU - Duggal, Niharika A.

AU - Hombrebueno, Jose R.

AU - Jones, Simon W.

AU - Lewis, Jonathan W.

AU - de Magalhães, João Pedro

AU - Martinez-Serrato, Yessica

AU - Mazaheri, Ali

AU - McGettrick, Helen M.

AU - Mondal, Sudip

AU - Naylor, Amy J.

AU - Nixon, Aline

AU - Nicholson, Thomas

AU - Partridge, Judith

AU - Pinkney, Thomas

AU - Rattray, Nicholas J. W.

AU - Steves, Claire

AU - Tomkova, Kristina

AU - Welch, Carly

AU - Jackson, Thomas

A2 - Torrado Pacheco, Alejandro

PY - 2026/6/17

Y1 - 2026/6/17

N2 - Background Ageing is associated with reduced resilience to physiological stressors such as infection and surgery. This reduced resilience is believed to be underpinned by the hallmarks of ageing, the key biological mechanisms driving the aged phenotype. Geroprotectors are drugs that are proposed to slow down the ageing process and promote longevity and healthspan. Despite this, mechanistic studies in healthy older adults are lacking. Methods and analysis This trial will test the hypothesis that geroprotectors targeted towards biological mechanisms associated with poor resilience can reverse these pathways within a three-week period. Three geroprotectors with a good safety profile in older adults and evidence of effect on the hallmarks of ageing will be administered to 60 (30 female; 30 male) adults 70 + . Participants will be randomised to one of three arms (Metformin MR 1500 mg, Fisetin 100 mg or Spermidine 15 mg). Participants will be extensively clinically characterised at baseline. Blood, abdominal adipose tissue and stool samples will be taken at baseline and following the three-week intervention. The primary research question will answer whether a three-week course of Metformin, Spermidine, or Fisetin reduce the number of senescent cells as measured by SA-β-GAL in adipose biopsies in healthy older volunteers. Additionally, there will be assessment of the effect of the geroprotectors on other hallmarks of ageing, including autophagy, immunosenescence, chronic inflammation, dysregulated mTOR signalling, epigenetic age, DNA damage, dysregulated metabolism, stem cell exhaustion and microbial composition. Ethics and dissemination Ethical approval is in place (24/LO/0549). The main trial report and any sub-studies will be published in high impact peer-reviewed gerontology journals, presented at academic conferences and through a series of public engagement events. Participants enrolled in the study will be informed of the results by a written summary. Trial registration REPROGRAM was registered with ISRCTN on 10/09/24. ISRCTN47919839. Available at https://www.isrctn.com/search?q=47919839.

AB - Background Ageing is associated with reduced resilience to physiological stressors such as infection and surgery. This reduced resilience is believed to be underpinned by the hallmarks of ageing, the key biological mechanisms driving the aged phenotype. Geroprotectors are drugs that are proposed to slow down the ageing process and promote longevity and healthspan. Despite this, mechanistic studies in healthy older adults are lacking. Methods and analysis This trial will test the hypothesis that geroprotectors targeted towards biological mechanisms associated with poor resilience can reverse these pathways within a three-week period. Three geroprotectors with a good safety profile in older adults and evidence of effect on the hallmarks of ageing will be administered to 60 (30 female; 30 male) adults 70 + . Participants will be randomised to one of three arms (Metformin MR 1500 mg, Fisetin 100 mg or Spermidine 15 mg). Participants will be extensively clinically characterised at baseline. Blood, abdominal adipose tissue and stool samples will be taken at baseline and following the three-week intervention. The primary research question will answer whether a three-week course of Metformin, Spermidine, or Fisetin reduce the number of senescent cells as measured by SA-β-GAL in adipose biopsies in healthy older volunteers. Additionally, there will be assessment of the effect of the geroprotectors on other hallmarks of ageing, including autophagy, immunosenescence, chronic inflammation, dysregulated mTOR signalling, epigenetic age, DNA damage, dysregulated metabolism, stem cell exhaustion and microbial composition. Ethics and dissemination Ethical approval is in place (24/LO/0549). The main trial report and any sub-studies will be published in high impact peer-reviewed gerontology journals, presented at academic conferences and through a series of public engagement events. Participants enrolled in the study will be informed of the results by a written summary. Trial registration REPROGRAM was registered with ISRCTN on 10/09/24. ISRCTN47919839. Available at https://www.isrctn.com/search?q=47919839.

KW - ageing

KW - resilience

KW - geroprotectors

U2 - 10.1371/journal.pone.0346347

DO - 10.1371/journal.pone.0346347

M3 - Article

SN - 1932-6203

VL - 21

JO - PLoS ONE

JF - PLoS ONE

IS - 6

M1 - e0346347

ER -

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

Abstract

Funding

UN SDGs

Keywords

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