REPROGRAM
Research type
Research Study
Full title
REsilience PROmotion with GeRoprotectors: AssessMent of biological effect
IRAS ID
338321
Contact name
Daisy Wilson
Contact email
Sponsor organisation
University of Birmingham
Duration of Study in the UK
1 years, 5 months, 26 days
Research summary
The number of people aged over 60 in the UK reached 15.5 million (23% of the population) in 2020 and their numbers continue to increase (1). Although more people are living for longer, they aren’t necessarily enjoying good health in their old age (2). Older age is associated with reduced resilience (ability to bounce back) to insults such as infections, falls or surgery. This loss of resilience with age is linked to many serious life events such as admission to hospital, loss of independence and even death (3). The underlying biological causes (changes within cells) of the loss of resilience are poorly understood which prevents healthcare professionals being able to intervene with a targeted medication to improve health in old age (4).
Recent research has described biological processes which are involved in the ageing of cells, animals and humans (5). These processes can be changed with drugs called ‘geroprotectors’ and when these drugs have been given to mice there has been an improvement in both their life expectancy and health in old age (6). In humans it is not clear whether geroprotectors work in real life and which patients would benefit the most (6).This trial aims to investigate three different geroprotectors: metformin, fisetin and spermidine. The trial will investigate the geroprotectors ability to change the underlying biological processes.
This trial is part of a wider project funded by a Wellcome Leap grant. This trial will be conducted entirely at the Queen Elizabeth Hospital Birmingham NHS Foundation Trust but within this application there are some references to Kings College London. Kings College London are our partners within the wider project and will be processing some of the samples (stool).
Purpose and Design
We know that as people age they are more likely to develop diseases of ageing, such as diabetes, heart disease, and dementia and are also more susceptible to infections. This leads to physical frailty and multimorbidity in some people (7). At the same time, life span is improving, so it is important we aim to increase the time people spend in good health (so called health span, or healthy life expectancy).
In recent years, research has focussed on describing biological processes which are involved in the ageing of cells, animals and humans (5). As a result, there has been an expansion in research focussing on ways to improve these underlying processes, and thus reduce the risks of people developing diseases of ageing and frailty. The focus is on treating the underlying processes, rather than focussing on individual diseases of ageing, to improve health span. These biological processes can be changed with drugs called ‘geroprotectors’ in mice but we are not sure whether they would work in humans and which patients would benefit the most (8). Research on geroprotector drugs is very important because the only other known successful management of ageing related processes are diet and exercise which not everyone can do (9).
The aim of the study is to investigate if three ‘geroprotector’ drugs can change the biological processes associated with ageing. The drugs are: fisetin, spermidine and metformin. These drugs have been chosen for two reasons. One, there is good evidence in cell and animal models that they have an effect on the underlying biological processes (10-18). Two, they are safe to use in an older adult population and are well tolerated in this group (19-21).To investigate whether these three drugs can change the biological processes contributing to ageing we have chosen to recruit a group of healthy older people and will give each participant one of the drugs. We will recruit 60 participants with 20 participants in each drug group. The participants will initially attend the research clinic twice. On the first visit they will undergo: consent, clinical assessment and safety and experimental blood samples. On the second visit they will undergo: adipose (fat) biopsy (following review of safety bloods) and distribution of drugs (they may have a second blood test taken as well). The participants taking spermidine and fisetin will take the drugs for three weeks and then have a rest week. They will then attend the research clinic again and have a further adipose (fat) biopsy and safety and experimental blood samples. The participants taking metformin will take the drug for one week at 500mg and then have a telephone consultation to discuss increasing the dose to the trial dose of 1500mg. If there are no experienced side effects the dose will be increased to 1500mg and the participants will take the drugs for three weeks and then have a rest week. They will then attend the research clinic again and have a further adipose (fat) biopsy and safety and experimental blood samples.
RecruitmentPotential participants will be approached using a database of healthy older people who have expressed an interest in the ageing research carried out at the University of Birmingham – the Birmingham 1000 Elders group. For this database older people have consented (GDPR compliant) to storage of their contact details to be approached with information about research projects that take place at the University of Birmingham. The group currently has over 600 members. We will send an initial approach through email. This will give a very brief outline of the trial, the Participant Information Sheet as an email attachment, as well as details for the potential participants to contact us (via email, telephone, or post) if they are interested in participating.
As we are hoping to recruit 60 participants, we also plan to hold a meeting, both in person and virtually, to explain the study and the rationale behind it to anyone who has shown an interest in participating. The Elders group have told us that they appreciate this method as often another person asks a question that they hadn’t thought of or didn’t want to ask. When the potential participant has said that they would like to be involved, the research team will phone or email to arrange an initial visit.
There will be no unacceptable incentives for the potential participants to be recruited. However, we will pay a single honorarium of £200 to cover travel expenses for the three visits to the clinical research facility and to recognise the participants commitment to the study. This payment will be made even if a participant has to withdraw from the study to ensure there is no undue pressure to remain involved. If a volunteer attends the first clinic assessment but following review of the inclusion and exclusion criteria is not recruited their travel expenses for that visit will be covered.
This has been a successful method of recruitment for our recent nCTIMP investigating the effect of a nutritional supplement on biological processes (22).1. Statistics OoN. Estimates of the population for the UK, England, Wales, Scotland, and Northern Ireland. In: Statistics OoN, editor. 2024.
2. Loh JC, Creaser J, Rourke DA, Livingston N, Harrison TK, Vandenbogaart E, et al. Temporal trends in treatment and outcomes for advanced heart failure with reduced ejection fraction from 1993-2010: findings from a university referral center. Circ Heart Fail. 2013;6(3):411-9.
3. Stenroth SM, Pynnonen K, Haapanen MJ, Vuoskoski P, Mikkola TM, Eriksson JG, et al. Association between resilience and frailty in older age: Findings from the Helsinki Birth Cohort Study. Arch Gerontol Geriatr. 2023;115:105119.
4. Bisset ES, Howlett SE. The biology of frailty in humans and animals: Understanding frailty and promoting translation. Aging Med (Milton). 2019;2(1):27-34.
5. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023;186(2):243-78.
6. Trendelenburg AU, Scheuren AC, Potter P, Müller R, Bellantuono I. Geroprotectors: A role in the treatment of frailty. Mechanisms of Ageing and Development. 2019;180:11-20.
7. Jaul E, Barron J. Age-Related Diseases and Clinical and Public Health Implications for the 85 Years Old and Over Population. Front Public Health. 2017;5:335.
8. Trendelenburg AU, Scheuren AC, Potter P, Muller R, Bellantuono I. Geroprotectors: A role in the treatment of frailty. Mech Ageing Dev. 2019;180:11-20.
9. Travers J, Romero-Ortuno R, Bailey J, Cooney MT. Delaying and reversing frailty: a systematic review of primary care interventions. Brit J Gen Pract. 2019;69(678):E61-E9.
10. Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018;36:18-28.
11. Zimmermann A, Madeo F. Spermidine promotes fertility in aged female mice. Nature Aging. 2023;3(11):1317-9.
12. Al-Habsi M, Chamoto K, Matsumoto K, Nomura N, Zhang B, Sugiura Y, et al. Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice. Science. 2022;378(6618):370-+.
13. Eisenberg T, Abdellatif M, Schroeder S, Primessnig U, Stekovic S, Pendl T, et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 2016;22(12):1428-+.
14. Ijima S, Saito Y, Nagaoka K, Yamamoto S, Sato T, Miura N, et al. Fisetin reduces the senescent tubular epithelial cell burden and also inhibits proliferative fibroblasts in murine lupus nephritis. Front Immunol. 2022;13.
15. Hambright WS, Mu XD, Gao XQ, Guo P, Kawakami Y, Mitchell J, et al. The Senolytic Drug Fisetin Attenuates Bone Degeneration in the
Progeria Mouse Model. J Osteoporos. 2023;2023.
16. Mullen M, Nelson AL, Goff A, Billings J, Kloser H, Huard C, et al. Fisetin Attenuates Cellular Senescence Accumulation During Culture Expansion of Human Adipose-Derived Stem Cells. Stem Cells. 2023;41(7):698-710.
17. Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4.
18. Alfaras I, Mitchell SJ, Mora H, Lugo DR, Warren A, Navas-Enamorado I, et al. Health benefits of late-onset metformin treatment every other week in mice. Npj Aging Mech Dis. 2017;3.
19. Bailey CJ. Metformin: historical overview. Diabetologia. 2017;60(9):1566-76.
20. Khan N, Syed DN, Ahmad N, Mukhtar H. Fisetin: a dietary antioxidant for health promotion. Antioxid Redox Signal. 2013;19(2):151-62.
21. Muñoz-Esparza NC, Latorre-Moratalla ML, Comas-Basté O, Toro-Funes N, Veciana-Nogués MT, Vidal-Carou MC. Polyamines in Food. Front Nutr. 2019;6.
22. McGee KC, Sullivan J, Hazeldine J, Schmunk LJ, Martin-Herranz DE, Jackson T, et al. A combination nutritional supplement reduces DNA methylation age only in older adults with a raised epigenetic age. Geroscience. 2024.REC name
East of England - Cambridge Central Research Ethics Committee
REC reference
24/EE/0211
Date of REC Opinion
23 Jul 2024
REC opinion
Favourable Opinion