# Lifestyle Intervention plus Metformin to Treat Frailty in Older Veterans with Obesity

> **NIH VA I01** · MICHAEL E DEBAKEY VA MEDICAL CENTER · 2021 · —

## Abstract

The continuing increase in prevalence of obesity in older adults has become a major health concern. In older
adults, obesity not only causes serious medical problems, but it also exacerbates the age-related decline in
physical function, which causes frailty, impairs quality of life, and increases nursing home admissions. Thus,
failure to help obese older patients in managing weight increases future demand for chronic health care services.
We reported not only that frailty is common in obese older adults due to sarcopenic obesity but also that lifestyle
therapy resulting in weight loss in this understudied population improves physical function and ameliorates frailty.
However, the improvement in physical function was modest and most obese older adults remained frail.
Moreover, the weight loss-induced reduction of muscle and bone mass could worsen age-related sarcopenia
and osteopenia. Accordingly, many health care providers remain reluctant to recommend lifestyle therapy that
includes weight loss in the frail, obese elderly because of the uncertainty of whether the benefits outweigh the
risks, although weight loss and exercise is recommended as part of standard care for obese patients in general.
 Metformin, a biguanide, is a widely available oral drug used as treatment of diabetes. Animal studies have
shown that metformin improves both lifespan and health span. However, whether metformin can ameliorate
frailty in humans is not known. If metformin improves or preserves physical function, this mostly safe and
commonly-used drug would revolutionize the approach to frailty in the elderly. Indeed, encouraging preliminary
data from our prior randomized controlled trials (RCT) in this population demonstrated that metformin users,
despite being still considered frail, have higher baseline scores in the Physical Performance Test (PPT)
compared to non-users. More importantly, the use of metformin during the trials predicted much larger
improvements in PPT scores in response to lifestyle interventions. Hence these data, in conjunction with results
from our prior studies, suggest that each of lifestyle therapy and metformin is associated with amelioration of
frailty, but the additive effects of both in combination could result in reversal of the frailty. In this project, we
propose the concept that the addition of metformin to lifestyle therapy reverses frailty by reducing cellular
senescence and senescence-associated phenotype (SASP), especially in obese older adults with a high burden
of senescent cells and accelerated aging. Accordingly, our objective is to conduct the first head-head,
comparative efficacy, placebo-controlled RCT to test the novel hypothesis that lifestyle therapy + metformin for
six months will be more effective than lifestyle therapy alone or metformin alone in improving physical function
and preventing the weight loss-induced reduction in muscle and bone mass in obese (BMI ≥ 30 kg/m2) older
(age ≥ 65 years) veterans with physical frail...

## Key facts

- **NIH application ID:** 10015506
- **Project number:** 1I01CX002161-01
- **Recipient organization:** MICHAEL E DEBAKEY VA MEDICAL CENTER
- **Principal Investigator:** DENNIS T. VILLAREAL
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2020-10-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10015506

## Citation

> US National Institutes of Health, RePORTER application 10015506, Lifestyle Intervention plus Metformin to Treat Frailty in Older Veterans with Obesity (1I01CX002161-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10015506. Licensed CC0.

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