# Does insulin sensitivity impact the potential of metformin to slow aging?

> **NIH NIH R01** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2021 · $631,878

## Abstract

SUMMARY
NIA issued PA-18-025 to explore “…clinical translational potential of metformin to delay deleterious aging
changes or to extend healthy human life span.” Within PA-18-025 was the critical need to explore what factors
potentially modulate the clinical effectiveness of metformin before more costly large-scale clinical trials. Although
there is epidemiological support for health benefits of metformin in patient populations, it is not clear if these
protective effects extend to those free of disease. Therefore, there is a need to perform human studies
determining which subjects free of chronic disease benefit from metformin treatment. Retrospective analysis of
a randomized, double-blinded clinical trial in our lab revealed that subjects who were insulin sensitive had no
effect or negative effects on insulin sensitivity when taking metformin during an exercise training program. These
data suggest that in some subjects, metformin has detrimental metabolic outcomes that could accelerate aging.
There are data both in support of and refuting that metformin inhibits mitochondrial complex I action and/or
mitochondrial remodeling. The overall objective of this application is to determine if subjects currently free of
disease benefit from metformin treatment. There are two critical questions that remain unanswered in human
subjects: 1) does antecedent metabolic health influence responses to metformin, and 2) does long-term
treatment with metformin lead to mitochondrial remodeling and changes in function. To better understand the
translational potential of a clinically relevant dose of metformin for the prevention of chronic conditions, this
proposal aims to determine how antecedent metabolic health affects the response to metformin treatment, and
identify the relationship between skeletal muscle mitochondrial remodeling and mitochondrial function with
metformin treatment. The hypotheses are that: 1) metformin treatment in subjects free of T2D will improve insulin
sensitivity and glucoregulation in insulin resistant individuals, but will decrease insulin sensitivity and
glucoregulation in insulin sensitive subjects, and 2) long-term metformin treatment will remodel mitochondria in
a way that decreases mitochondrial function in subjects that are insulin sensitive, but improves mitochondrial
function in subjects that are insulin resistant. To test these hypotheses, a 12-week randomized, double-blind
clinical trial will be performed in subjects 40-75 yrs of age, free of disease, and stratified by insulin sensitivity
(insulin sensitive and insulin resistant). Pre and post-training assessments include the hyperinsulinemic-
euglycemic clamp to measure hepatic and peripheral insulin sensitivity, continuous glucose monitoring to
determine glucoregulation, and proposed blood-based biomarkers of aging. Further, the use of novel stable
isotope labeling with proteomic analysis will determine individual and complex-specific mitochondrial remodeling.
This approach w...

## Key facts

- **NIH application ID:** 9999395
- **Project number:** 5R01AG064951-02
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** Benjamin Francis Miller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $631,878
- **Award type:** 5
- **Project period:** 2019-09-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999395

## Citation

> US National Institutes of Health, RePORTER application 9999395, Does insulin sensitivity impact the potential of metformin to slow aging? (5R01AG064951-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9999395. Licensed CC0.

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