Does Metformin Modulate the Pillars of Aging in Older Adults?

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Based upon epidemiological data and interventional studies in invertebrates and rodents, metformin is a leading candidate to modulate aging. Yet, these animal studies have limited applicability to human subjects because they usually are of short duration and apply metformin doses that are much higher than the doses used in humans. Thus, the impact that metformin has on aging-focused outcomes and the mechanism by which metformin may promote healthy life extension in older human subjects is unknown. This grant application targets RFA-AG-20-044 “The Biological Mechanisms of Metformin Effects on Aging and Longevity” to test the hypothesis that metformin modulates critical pillars of aging in older adults to improve healthspan. We will leverage our ongoing NIA-funded randomized, placebo-controlled trial of metformin to prevent frailty in older adults (R01AG052697). The parent trial (n=120) is testing whether metformin administration for 24 months can prevent or delay the onset of frailty in older (≥ 65 years) adults. Deep aging- focused phenotyping includes changes in frailty (Fried phenotype score and Rockwood deficit accumulation index), physical function (short physical performance battery and 6-minute walk), muscle strength/mass, glucose metabolism (insulin clamping and glucose tolerance) and cognition (Mini-Mental State Exam). The parent trial also collects several biospecimens including blood, skeletal muscle and adipose tissue before and during metformin/placebo administration for measures of metabolic (AMPK and insulin signaling) and inflammation (NFκB and MAPKs) pathways. By applying innovative metabolomic, proteomic, molecular and biostatistical methodologies we will take advantage of these rich phenotypic data and biospecimens to evaluate the effect of metformin on 1) mitochondrial function; 2) cellular senescence; 3) epigenetics (DNA methylation), which will be in addition to the pillars of aging studied in the parent grant (metabolism and inflammation). Our objectives are: Aim 1) To determine the effect of metformin on pillars of aging in older adults. Aim 2) To determine the link between metformin-induced modifications in pillars of aging and changes in aging-focused phenotypic outcomes. We have assembled an interdisciplinary group across three institutions (UTHSCSA, Mayo, UCLA) that is well poised to help clarify the molecular and cellular mechanisms by which metformin promotes healthy life extension.