Summary: Administration of metformin increases healthspan and lifespan in model systems, and evidence from clinical trials and observational studies suggests that metformin delays a variety of age‐related morbidities. Although metformin has been shown to modulate multiple biological pathways at the cellular level, these pleiotropic effects of metformin on the biology of human aging have not been studied. We studied ~70‐year‐old participants (n = 14) in a randomized, double‐blind, placebo‐controlled, crossover trial in which they were treated with 6 weeks each of metformin and placebo. Following each treatment period, skeletal muscle and subcutaneous adipose tissue biopsies were obtained, and a mixed‐meal challenge test was performed. As expected, metformin therapy lowered 2‐hour glucose, insulin AUC, and insulin secretion compared to placebo. Using FDR<0.05, 647 genes were differentially expressed in muscle and 146 genes were differentially expressed in adipose tissue. Both metabolic and nonmetabolic pathways were significantly influenced, including pyruvate metabolism and DNA repair in muscle and PPAR and SREBP signaling, mitochondrial fatty acid oxidation, and collagen trimerization in adipose. While each tissue had a signature reflecting its own function, we identified a cascade of predictive upstream transcriptional regulators, including mTORC1, MYC, TNF, TGFß1, and miRNA‐29b that may explain tissue‐specific transcriptomic changes in response to metformin treatment. This study provides the first evidence that, in older adults, metformin has metabolic and nonmetabolic effects linked to aging. These data can inform the development of biomarkers for the effects of metformin, and potentially other drugs, on key aging pathways.

Common chronic diseases represent the greatest driver of rising healthcare costs, as well as declining function, independence, and quality of life. Geroscience‐guided approaches seek to delay the onset and progression of multiple chronic conditions by targeting fundamental biological pathways of aging. This approach is more likely to improve overall health and function in old age than treating individual diseases, by addressing aging the largest and mostly ignored risk factor for the leading causes of morbidity in older adults. Nevertheless, challenges in repurposing existing and moving newly discovered interventions from the bench to clinical care have impeded the progress of this potentially transformational paradigm shift. In this article, we propose the creation of a standardized process for evaluating FDA‐approved medications for their geroscience potential. Criteria for systematically evaluating the existing literature that spans from animal models to human studies will permit the prioritization of efforts and financial investments for translating geroscience and allow immediate progress on the design of the next Targeting Aging with MEtformin (TAME)‐like study involving such candidate gerotherapeutics.

Resveratrol, a plant-derived polyphenol, has been reported to improve glucose metabolism and vascular function and to extend life span in animal models, but studies in humans have been inconclusive. In a randomized, double-blind crossover study, we treated older glucose-intolerant adults (n = 30) with resveratrol (2−3 g/daily) or placebo, each for 6 weeks. A standard mixed-meal test was used to assess insulin sensitivity (Matsuda index) and secretion (C-peptide deconvolution) and vascular function by reactive hyperemia peripheral arterial tonometry. Skeletal muscle samples were obtained for gene expression using RNA-Seq analysis and to assess mitochondrial morphology. There were no changes in glucose tolerance, insulin sensitivity, weight, blood pressure, or lipid profile following resveratrol treatment. Fasting reactive hyperemia index improved with resveratrol (2.02 ± 0.2 vs 1.76 ± 0.02, p = .002). RNA-Seq analysis yielded 140 differentially expressed transcripts (corrected p-value ≤ .05), predominantly associated with mitochondrial genes and noncoding RNA. Ingenuity Pathway Analysis confirmed that mitochondrial dysfunction (p = 2.77 × 10⁻¹²) and oxidative phosphorylation (p = 1.41 × 10⁻¹¹) were the most significantly perturbed pathways. Mitochondrial number, but not size, was increased. Resveratrol treatment of older adults with impaired glucose regulation may have beneficial effects on vascular function, but not glucose metabolism or insulin sensitivity. Changes in gene expression suggest effects similar to those observed with caloric restriction, which has been shown to increase life and health span in animal models, although its significance for humans is uncertain. Future human studies should address the appropriate dose range and low bioavailability of resveratrol.

Significance: Redox regulation of breast cancer underlies malignant progression. Loss of the antioxidant glutathione peroxidase 2 in breast cancer cells increases reactive oxygen species, thereby activating hypoxia inducible factor-α (HIF1α) signaling. This in turn causes vascular malfunction, resulting in hypoxia and metabolic heterogeneity. HIF1α suppresses oxidative phosphorylation and stimulates glycolysis (the Warburg effect) in most of the tumor, except for one cancer subpopulation, which was capable of using both metabolic modalities. Hence, adopting a hybrid metabolic state may allow tumor cells to survive under aerobic or hypoxic conditions, a vulnerability that may be exploited for therapeutic targeting by either metabolic or redox-based strategies.