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Background: Frailty is a geriatric syndrome that leads to poor health outcomes with aging. Previous studies have demonstrated that insulin resistance and inflammation predict frailty onset. Metformin is a widely used, well-tolerated drug that improves insulin sensitivity and displays anti-inflammatory properties. It is also known to prevent diabetes onset in adults with prediabetes. We hypothesize that metformin in older adults with prediabetes will promote healthy aging and prevent frailty. Here we describe an ongoing placebo-controlled, double-blinded clinical trial of metformin for the prevention of frailty in older adults with prediabetes.Methods: Older adults aged more than 65 years are randomized to metformin or placebo and are followed for 2 years. Prediabetes, required for inclusion, is assessed by 2-hour oral glucose tolerance test. Exclusion criteria are baseline frailty (Fried criteria), diabetes, dementia, untreated depression, active malignancy, or severe cardiovascular, pulmonary, and neurologic diseases. Primary outcome is frailty; secondary outcomes are physical function (Short Physical Performance Battery), systemic and skeletal muscle tissue inflammation, muscle insulin signaling, insulin sensitivity (insulin clamp), glucose tolerance (oral glucose tolerance test), and body composition (dual-energy x-ray absorptiometry). Subjects are followed every 3 months for safety assessments and every 6 months for frailty assessment (Fried criteria) and oral glucose tolerance test, and every 12 or 24 months for secondary outcomes. Enrollment of 120 subjects (completers) will take place over a 2-year period.Conclusion: Metformin is being examined in this study as a potential therapeutic agent to prevent frailty in older adults with prediabetes. Findings from this trial may have future implications for the screening and potential treatment of prediabetes in older patients with metformin for the prevention of frailty. [ABSTRACT FROM AUTHOR]

Background: Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme in cellular metabolism. NAD(+) levels decrease with aging. Experimentally boosting NAD(+) improves cognitive function and synaptic plasticity in Alzheimer's disease mouse models. NAD(+) can be synthesized from dietary intake of its precursors, including nicotinamide riboside (NR), a readily available non‐prescription nutritional supplement. Recent studies have demonstrated that dietary NR increases blood NAD(+) levels in healthy older adults. We hypothesize that NR supplementation will positively affect brain function in older adults with mild cognitive impairment (MCI). Method: Phase 2 randomized, double‐blind, placebo‐controlled trial with a 10‐week treatment period. Adults aged ≥65‐years‐old with a prior diagnosis of normal cognition [Montreal Cognitive Assessment (MoCA) score 26‐30] or MCI (MoCA score of 21‐25) participated at UT Health San Antonio. Dose escalation with NR over a 4‐week period was used to reach 1g/day, or maximum tolerated dose, for the final 6 weeks of the study. The primary outcomes were change from baseline on the MoCA and hippocampal blood flow as assessed by functional MRI (fMRI). Secondary outcomes included psychometric and frailty measures. Levels of blood NAD(+) and metabolites were determined at baseline and at the end of the study. Result: Baseline levels of NAD(+) did not significantly differ between MCI and control groups (21.4 ± 0.75 versus 19.3 ± 2.04μM, mean ± SEM, MCI and control, respectively; p = 0.24). NR was well tolerated and significantly increased blood NAD(+), NAAD, and Me4PY (log2fold change: 1.2, 2.6, 3.3, respectively; p < 0.0001). NR treatment was associated with positive functional changes in the brain and frailty measures, but changes in cognitive measures were not observed. Conclusion: A 10‐week supplementation of NR was well tolerated and significantly increased NAD(+) and associated metabolites in the blood of older adults with MCI. NR improved fMRI and physical function, our primary and secondary outcome measures, respectively. However, differences in cognition were not achieved in this small pilot study. Our results provide supporting evidence for further testing of NR as a method to maintain brain structure and function in older adults with MCI. [ABSTRACT FROM AUTHOR]