VO2Max is one of the key drivers of health. But as people age, VO₂max declines because multiple systems degrade in parallel: cardiac output falls, vascular stiffness increases, hemoglobin drops, and skeletal muscle loses mitochondrial density and capillary support. The most promising pharmaceutical and supplement strategies target these specific failure modes.
The strongest mechanistic levers—those capable of substantially slowing VO₂max decline or even increasing VO₂max despite aging—are agents that target oxygen transport or mitochondrial phenotype. HIF-PH inhibitors and EPO directly increase hemoglobin and oxygen-carrying capacity and remain the most powerful VO₂max enhancers known, though these are not practical for general use. PPAR-δ agonists and pan-ERR agonists (e.g., SLU-PP-332) reprogram muscle toward a highly oxidative, endurance-oriented state with increased mitochondrial content and improved substrate utilization; in animal models these produce large endurance gains and represent some of the most compelling future “VO₂max-trajectory” drugs.
For long-term preservation, rapamycin and urolithin A stand out for improving mitochondrial quality and turnover, reducing inflammation, and preserving both cardiac and skeletal muscle function. Nitrates, PDE-5 inhibitors, and telmisartan improve vascular function and nitric-oxide signaling, which enhances muscle perfusion and reduces the oxygen cost of exercise. NAD⁺ boosters offer modest support to mitochondrial biogenesis. Myostatin inhibitors can help maintain muscle mass and training capacity with age, indirectly supporting VO₂max if combined with endurance training.
Lower-impact adjuncts include creatine, epicatechin, citrulline, CoQ10, and mitochondria-targeted antioxidants; these provide small improvements in training capacity or mitochondrial efficiency. TMG has minimal direct effect on VO₂max but may modestly support endothelial function and training quality.
In aggregate, (and much more research needs to be done) the best mechanistic strategy might combine mitochondrial-centric agents (rapamycin, urolithin A, ERR/PPAR-δ modulators), vascular NO-axis support (nitrates, PDE-5), and interventions that sustain muscle and cardiac resilience, giving the highest probability of preserving high VO₂max into older age.
Read the full thread: Supplements and Drugs that may help maintain VO2max levels during aging?
Related: Exercise, VO2 max, and longevity | Mike Joyner, M.D
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