“Exercise as medicine” is an important component of lifestyle medicine and has been garnering increasing attention. It is seen as an important adjunct to the treatment of a whole range of chronic diseases, from cancer to cardiac rehabilitation to interventions for Mild Cognitive Impairment.“Exercise as longevity medicine” is a far newer version that seeks not only the alleviation of chronic illnesses but the primordial prevention of these diseases where the greatest risk factor is aging. It also seeks to address not just life extension, but also the prolongation of healthspan, in other words, the compression of morbidity.This sets the next stage to implement exercise as personalized and as precision medicine and thisfocus has been the subject of recent biomedical literature. However, work on the relationshipbetween exercise for longevity and the interactions with supplements is even more nascent. Research on sports supplements have a much longer history, but the focus here is on performance rather than its effects on healthspan and lifespan.Based on a brief survey of extant literature, this paper presents 5 key questions and considerations to be investigated if supplements are to be useful for augmenting the beneficial effects of exercise and physical activities.Examples of supplements commonly used in each category and supported by the literature aregiven in parentheses. With regard to these specific supplements, where there is also research toanswer the questions posed, it will also be cited.1. Could supplements for enhancing athletic performance be re-purposed for enhancing theeffects of exercise as longevity medicine? (Creatine, Hydroxymethylbutyrate)2. Could the use of ergogenic aids be useful as a motivational tool for exercise adherence?(Coffee, not decaffeinated)3. Are there instances when supplements could ameliorate risks of more intense exercise?(Aspirin, Taurine, Niacinamide, Nettle leaf)4. Are there senolytics that interfere with the benefits of exercise? (Metformin, Nicotinamideriboside, Alpha-ketoglutarate, Curcumin)5. What insights can we obtain from medical anthropology studies of hunter gatherer societies,and research relating to longevity hotspots and masters athletes? (Lithium orotate, Fucoidan)Just as drug interactions are of importance in polypharmacy, so too the interactions betweensupplements and exercise, as both become the standard of care for smart aging.This is of especial importance as proven exercise mimetics are yet to be discovered. Until then supplements enhancing the benefits of exercise are an essential adjunct for a large segment of older adults who are unable to engage fully in physical activities to the recommended levels.