Physical inactivity is a serious health problem worldwide, contributing to early development of obesity, diabetes mellitus, hypertension, and cardiovascular diseases (CVD).1 In fact, our hypokinetic lifestyle is now widely recognized among the most proximal risk factors for heart disease (Figure 1), along with poor dietary habits and cigarette smoking.2–4 To address these concerns, public health strategies commonly incorporate the goal of safely increasing physical activity levels in the populations of industrialized societies. Accordingly, the number of health/fitness facilities and members is expected to increase exponentially over the next decade. Current market research indicates that the fastest-growing user subsets are those aged 35 to 54 years and those ≥55 years of age. These data, coupled with the recent finding that regular exercise prevents cellular senescence, have led an increasing number of adults, many of whom have known or occult chronic disease, to the conclusion that “more exercise is better.” Marathon running, for example, has increased in popularity over the past 3 decades, with participation increasing from 25 000 runners in 1976 to ≈2 million in 2010. Thus, we have a population paradox in which there is an expansion in the number of habitually sedentary individuals paralleling a concomitant increase in those taking part in unprecedented hours of vigorous exercise. Figure 1. The evolutionary cardiovascular disease pyramid. Unhealthy lifestyle practices lead to risk factors, the progression of cardiovascular disease, and ultimately, adverse outcomes or clinical end points. The first-line strategy to prevent initial or recurrent cardiac events is to favorably modify unhealthy lifestyle habits, including cigarette smoking and poor dietary habits and physical inactivity. In 2000, these habits were responsible for an estimated 435 000 and 365 000 deaths, respectively.4 CHF indicates congestive heart failure; MI, myocardial infarction; and PAD, peripheral arterial disease. Adapted from Mozaffarian et al2 …