Swim exercise in C. elegans extends neuromuscular and intestinal healthspan, enhances learning ability, and protects against neurodegeneration

Exercise can protect against cardiovascular disease, neurodegenerative disease, diabetes, cancer, and age-associated declines in muscle, immune, and cognitive function. In fact, regular physical exercise is the most powerful intervention known to enhance robustness of health and aging. Still, the molecular and cellular mechanisms that mediate system-wide exercise benefits remain poorly understood, especially as applies to \"off target\" tissues that do not participate directly in training activity. Elaborating molecular mechanisms of whole-animal exercise benefits is therefore of considerable importance to human health. The development of exercise protocols for short-lived genetic models holds great potential for deciphering fundamental mechanisms of exercise trans-tissue signaling during the entire aging process. Here, we report on the optimization of a long-term swim exercise protocol for C. elegans and we demonstrate its benefits to diverse aging tissues, even if exercise occurs only during a restricted phase during early adulthood. We found that multiple daily swim sessions are essential for exercise adaptation in C. elegans, leading to body wall muscle improvements in structural gene expression, locomotory performance, and mitochondrial morphology. Swim exercise training enhances whole-animal health parameters such as mitochondrial respiration and mid-life survival and increases the functional healthspan of pharynx and intestine. Importantly, we show that swim exercise also enhances nervous system health: exercise increases learning ability of adult animals and protects against neurodegeneration in C. elegans models of tauopathy, Alzheimers disease, and Huntingtons disease. An important point is that swim training only during C. elegans early adulthood induces long-lasting systemic benefits that in several cases are still detectable well into mid-life. Overall, our data reveal the broad impact of swim exercise in promoting extended healthspan of multiple C. elegans tissues, underscore the potency of early exercise experience to influence long-term health (even after cessation of exercise), and establish the foundation for exploiting the powerful advantages of this genetic model to dissect the exercise-dependent molecular circuitry that confers long-lasting system-wide health benefits to aging or diseased adults.