Aim: To determine whether early exercise in the form of instinctive upward walking can mitigate the negative effects of cardiac aging in Drosophila with cardiac-specific Nmnat Knockdown and overexpression. Methods: Flies were given exercise periods of 2 h per day, 5 days a week for 3 weeks starting when they were 2 days old. The heart model was used in conjunction with M-mode echocardiography traces to analyze cardiac function. Exercise capacity was assessed using a climbing index, and the

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... val rate was calculated with respect to the age of each subject upon death. Results: Cardiac-specific Nmnat knockdown severely compromised cardiac function with age by increased incidence of arrhythmias and decreased fractional with extreme dilation. The repeated exercise regimen was found to mitigate the deterioration of systolic function and rhythm caused by knockdown of myocardial Nmnat. Unexpectedly, hearts overexpressing Nmnat exhibited similar cardiac function to those of flies with normal expression after exercise training, and provided notable benefits with respect to lifespan and age-related locomotor decline. Conclusions: Nmnat plays a critical role in maintaining cardiac function and that beginning a repeated exercise regimen later in life may improve cardiac health. It may provide a basis for further research in mammals.