Considerations for Age-specific Exercise-induced Cardiac Remodeling
Exercise Intensity and Modality in the Young and Aged
In nearly all studies discussed in this review, aged models exercised at lower intensities than young. Lower exercise intensities are not unexpected, given age-related declines in maximum cardiorespiratory fitness and that voluntary physical activity declines with age. However, few investigations have directly compared responses of the young and aged heart to exercise, and where these studies exist, matching for exercise intensity is difficult. Even in cases when intensity was matched such as in young and aged treadmill-trained rats, cardiac hypertrophy and activation of protective molecular signaling differed by age. Emerging work suggests that exercise-induced cardiac hypertrophy and systolic function are intensity dependent at least in young animals. This notion of the importance of intensity is supported by data suggesting that, although moderate-intensity aerobic exercise seems not to largely affect systolic function in older adults,[29,56] HIIT imparts systolic benefits, with previously sedentary older adults demonstrating improvements in LV EF after 8 wk of training. These data suggest that future efforts should assess whether exercise could elicit more profound outcomes if aged animals were forced to exercise at higher intensities.
Further complicating age-specific cardiac adaptations are differences between forced treadmill and voluntary wheel running, with some preclinical models performing well in one type of training compared with the other. We were unable to find reports comparing these two commonly used preclinical exercise modalities with respect to cardiac remodeling, and definitely not in an aged model where low engagement of aged males in voluntary wheel running is significant. However, we recently compared cardiac function by echocardiography in 18-month-old mice that underwent 4 wk of voluntary wheel running or forced exercise training by ramped treadmill protocol (Bruns DR, unpublished data, 2022). Treadmill training in aged males imparted larger changes in systolic function as evidenced by higher EF, FAC, and CO — effects that were either less robust or not improved with wheel running (Figures 2A–C). Given the low voluntary wheel-running distances in aged male mice (1 km per night), these findings are not surprising. The low engagement of aged males in voluntary exercise suggests that future work that aims to understand exercise-induced cardiac remodeling in the aged heart must do so with careful selection of exercise intensity and modality.
Changes in cardiac function in aged mice in response to voluntary wheel running or forced treadmill training. A. Treadmill running improved ejection fraction (EF) in aged male mice. B. Treadmill and wheel running improved fractional area change (FAC) in aged male mice, with treadmill training more robustly improving FAC. In female mice, wheel running and treadmill running both resulted in lower FAC. C. Improved cardiac output (CO) in aged male mice in response to treadmill training. Eighteen-month old C57Bl6 mice underwent 3 wk of voluntary wheel running or forced treadmill training. Treadmill training occurred in the dark period between 7 p.m. and 8 p.m. Training followed a ramped protocol, with increasing speed and time of exercise on a fixed incline treadmill. Sed, sedentary; Treadmill, forced treadmill exercise; Wheel, voluntary wheel running. *P < 0.05, sed versus exercise group within sex. #P < 0.05, wheel versus treadmill within sex. Data were analyzed by one-way analysis of variance. Bruns DR, Unpublished data, 2022.
Sex and Gender Differences in the Young and Aged
Although not a primary focus of the current review, both clinical and preclinical reports demonstrate clear sex differences in exercise-induced cardiac remodeling. Importantly and in line with similar exercise physiology, sex differences in preclinical models often reflect the same differences in human models. For example, in humans and in rodents, females generally undergo more pronounced exercise-induced LV hypertrophy compared with males, even when matched for level of activity, which is typically higher in female animals. Sex differences in cardiac aging also are significant and likely also contribute to differences between sexes in response to exercise. In aged rats, voluntary wheel running elicited better systolic and diastolic improvements in males compared with females, which the authors posited was due to more dramatic deterioration of cardiac function in males with advanced age. Historically, sex differences in exercise-induced cardiac remodeling have been attributed to estrogen — a conclusion largely based on the robust cardioprotection afforded by estrogen (reviewed in.) However, estrogen likely does not account for all mechanisms of sex-specific cardiac remodelling, particularly given the persistence of sex differences into advanced age when estrogen levels decrease with human menopause or cessation of rodent estrous cycling. Taken together, sex differences are clearly important in exercise-induced cardiac remodeling, both in the aged and young heart, likely because of complex interactions between genetic, hormonal, and environmental factors.
Timing of Exercise for Cardioprotection
Although exercise is cardioprotective at any age, several lines of evidence suggest that early in life exercise is better than initiation later in life. Changes in age-related LV stiffness begin around midlife at 55 yr of age. If training begins around this time, exercise can prevent the increase in cardiac stiffness attributable to sedentary aging, unlike similar training programs administered later in life that do not improve LV stiffness. Master athletes who trained for the majority of their adult life had LV compliance that was indistinguishable from young controls, again suggesting that early or lifelong exercise slows cardiac aging and may permit more robust physiological adaptations than when initiated later in life. Age-related declines in diastolic dysfunction can be attenuated by voluntary wheel running in mice, with differences in sedentary and running animals evident by the second quarter of the lifespan (10 months of age). The authors posited that an early critical period is optimal for exercise-induced anatomical and physiological remodelling, given the timing of age-associated declines in activity and cardiac function. Why late in life exercise is less robust than earlier interventions is not clear but may be due to age-related cardiac changes like hypertrophy and fibrosis that become difficult to overcome at advanced age or activation of different molecular signals. The aged myocardium displays a diminished response to pathological hypertrophic stimuli and is well characterized to be desensitized to adrenergic stimulation, suggesting that the aged heart may lose sensitivity to external stimuli. However, this hypothesis does not yet have consensus. Given the paucity of work that has directly compared how the young and aged hearts respond to exercise, the identification of the mechanisms that contribute to age-specific remodeling is an area ripe for research.
Exerc Sport Sci Rev. 2022;50(3):137-144. © 2022 American College of Sports Medicine