The Panacea of Human Aging

Calorie Restriction Versus Exercise

Nicholas T. Broskey; Kara L. Marlatt; Jasper Most; Melissa L. Erickson; Brian A. Irving; Leanne M. Redman


Exerc Sport Sci Rev. 2019;47(3):169-175. 

In This Article


Traditionally, exercise is defined as physical activity that is planned, structured, repetitive, and purposefully conducted and can range from recreational activities to competitive sports. Although resistance training has profound effects on both muscle and cardiometabolic health, the majority of studies examining the ability of lifelong exercise to extend the healthspan or lifespan in preclinical and clinical models has focused on endurance (aerobic)-based physical activities. For the purpose of this review, exercise that is purposely conducted to meet physical activity recommendations, though not to the extent of extreme training (e.g., marathons), is discussed. Despite much interest, researchers have unsuccessfully demonstrated that lifelong physical activity or exercise can extend maximal lifespan by slowing primary aging in well-controlled longitudinal studies in humans. However, maintaining physical activity at this level increases the disability-free mean/median lifespans. Specifically, lifelong exercise is associated with reductions in the risk of premature CVD mortality and related risk factors (e.g., hypertension, hypercholesterolemia, and type 2 diabetes).[32] These improvements share common and independent mechanisms with CR related to primary and secondary aging.

Primary Aging

Exercise improves physiological functioning (e.g., increases mitochondrial content and oxidative capacity, reduces oxidative stress, and enhances protein quality control), which may attenuate primary aging. To date, it is unclear whether exercise affects metabolic rate after the recovery phase (24–72 h), independent of changes in body composition. Only when combined with caloric restriction has a reduction in metabolic rate been reported after a 6-month intervention.[11] The effects of exercise and physical activity on oxidative stress and mitochondrial capacity are better characterized. Seminal work in controlled intervention studies performed in the late 1960s reported that exercise increases mitochondrial abundance and upregulates oxidative enzyme activities, as well as increases oxidative capacity in skeletal muscle.[33] In preclinical studies from the laboratory of the late John Holloszy, sustained periods of exercise increased the mean/median lifespan in rodents with little evidence that exercise extends maximal lifespan.[34] Studies in humans show that regular exercise increases mitochondrial oxidative capacity[35,36] and partially normalizes mitochondrial oxidative capacity as well as enzyme activities in trained older adults compared with sedentary younger adults.[36] Despite these improvements in mitochondrial bioenergetics, regular exercise does not completely ameliorate age-related reductions in mtDNA content, which may reflect a true defect in primary aging.[37] These mtDNA mutations could reduce the ability of older adults to increase their mtDNA abundance in response to exercise. However, sedentary elderly subjects participating in an aerobic exercise training program increased skeletal muscle mitochondrial content and function, which suggests that overall exercise-induced mitochondrial biogenesis is preserved with age.[38]

Exercise acutely increases oxidative stress, which stimulates antioxidant defense mechanisms that reflect a negative feedback. Excess acute exercise or insufficient antioxidant responses carries the risk of increasing rather than decreasing oxidative stress. The induction of a sufficient response to counteract exercise-induced stress is referred to as adaptive homeostasis.[39] Through this process, an individual can cope with oxidative stress by repairing damage by free radicals to maintain homeostasis. It should be noted, however, that the balance between exercise-induced energy flux and levels of antioxidants, ROS, and reactive nitrogen species may be differentially impacted by disease state, intensity, duration, sex, age, and level of fitness.[40] Although adaptive homeostasis is crucial for the training effect, it may be deleterious when increased chronically (overtraining) or in the presence of insufficient antioxidant capacity (intrinsic or dietary).

Secondary Aging

Insufficient levels of moderate to vigorous physical activity are routinely associated with reductions in average lifespan, which is indicative of accelerated secondary aging.[41] Lifelong exercise in humans increases the disability-free and mean/median lifespans likely due to reductions in secondary aging and premature mortality. Masters athletes who have maintained high levels of lifelong exercise have reduced risk of premature mortality and increased mean/median lifespans compared with sedentary controls likely due to reductions in secondary aging parameters including adiposity, insulin resistance, and hyperlipidemia.[42] However, because of the healthier lifestyle that masters athletes tend to practice including healthy eating habits, reductions in premature mortality and elevations in their mean/median lifespan cannot be exclusively attributed to exercise.

Regular exercise is important for reducing the risk of premature mortality in part by counteracting contributors to secondary aging. For example, regular exercise reduces risk of developing cardiometabolic diseases by reducing abdominal visceral fat,[36,43] dyslipidemia,[44] and inflammation,[26] while also improving insulin sensitivity.[26,36] Age-related declines in skeletal muscle quality and function often are attributed to declines in physical activity and, thus, likely contribute to the deleterious impact of secondary aging on overall muscle health. Collectively, these improvements in muscle health serve as an excellent countermeasure against the development of physical frailty and disability. In addition, regular exercise reduces the risk of physical frailty and disability by increasing cardiorespiratory fitness (i.e., V̇O2max),[35–37] and skeletal muscle mass, strength, and quality.[35] Indeed, lifelong exercise has been shown to help maintain cardiorespiratory fitness values that are well above the critical threshold for developing frailty (~5 METS or 17.5 mL·kg−1·min−1).[37] In addition, a 1-MET increase in V̇O2max is associated with ~15% reduction in all-cause mortality.[37]

The role of exercise in reducing adiposity, particularly visceral adiposity, is still not fully elucidated. For instance, although a systematic review concluded reductions in visceral adiposity occur in a dose-dependent manner,[45] a more recent RCT in middle-aged men and women with obesity revealed that there were no differences between exercise doses (volume and intensity) in the reduction of visceral fat.[43] To add further complexity, energy expenditures may need to be greater than 500–600 kilocalories per exercise session to achieve exercise-induced weight and visceral fat loss, which is well above the recommended levels of physical activity.[46] Furthermore, the inability of exercise to consistently reduce visceral fat stores could be attributed to the following factors: 1) low exercise doses may be inadequate for inducing a negative energy balance; 2) exercise may induce a compensatory increase in energy intake; 3) poor adherence to exercise prescriptions; or 4) their synergistic effects.[47]

An important consideration for use of exercise as part of anti-aging interventions is the implementation of appropriate exercise dosing. Exercise doses above the general exercise recommendations for overall health result in compensatory mechanisms (e.g., increased energy intake or decreased spontaneous physical activity) that can counteract weight loss success.[47] As a result, exercise may be a better strategy for weight maintenance after initial weight loss rather than an immediate first-line approach. Future studies are warranted to determine optimal exercise dosing strategies that counteract secondary aging by inducing a negative energy balance that are both sustainable and attainable in the long term, which could lead to reductions in premature mortality and improvements in overall quality of life.