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

Disclosures

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

In This Article

Calorie Restriction

CR with adequate nutrition is the most studied, experimental, nongenetic, nonpharmacological intervention used to extend healthspan and lifespan. CR is defined as a sustained reduction of habitual energy intake, typically by 20%–50%, with maintenance of adequate micronutrient intake.[9] The review will focus on studies of CR (10%–30%) in the absence of malnutrition (e.g., extreme CR or chronic eating disorders such as anorexia nervosa). In animal studies, CR prolongs median and maximal lifespan up to 50% and prevents or delays the onset of many chronic diseases, such as obesity, type 2 diabetes, and cancer.[10]

The first randomized controlled trials (RCTs) of CR in healthy, nonobese humans were the CALERIE-1 and CALERIE-2 trials. In CALERIE-1, different modalities to induce CR were tested over 6–12 months, which included CR, CR plus exercise, and a very-low-calorie diet to induce weight loss as fast as possible. CALERIE-2 subsequently tested the most effective intervention on aging parameters, which was CR without exercise, over 24 months.[11,12] Evidence on the effect of longer CR on human aging is derived from observational studies in members of the Calorie Restriction Society, who follow a regimen of self-imposed CR with Optimal Nutrition (CRON) with the belief that this dietary lifestyle will prolong lifespan. Individuals adherent to a CRON-diet (referred to as "CRONIES") for 3–15 yr have been reported to voluntarily restrict their caloric intake by approximately 50% as compared with a group of individuals (matched for age, sex, and socioeconomic status) consuming a typical Western diet and not following CR.[13]

Primary Aging

CR mitigates central mechanisms involved in primary aging in both short-term and long-term trials by reducing energy flux and oxidative stress, as well as improving mitochondrial function. First, energy expenditure measured over 24 h, during sleep, or at rest, decreased by 6% more than what was expected from a reduced body mass — otherwise known as a "metabolic adaptation" — after 6 and 12 months.[11,12,14] The decrease in resting metabolic rate was diminished at 24 months due to reduced adherence; however, the metabolic adaptation observed during sleep was still present at 24 months in subjects who maintained more than 5 kg of weight loss.[14] Second, moderate CR (~15%–25%) achieved in both CALERIE-1 and CALERIE-2 reduced oxidative stress as indicated by reduced DNA-damage, superoxide dismutase (SOD)-activity, and F2-isoprostane concentrations in whole blood cells and in plasma, respectively.[10,14–16] These improvements were likely mediated by CR-induced improvements in mitochondrial capacity by increasing mtDNA content or inducing mitochondrial biogenesis.[15] Furthermore, CR induced a more coupled mitochondrial phenotype (P:O-ratio);[17] however, these effects were observed only in subjects with higher coupling rates before initiating CR.

The results of our CALERIE trials are supported by studies on the CRONIES. Although no measurements of metabolic rate have been performed among the CRONIES, skeletal muscle biopsies revealed that PI3K/AKT/FOXO and AMP-activated protein kinase/Sirtuin pathways resemble younger-aged individuals.[18] For instance, FOXO activation is upregulated in several anti-aging genes and proteins, including the antioxidant enzyme SOD2, the DNA repair transcript DDB1, and autophagy genes beclin-1 and LC3.[18,19] Transcript and protein expression levels of stress-induced cytosolic chaperones HSP70 and GRP78 were also significantly higher in skeletal muscle after CR.[19] To our knowledge, this is the first set of data showing that long-term CR in humans upregulates the HSF/HSP pathway and downregulates the activity of the insulin/IGF pathway, which have been shown to play key roles in promoting health and longevity in several experimental model organisms.[20,21]

Secondary Aging

CR also mitigates mechanisms involved in secondary aging. Specifically, 25% CR significantly reduced body weight (−10%) and fat mass (−24%) after 6 months, and these losses were maintained after 2 yr of sustained CR.[11,12,22] Sustained CR also reduced ectopic lipid accumulation,[23] lipidemia,[24] systemic inflammation,[25] and blood pressure,[24] as well as increased insulin sensitivity[23,24] and pancreatic β-cell function.[23] Collectively, these improvements lower the 10-yr risk for cardiovascular mortality[24,25] and risk for developing type 2 diabetes. In support of the longer-term benefit and feasibility of CR, CRONIES had remarkably low-risk factors for secondary aging (e.g., body mass index, 19.7 ± 1.8 kg·m−2), which are comparable to age-, sex-, and body fat-matched endurance runners.[13,26,27]

Despite these beneficial effects of CR, sustained CR also has some drawbacks. CR results in the loss of fat-free (muscle) mass and a decline in concentric isokinetic and isometric strength, and cardiorespiratory fitness.[28,29] When expressed per kilogram of body mass, however, maximal aerobic capacity (V̇O2peak/V̇O2max) was maintained or increased with CR and suggests that a reduced body weight may preserve or even improve physical functioning. These effects may be dependent on sex (strength and function increased more in males than females) or on ad libitumphysical activity levels (males maintained physical activity, whereas physical activity decreased in females).

The reduction in energy expenditure observed with CR while beneficial toward primary aging may favor a positive energy balance (e.g., weight gain) if CR is temporarily discontinued and is, therefore, a risk factor for secondary aging.[30] Reduced fat-free mass and hence muscle mass also may increase the risk for frailty in older populations. Indeed, reductions in bone mineral density have been observed with CR in older adults.[31] Whether bone loss is larger than expected on the basis of weight loss is important to assess on an individualized basis especially among individuals whose bone mineral density may be compromised, such as elderly individuals.[31]

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