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

Abstract and Introduction

Abstract

Primary aging is the progressive decline in health and fitness and depends on metabolic rate and oxidative stress. Untoward changes in body composition and metabolic function characterize secondary aging. We hypothesize that both exercise and calorie restriction (CR) improve secondary aging, but only CR improves primary. However, CR followed with exercise is a superior strategy to maintain overall health and quality of life with age.

Introduction

Human aging describes the progressive decline in the body's ability to maintain physiological homeostasis, ultimately causing death. Aging results from a complex set of lifespan-associated declines in molecular, cellular, tissue, and organ fidelity. This set of changes has been categorized into "Seven Pillars of Aging" and includes macromolecular damage, epigenetics, inflammation, adaptation to stress, proteostasis, stem cells and regeneration, and metabolism.[1] With advanced biological age, homeostasis of these processes deteriorates independently and synergistically. Despite the inevitable advancement of biological age, the deterioration of physiological homeostasis is variable.

The underlying causes of these physiological deteriorations remain controversial and there are over 300 theories of mammalian aging. The most prominent and most studied causes of aging can be partitioned into either primary or secondary aging. Primary aging describes the effect of the inevitable, yet variable, progression of physiological decline, whereas secondary aging describes the effect of external factors such as diet and physical activity that can accelerate or decelerate the aging process. Both primary and secondary aging factors influence each other in a cyclic, bi-directional fashion, which can either potentiate or attenuate effects on physiological homeostasis (Figure 1).

Figure 1.

Schematic of the interplay between primary and secondary aging. Primary aging is an unavoidable consequence of living stemming from the accumulation of macromolecular damage during lifespan progression. These processes are cyclic, and thus continual oxidative damage favors further generation of reactive oxygen species (ROS) ultimately impairing homeostasis and function of cells and tissues, and hence defines primary aging. Alternatively, secondary aging results from external influences originating throughout the lifespan as the result of noncommunicable diseases, environmental exposures, and social behaviors such as overeating or low physical activity. These two intertwined factors encompass the seven unique pillars of aging.

Primary aging relates to the age-associated decline in physiological homeostasis to high energy expenditure and increased oxidative stress and is based on the Rate of Living Theory. This theory postulates that organisms with higher mass-specific energy expenditures have shorter lifespans.[2] The Rate of Living Theory has received mechanistic support by the Free Radical Theory of Aging.[3] The Free Radical Theory of Aging assumes that approximately 1%–3% of oxygen consumed by the electron transport system leads to generation of the free radical, superoxide O2−•, by the one-electron reduction of O2. Therefore, with higher energy expenditure, more reactive oxygen species (ROS) are generated, which can lead to more oxidative damage to mitochondrial DNA (mtDNA), proteins, and lipids that are essential for normal cellular function.[3,4] These processes are cyclic, and thus continual oxidative damage favors further generation of ROS ultimately impairing homeostasis and function of cells and tissues, and hence defines primary aging.[5]

Secondary aging results from external influences originating throughout the lifespan as the result of noncommunicable diseases, environmental exposures, and social behaviors such as overeating or low physical activity.[6] Overeating increases fat mass, and together with insufficient physical activity, results in declines in skeletal muscle strength, mass, and quality. This body composition phenotype leads to the development of metabolic dysfunction, such as impaired clearance and storage of postprandial blood glucose and lipids. The consequent hyperglycemia, hyperinsulinemia, insulin resistance, and hyperlipidemia produces a disproportionate accumulation of fat in both visceral and ectopic depots, increasing risk for type 2 diabetes and cardiovascular diseases (CVDs).[7,8] Aside from the increased mortality directly associated with these diseases, determinants of secondary aging also impair mitochondrial function and increase oxidative stress, and thereby contribute to primary aging.

In efforts to extend healthspan and lifespan in humans, science has focused on investigating the independent and synergistic effects of energy restriction (termed calorie restriction (CR)) and physical activity (exercise) modifications as strategies to mitigate both intrinsic and extrinsic factors that accelerate primary and secondary aging, respectively. This review outlines key studies — particularly human studies performed by the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) team — that examined how CR, exercise, or a combination can improve overall health. Based on the available literature, we hypothesize that CR yields more robust and consistent improvements in mechanisms associated with healthspan and lifespan because of its independent effects on attenuating the rate of living and oxidative damage (primary aging), as well as reducing adiposity (secondary aging).

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