Review
Of mice and men: The benefits of caloric restriction, exercise, and mimetics

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Abstract

During aging there is an increasing imbalance of energy intake and expenditure resulting in obesity, frailty, and metabolic disorders. For decades, research has shown that caloric restriction (CR) and exercise can postpone detrimental aspects of aging. These two interventions invoke a similar physiological signature involving pathways associated with stress responses and mitochondrial homeostasis. Nonetheless, CR is able to delay aging processes that result in an increase of both mean and maximum lifespan, whereas exercise primarily increases healthspan. Due to the strict dietary regime necessary to achieve the beneficial effects of CR, most studies to date have focused on rodents and non-human primates. As a consequence, there is vast interest in the development of compounds such as resveratrol, metformin and rapamycin that would activate the same metabolic- and stress-response pathways induced by these interventions without actually restricting caloric intake. Therefore the scope of this review is to (i) describe the benefits of CR and exercise in healthy individuals, (ii) discuss the role of these interventions in the diseased state, and (iii) examine some of the promising pharmacological alternatives such as CR- and exercise-mimetics.

Highlights

► Caloric restriction increases mean and maximum lifespan in the healthy state. ► Exercise increase healthspan in healthy individuals. ► CR and exercise reduce the risk of metabolic disorders and sarcopenia. ► CR mimetics and exercise do not produce synergistic benefits. ► The feasibility and efficacy of exercise mimetics is debatable.

Introduction

“The only things certain in life are death and taxes.” – Benjamin Franklin

While taxes may be unavoidable, researchers throughout the world are focused on developing ways to increase lifespan and postpone death. Such research is emerging at the start of an expanding older population. According to the Administration on Aging, the U.S. population of persons age 65 years or older is expected to grow from 12.4% in 2000 to 19% in 2030, roughly equal to 72.1 million individuals (http://www.aoa.gov/aoaroot/aging_statistics/index.aspx, 2011). While advances in healthcare, nutrition, and technology have resulted in increased lifespan, such beneficial effects have not necessarily translated into improved healthspan, defined as the number of ‘healthy, fully functional’ years attained before the onset of disease. In 2011, it is estimated that approximately one in three adults is obese (http://www.cdc.gov/obesity/data/adult.html, 2011). Alarmingly, both obesity and aging are major risk factors for several diseases such as cardiovascular disease, diabetes, and even some cancers. While increased caloric intake and decreased physical activity may lead to these disorders, caloric restriction (CR) and exercise have been shown to delay these age-related diseases. In addition, since most individuals would be unable to commit to such a rigorous dietary program, novel research is focusing on developing CR mimetics in order to achieve the benefits of CR without decreasing food intake. This review will first describe the benefits of CR and exercise in healthy individuals. Secondly, we turn to evidence for such interventions in the diseased state. We will conclude by discussing some of the promising pharmacological alternatives such as CR- and exercise-mimetics.

Section snippets

Caloric restriction and exercise in the healthy state

The aging processes threaten to steal an individual's sense of self by targeting their motility and independence. For many decades, scientists have been trying to evade these processes through various interventions in the hopes of finding the ‘Fountain of Youth.’ Two possible, and well-known, interventions include CR and exercise. This section of the review will briefly focus on the effects of CR and/or exercise on both lifespan and healthspan, covering studies from mice to men.

Caloric restriction and exercise in the diseased state

There has been a recent increase in the number of metabolic disorders caused by overeating accompanied with a decrease in physical activity (Fontana, 2008) which increases in prevalence with age (Colman et al., 2009). This energy imbalance leads to chronic metabolic diseases such as obesity, diabetes, and cardiovascular disease (CVD) (Hawley and Holloszy, 2009). The decline in physical activity may also be responsible for changes in body composition with age (Stenholm et al., 2008), such as a

Alternative interventions

While CR offers numerous benefits to both lifespan and healthspan, it is unlikely that most people would adopt and maintain such a rigorous dietary program. Therefore, there is vast interest in the development of compounds that would activate the same metabolic- and stress-response pathways induced by CR without lowering food intake, particularly in mid- to late-life stages. Such compounds include pharmaceuticals, nutraceuticals, and hormones, while omitting practices such as stomach stapling

Conclusions

Faced with an ever-increasing aging population in the middle of an obesity epidemic, the need for interventions to combat age- and obesity-associated diseases has never been greater. Of particular interest, CR and exercise are two interventions that have consistently received the most attention. CR is currently the only intervention known to increase maximum lifespan, demonstrated primarily in rodents and lower species with promising outcomes in non-human primates. Alternatively, both CR and

Acknowledgments

We thank Ann Carboneau and Chris Lyman for the critical reading of this manuscript. This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging.

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