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The science of nutritional modulation of aging.

L. Fontana

Published 2017 in Ageing Research Reviews

ABSTRACT

That nutrition is one of the most powerful tools for preventing chronic diseases and promoting health has been known since antiquity. Hippocrates of Kos (c. 460–c. 370 BCE), the father of Modern Medicine, wrote in his book entitled Aphorisms: “When more food than is proper has been taken, it occasions disease. We must consider, also, in which cases food is to be given once or twice a day, and in greater or smaller quantities, and at intervals. Something must be conceded to habit, to season, to country, and to age”. Su Shi (1037–1101CE), a famous physician of the Chinese Song dynasty, wrote in his treatise that to stay healthy we should eat only when hungry and stop taking food well before being completely full. The importance of the quantity and quality of the nutrients we introduce every day in our bodies has finally returned to prominence in modern medicine as well. Indeed, solid scientific data indicate that calorie restriction, intermittent fasting, timerestricted feeding, protein and specific amino acid restriction play prominent roles in regulating key metabolic and molecular pathways. This special issue explores the science behind the health effects of these and other nutritional manipulations. The creation of this issue has relied upon the generous contribution of many enthusiastic authors and dedicated reviewers, and we would like to thank them for their time, effort, and irreplaceable insights. The science of calorie restriction: from model organisms to humans Hundreds of studies have shown that calorie restriction (CR) without malnutrition is a robust intervention for extending healthspan and lifespan in multiple model organisms, with some caveats. In the Review that opens this issue (pp. 3–14), Kapahi, Kaeberlein and Hansen describe recent advances in understanding the molecular mechanisms that mediate lifespan extension by CR in three major invertebrate models, the budding yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans, and the fruit fly Drosophila melanogaster. In the second review, Don Ingram and Rafa DeCabo look at the past, present, and future of CR research in rodents, addressing a number of important questions regarding the robustness of some old dogmas in this field. On pages 29–35, Julie Mattison and Roz Anderson provide an up-to-date view of the findings of two parallel CR monkey randomized trials started in the late 1980s, i.e. the University of Wisconsin and the National Institute on Aging studies. Finally, in the fourth review (pp. 36–45), Leanne Redman and myself present findings from the NIH funded CALERIE randomized clinical trials and ongoing longitudinal studies on the effects of CR on human health. The data accumulated so far indicate that CR in humans results in some of the same physiologic, metabolic and molecular adaptations that have been shown to improve health and retard the accumulation of molecular damage in multiple animal models of enhanced longevity. The science beyond fasting and time-restricted feeding Typically, in human studies of caloric restriction, we prescribe diets that reduce, for example by 20–25%, the amount of calories at each meal: breakfast, lunch and dinner. However, in experimental facilities, mice are typically fed only once a day, but because these CR mice are “super-hungry”, they consume all the allotted food within 2–3 h, and then fast for the remaining 21–22 h. Thus, it is possible that the effects on health and longevity that we have noticed so far in the CR animals may be due, at least in part, to intermittent fasting or daily time-restricted feeding. On pag. 46–58, Mattson, Longo and Harvie gather evidence for the effects of meal frequency and timing on health and disease. The mechanisms through which intermittent fasting and periodic fasting induce some of their beneficial effects are not clear yet, but may involve a metabolic shift to fat metabolism and ketone production, and activation of a number of hormetic molecular stress responses that prevent and repair molecular damage. On pp. 59–67, Manoogian and Panda review the biological basis for clock adaptation to rhythmic food intake. Accumulating preclinical data indicate that sustained feeding-fasting cycles, or time-restricted feeding, deeply impact metabolism and health. Finally, Longo, Mitchell and colleagues (pp. 68–77) discuss the latest findings on the potential role of short-term fasting or protein restriction in modulating the acute detrimental effects of surgery and chemotherapy. The science of macronutrient modulation of aging Until recently, reduced intake of calories, rather than of specific macronutrients, was considered to be essential for the extension of lifespan in animal models (Maeda et al., 1985). Accumulating data from studies in invertebrate model organisms and rodents have challenged this dogma, and indicate that a reduction in dietary protein or specific amino acids play a major role in modulating healthspan and lifespan. Simpson and colleagues illustrate in an interesting review article (pp. 78–86) all the recent studies in insects and rodents supporting a role for low protein, high carbohydrate diets in promoting extension of lifespan in ad libitum fed animals and in the protection against some age-associated disease such as cancer. The effects of dietary methionine and tryptophan restriction in longevity and healthspan are the focus of Holly Brown-Borg and Rochelle Buffenstein’s Review (pp. 87–95).

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