Beyond calorie restriction: aging as a biological target for nutrient therapies

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Arguably, the most important discovery in the biology of aging to date was that simply reducing food intake extended life and improved many aspects of health in a diversity of animal species. The conventional wisdom that emerged from first 50 years of rodent food restriction studies included (1) that the longevity impact of restriction was greater the longer restriction was imposed, and (2) that restricting calories rather than any specific macronutrient was critical to its health and longevity benefits. However these assumptions began to crumble as more and more restriction research was performed on other species besides laboratory rodents. Recent investigations of flies, rodents, monkeys, and increasingly humans, has begun to parse how calorie restriction, protein restriction, intermittent fasting, and the temporal pattern of eating all impact the health benefits of food restriction. Fly research continues to inform, as it has repeatedly shown that genotype, age, sex, duration, and tempo restriction all affect the health impact. Ultimately, optimizing human diets will require a personalized approach using omics approaches.

Introduction

Arguably, the most important discovery in the biology of aging to date – and also one of the oldest discoveries – was that simply reducing food intake extended life and improved many aspects of health in a diversity of animal species [1,2]. The field of what was most often called food restriction or dietary restriction (DR) was dominated for many decades by a relatively small group of researchers using laboratory rodents in long-term survival studies. Following McCay’s original research paradigm using rats [3], one key research assumption was that the health and longevity effects of food restriction, which we will call the DR effect, required chronic, long-term restriction. Another assumption based on rodent studies was that restricting calories, rather than specific macronutrients was responsible for the DR effect [1,4]. As a consequence, DR was more and more frequently called caloric restriction. In the late 20th century as invertebrate models such as Drosophila melanogaster flies and Caenorhabditis elegans nematodes became more and more influential in aging studies, researchers using those models did not automatically accept these assumptions. Largely because of research initiated in invertebrate models, these assumptions have begun to crumble. Also, as research attention has shifted from focusing mainly on lifespan to focusing on healthspan, and as humans have become more eager for evidence-based nutritional advice on healthy diets for themselves, macronutrient composition of the diet, as well as the length and timing of restriction have emerged as important contributors to the healthful impact of DR. In this review, we will highlight some of these recent variations on an old paradigm (Figure 1).

Section snippets

Translation, short-term fasting and protein restriction

Two long-term DR studies in nonhuman primates revealed that the translation of DR rodent studies to humans was anything but straightforward. Laboratory rodents spend their lives in cages only a few times bigger than their body length so have little opportunity for physical activity. They have food available 24 hours per day, and not surprisingly are significantly more obese than rodents living in the field [5]. When we restrict their diets are we returning them to a body composition more like

Other forms of restriction

Another revision to the traditional DR regime came from the observation that because restricted rodents were hungry they ate their food quickly, usually in less than an hour, so that the standard research paradigm could be re-interpreted as a 23 hour daily fast. Modern research on the physiological and molecular biology of fasting shows that fasting can quickly and profoundly alter cellular fuel use as well as gene expression in organ-specific ways [32]. For instance, fasting rodents show a

Conclusion

The amount, composition, and timing of nutrient intake are all turning out to be important in the preservation of human health. Now that more translational dietary and nutritional regimes have been developed, along with ‘omic’ tools to assess their impact, we expect rapid expansion in our knowledge of optimized, personalized diets in the coming years.

Conflict of interest statement

Nothing declared.

CRediT authorship contribution statement

Steven N Austad: Funding acquisition, Writing - original draft, Writing - review & editing. Jessica M Hoffman: Funding acquisition, Writing - original draft, Writing - review & editing.

Acknowledgements

Our research is funded by N.I.H. grants R01 AG057434, R21 AG058811, P30 AG050886 (S.N.A.) and K99AG059920 (J.M.H.) and the Glenn Foundation for Medical Research.

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