Dietary Restriction and Nutrient Balance in Aging

Hindawi Publishing Corporation Oxidative Medicine and Cellular Longevity Volume 2016, Article ID 4010357, 10 pages http://dx.doi.org/10.1155/2016/4010357 Review Article Dietary Restriction and Nutrient Balance in Aging Júlia Santos,1,2 Fernanda Leitão-Correia,1,2 Maria João Sousa,3 and Cecília Leão1,2 1 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal ICVS/3B’s-PT Government Associate Laboratory, Braga/Guimarães, Portugal 3 Molecular and Environmental Biology Centre (CBMA), Department of Biology, University of Minho, 4710-057 Braga, Portugal 2 Correspondence should be addressed to Maria João Sousa; Received 24 April 2015; Revised 23 July 2015; Accepted 28 July 2015 Academic Editor: Eric E. Kelley Copyright © 2016 Júlia Santos et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Dietary regimens that favour reduced calorie intake delay aging and age-associated diseases. New evidences revealed that nutritional balance of dietary components without food restriction increases lifespan. Particular nutrients as several nitrogen sources, proteins, amino acid, and ammonium are implicated in life and healthspan regulation in different model organisms from yeast to mammals. Aging and dietary restriction interact through partially overlapping mechanisms in the activation of the conserved nutrientsignalling pathways, mainly the insulin/insulin-like growth factor (IIS) and the Target Of Rapamycin (TOR). The specific nutrients of dietary regimens, their balance, and how they interact with different genes and pathways are currently being uncovered. Taking into account that dietary regimes can largely influence overall human health and changes in risk factors such as cholesterol level and blood pressure, these new findings are of great importance to fully comprehend the interplay between diet and humans health. 1. Introduction The primary molecular mechanisms underlying aging have attracted increased attention, as healthy aging becomes one of the main concerns of the modern society. Cellular activities such as the regulation of metabolism, growth, and aging are modulated by a network of nutrient and energy sensing signalling pathways that are highly conserved among organisms, from yeasts to mammals (reviewed in [1]). Three major signalling pathways involved in longevity regulation have been described: the insulin/insulin-like growth factor (IIS), the Target Of Rapamycin TOR/Sch9 (ortholog of the mammalian S6 kinase), and adenylate cyclase/protein kinase A (AC/PKA). Reducing activity of these pathways is known to promote health and lifespan extension [1]. Signalling through IIS/TOR pathways starts with the binding of ligands, such as insulin and insulin-like growth factor (IGF-1 and IGF-2) in the case of mammals, to specific receptors, which in turn activate the PI3K/Akt/mTOR intracellular signalling cascade that regulates metabolism and stress resistance and consequently aging [2]. Akt kinase directly inhibits the antiaging forkhead FoxO family transcription factor (FOXO), known to regulate autophagy, DNA repair, ubiquitin-proteasome system, and other stress resistance genes [3]. Besides being activated by insulin and IGF-1 via Akt, highly conserved TOR can also respond to dietary amino acids while signalling through other pathways such as the energy sensing pathway AMP-activated protein kinase (AMPK) and sirtuin pathway (SIRT1), downregulating rapamycin-sensitive TOR complex 1 (TORC1) activity. AMPK and SIRT1 are known to mediate longevity in several model organisms in response to dietary regimens [4]. Detailed description of these nutrient signalizing pathways in different models can be found in recently published reviews [5–9]. The study of aging regulating mechanisms can be accomplished by genetic manipulations of these well conserved nutrient-signalling pathways or by using dietary restriction (DR) protocols, in which the intake of one or more macronutrients is reduced without causing malnutrition. One of the best documented DR protocols involves reduction of caloric intake without lack of essential nutrients, termed calorie restriction (CR). The benefits of CR were first described in 1935, by showing that reduced food intake extended lifespan of rats [10]. Since then many studies have demonstrated the beneficial effects of CR on lifespan extension of multiple organisms (yeast, flies, worms, fish, rodents, and rhesus 2 monkeys), as well as on the improvement of overall health in rodent models. However, new evidences have recently emerged from studies in yeast [11, 12] and in higher eukaryotes [13–15] showing the importance of nutrient balance in dietary regimens and its effects on longevity regulation, challenging the notion that the indiscriminate reduction of caloric intake per se extends lifespan. These studies increasingly suggest that not only caloric restriction but rather a balance of different nutrients and their ratios have a pivotal role in regulating lifespan [13, 14, 16–18]. In the following sections we start with an overview of different eukaryotic model organisms that allowed establishing the role of metabolic and growth pathways in longevity. The subsequent sections highlight the impact of nutrient balance on the beneficial effects of dietary restriction regimes on longevity regulation and age-related pathologies. 2. Aging and Dietary Regimens in Different Eukaryotic Model Organisms Studies in different eukaryotic model organisms revealed that the pathways regulating metabolism and growth, once active, are also able to modulate aging and increase mortality. The yeast Saccharomyces cerevisiae has been a highly exploited eukaryotic model to study the mechanisms involved in longevity regulation through the assessment of cell survival in stationary phase cultures (known as chronological lifespan—CLS) [19–23]. These studies carried under different nutrient dietary regimens show that reducing glucose concentration in the media (usually from 2% to 0.5 or 0.05%) increase CLS [20, 23–28]. Furthermore, several other single nutrients from the culture medium were also shown to affect longevity regulation (reviewed in [29]). As in higher eukaryotes, in S. cerevisiae these nutrients, depending on their abundance, can activate multiple proaging signalling pathways, such as the TOR1-Sch9, primarily activated by amino acids, and the Ras/PKA which mainly responds to glucose but is also regulated by other major nutrients [30–32]. These pathways promote cell division and growth in response to nutrients while inhibiting the general stress response and autophagy [26, 33]. CR further promotes CLS extension in TOR and Sch9p deficient mutants, indicating the presence of other mechanisms in CR-mediated lifespan extension [26]. The Ras/PK (...truncated)