Aging and Survival: The Genetics of Life Span Extension by Dietary Restriction

The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Annual Review of Biochemistry (Impact Factor: 30.28). 02/2008; 77(1):727-54. DOI: 10.1146/annurev.biochem.77.061206.171059
Source: PubMed

ABSTRACT Reducing food intake to induce undernutrition but not malnutrition extends the life spans of multiple species, ranging from single-celled organisms to mammals. This increase in longevity by dietary restriction (DR) is coupled to profound beneficial effects on age-related pathology. Historically, much of the work on DR has been undertaken using rodent models, and 70 years of research has revealed much about the physiological changes DR induces. However, little is known about the genetic pathways that regulate the DR response and whether or not they are conserved between species. Elucidating these pathways may facilitate the design of targeted pharmaceutical treatments for a range of age-related pathologies. Here, we discuss how recent work in nonmammalian model organisms has revealed new insight into the genetics of DR and how the discovery of DR-specific transcription factors will advance our understanding of this phenomenon.

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Available from: William Mair, Jun 03, 2014
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    • "Modest restriction of caloric intake with adequate essential nutrients, referred to as calorie restriction (CR), increases the life span of a range of organisms, including AGE (2015) 37:45 DOI 10.1007/s11357-015-9787-8 Electronic supplementary material The online version of this article (doi:10.1007/s11357-015-9787-8) contains supplementary material, which is available to authorized users. the replicative life span of yeasts (Mair et al. 2008). The effects of CR have also been tested in non-human primates , and the results to date suggest that CR extends the disease-free life span in monkeys but may not increase overall survival (Colman et al. 2009; Mattison et al. 2012). "
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    ABSTRACT: Calorie restriction (CR), a non-genetic intervention that promotes longevity in animals, may exert anti-aging effects by modulating mitochondrial function. Based on our prior mitochondrial proteome analysis, we focused on the potential roles of cytochrome c oxidase (Cox or Complex IV) subunit 6b1 on formation of mitochondrial supercomplexes comprised of Complex I, III, and IV. Blue native polyacrylamide gel electrophoresis followed by immunoblotting showed that the amount of Cox6b1 and the proportion of high molecular weight supercomplexes (SCs) comprised of Complexes I, III, and IV were increased in the liver of mice subjected to 30 % CR, compared with the liver of mice fed ad libitum. In in vitro experiments, in Cox6b1-overexpressing NIH3T3 (Cox6b1-3T3) cells, Cox6b1 was increased in the SC, III2IV1, and III2IV2 complexes and Cox was concomitantly recruited abundantly into the SC, compared with control (Con)-3T3 cells. The proportions of III2IV1, and III2IV2, relative to IV monomer were also increased in Cox6b1-3T3 cells. Cox6b1-3T3 cells showed increased oxygen consumption rates, Cox activity, and intracellular ATP concentrations, indicating enhanced mitochondrial respiration, compared with Con-3T3 cells. Despite the increased basal level of mitochondrial reactive oxygen species (ROS), cell viability after inducing oxidative stress was greater in Cox6b1-3T3 cells than in Con-3T3 cells, probably because of prompt activation of protective mechanisms, such as nuclear translocation of nuclear factor E2-related factor-2. These in vivo and in vitro studies show that Cox6b1 is involved in regulation of mitochondrial function by promoting the formation of SC, suggesting that Cox6b1 contributes to the anti-aging effects of CR.
    Age 06/2015; 37(3):9787. DOI:10.1007/s11357-015-9787-8 · 3.45 Impact Factor
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    • "Although longevity extension strategies will not eliminate aging-related diseases, they are expected to postpone their age of onset, thus contributing to the objective of extending healthspan [10]. Calorie restriction (CR), which usually refers to a 20–40% reduction in calorie intake without malnutrition, is the most robust environmental intervention that slows aging and extends lifespan in yeast, worms, fruit flies, rodents, and perhaps also in primates [10] [11] [12] [13], through largely conserved mechanisms. "
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    ABSTRACT: Dietary restriction (DR) attenuates many detrimental effects of aging and consequently promotes health and increases longevity across organisms. While over the last 15 years extensive research has been devoted towards understanding the biology of aging, the precise mechanistic aspects of DR are yet to be settled. Abundant experimental evidence indicates that the DR effect on stimulating health impinges several metabolic and stress-resistance pathways. Downstream effects of these pathways include a reduction in cellular damage induced by oxidative stress, enhanced efficiency of mitochondrial functions and maintenance of mitochondrial dynamics and quality control, thereby attenuating age-related declines in mitochondrial function. However, the literature also accumulates conflicting evidence regarding how DR ameliorates mitochondrial performance and whether that is enough to slow age-dependent cellular and organismal deterioration. Here, we will summarize the current knowledge about how and to which extent the influence of different DR regimes on mitochondrial biogenesis and function contribute to postpone the detrimental effects of aging on healthspan and lifespan. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 05/2015; DOI:10.1016/j.bbabio.2015.05.005 · 4.66 Impact Factor
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    • "For the purposes of this review, dietary restriction (DR) will incorporate both calorie restriction and those interventions in which macro/micronutrients are altered without any overall change in energy intake. DR is the most reproducible intervention, to date, to extend medium and maximum lifespan in various model species (Mair & Dillin, 2008; Speakman & Selman, 2011; Selman, 2014). In mice, there seems to be a strainspecific association with DR and longevity, and in primates, the link between lifespan extension and DR may also be confounded by genetic heterogeneity (reviewed by Selman, 2014). "
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    ABSTRACT: Advancing age is associated with a progressive loss of skeletal muscle (SkM) mass and function. Given the worldwide aging demographics, this is a major contributor to morbidity, escalating socio-economic costs and ultimately mortality. Previously, it has been established that a decrease in regenerative capacity in addition to SkM loss with age coincides with suppression of insulin/insulin-like growth factor signalling pathways. However, genetic or pharmacological modulations of these highly conserved pathways have been observed to significantly enhance life and healthspan in various species, including mammals. This therefore provides a controversial paradigm in which reduced regenerative capacity of skeletal muscle tissue with age potentially promotes longevity of the organism. This paradox will be assessed and considered in the light of the following: (i) the genetic knockout, overexpression and pharmacological models that induce lifespan extension (e.g. IRS-1/s6K KO, mTOR inhibition) versus the important role of these signalling pathways in SkM growth and adaptation; (ii) the role of the sirtuins (SIRTs) in longevity versus their emerging role in SkM regeneration and survival under catabolic stress; (iii) the role of dietary restriction and its impact on longevity versus skeletal muscle mass regulation; (iv) the crosstalk between cellular energy metabolism (AMPK/TSC2/SIRT1) and survival (FOXO) versus growth and repair of SkM (e.g. AMPK vs. mTOR); and (v) the impact of protein feeding in combination with dietary restriction will be discussed as a potential intervention to maintain SkM mass while increasing longevity and enabling healthy aging. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
    Aging cell 04/2015; 14(4):511-23. DOI:10.1111/acel.12342 · 6.34 Impact Factor
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