Calorie Restriction Extends Life Span Research Articles

Ketone bodies mimic the life span extending properties of caloric restriction.

The extension of life span by caloric restriction has been studied across species from yeast and Caenorhabditis elegans to primates. No generally accepted theory has been proposed to explain these observations. Here, we propose that the life span extension produced by caloric restriction can be duplicated by the metabolic changes induced by ketosis. From nematodes to mice, extension of life span results from decreased signaling through the insulin/insulin-like growth factor receptor signaling (IIS) pathway. Decreased IIS diminishes phosphatidylinositol (3,4,5) triphosphate (PIP3 ) production, leading to reduced PI3K and AKT kinase activity and decreased forkhead box O transcription factor (FOXO) phosphorylation, allowing FOXO proteins to remain in the nucleus. In the nucleus, FOXO proteins increase the transcription of genes encoding antioxidant enzymes, including superoxide dismutase 2, catalase, glutathione peroxidase, and hundreds of other genes. An effective method for combating free radical damage occurs through the metabolism of ketone bodies, ketosis being the characteristic physiological change brought about by caloric restriction from fruit flies to primates. A dietary ketone ester also decreases circulating glucose and insulin leading to decreased IIS. The ketone body, d-β-hydroxybutyrate (d-βHB), is a natural inhibitor of class I and IIa histone deacetylases that repress transcription of the FOXO3a gene. Therefore, ketosis results in transcription of the enzymes of the antioxidant pathways. In addition, the metabolism of ketone bodies results in a more negative redox potential of the NADP antioxidant system, which is a terminal destructor of oxygen free radicals. Addition of d-βHB to cultures of C. elegans extends life span. We hypothesize that increasing the levels of ketone bodies will also extend the life span of humans and that calorie restriction extends life span at least in part through increasing the levels of ketone bodies. An exogenous ketone ester provides a new tool for mimicking the effects of caloric restriction that can be used in future research. The ability to power mitochondria in aged individuals that have limited ability to oxidize glucose metabolites due to pyruvate dehydrogenase inhibition suggests new lines of research for preventative measures and treatments for aging and aging-related disorders. © 2017 The Authors IUBMB Life published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology, 69(5):305-314, 2017.

Nutritional Control of Chronological Aging and Heterochromatin in Saccharomyces cerevisiae.

Calorie restriction extends life span in organisms as diverse as yeast and mammals through incompletely understood mechanisms.The role of NAD+-dependent deacetylases known as Sirtuins in this process, particularly in the yeast Saccharomyces cerevisiae, is controversial. We measured chronological life span of wild-type and sir2Δ strains over a higher glucose range than typically used for studying yeast calorie restriction. sir2Δ extended life span in high glucose complete minimal medium and had little effect in low glucose medium, revealing a partial role for Sir2 in the calorie-restriction response under these conditions. Experiments performed on cells grown in rich medium with a newly developed genetic strategy revealed that sir2Δ shortened life span in low glucose while having little effect in high glucose, again revealing a partial role for Sir2 In complete minimal media, Sir2 shortened life span as glucose levels increased; whereas in rich media, Sir2 extended life span as glucose levels decreased. Using a genetic strategy to measure the strength of gene silencing at HML, we determined increasing glucose stabilized Sir2-based silencing during growth on complete minimal media. Conversely, increasing glucose destabilized Sir-based silencing during growth on rich media, specifically during late cell divisions. In rich medium, silencing was far less stable in high glucose than in low glucose during stationary phase. Therefore, Sir2 was involved in a response to nutrient cues including glucose that regulates chronological aging, possibly through Sir2-dependent modification of chromatin or deacetylation of a nonhistone protein.

Linking Peroxiredoxin and Vacuolar-ATPase Functions in Calorie Restriction-Mediated Life Span Extension.

Calorie restriction (CR) is an intervention extending the life spans of many organisms. The mechanisms underlying CR-dependent retardation of aging are still poorly understood. Despite mechanisms involving conserved nutrient signaling pathways proposed, few target processes that can account for CR-mediated longevity have so far been identified. Recently, both peroxiredoxins and vacuolar-ATPases were reported to control CR-mediated retardation of aging downstream of conserved nutrient signaling pathways. In this review, we focus on peroxiredoxin-mediated stress-defence and vacuolar-ATPase regulated acidification and pinpoint common denominators between the two mechanisms proposed for how CR extends life span. Both the activities of peroxiredoxins and vacuolar-ATPases are stimulated upon CR through reduced activities in conserved nutrient signaling pathways and both seem to stimulate cellular resistance to peroxide-stress. However, whereas vacuolar-ATPases have recently been suggested to control both Ras-cAMP-PKA- and TORC1-mediated nutrient signaling, neither the physiological benefits of a proposed role for peroxiredoxins in H2O2-signaling nor downstream targets regulated are known. Both peroxiredoxins and vacuolar-ATPases do, however, impinge on mitochondrial iron-metabolism and further characterization of their impact on iron homeostasis and peroxide-resistance might therefore increase our understanding of the beneficial effects of CR on aging and age-related diseases.

Calorie Restriction Reduces Oxidative Stress by SIRT3-Mediated SOD2 Activation

A major cause of aging and numerous diseases is thought to be cumulative oxidative stress, resulting from the production of reactive oxygen species (ROS) during respiration. Calorie restriction (CR), the most robust intervention to extend life span and ameliorate various diseases in mammals, reduces oxidative stress and damage. However, the underlying mechanism is unknown. Here, we show that the protective effects of CR on oxidative stress and damage are diminished in mice lacking SIRT3, a mitochondrial deacetylase. SIRT3 reduces cellular ROS levels dependent on superoxide dismutase 2 (SOD2), a major mitochondrial antioxidant enzyme. SIRT3 deacetylates two critical lysine residues on SOD2 and promotes its antioxidative activity. Importantly, the ability of SOD2 to reduce cellular ROS and promote oxidative stress resistance is greatly enhanced by SIRT3. Our studies identify a defense program that CR provokes to reduce oxidative stress and suggest approaches to combat aging and oxidative stress-related diseases.

Solving puzzles of aging: From disposable soma to signal-transduction pathways

Aging is believed to be caused by accumulation of unrepaired damage. The repair is believed to be limited by energetic resources. A testable prediction is: the less resources (calorie restriction), the shorter lifespan. In contrast, calorie restriction extends life span. To explain the conflicting result, paradoxical “allocation of resources” was proposed, thus creating the “odd science of aging.” However, evidence emerges that aging is not driven by damage but instead is driven by nutrient-activated signaling pathways such as TOR (target of rapamycin). This immediately explains how calorie restriction extends life span and solves all “odd” puzzles of aging. Here I suggest that aging is neither random damage nor a program but instead is a quasiprogram (a harmful continuation of valuable developmental programs). It is a genetic process that can be slowed down pharmacologically. And several drugs that directly or indirectly inhibit TOR are available for clinical use.

Long-lived Indy and calorie restriction interact to extend life span

Calorie restriction (CR) improves health and extends life span in a variety of species. Despite many downstream molecules and physiological systems having been identified as being regulated by CR, the mechanism by which CR extends life span remains unclear. The Drosophila gene Indy (for I'm not dead yet), involved in the transport and storage of Krebs cycle intermediates in tissues important in fly metabolism, was proposed to regulate life span via an effect on metabolism that could overlap with CR. In this study, we report that CR down regulates Indy mRNA expression, and that CR and the level of Indy expression interact to affect longevity. Optimal life span extension is seen when Indy expression is decreased between 25 and 75% of normal. Indy long-lived flies show several phenotypes that are shared by long-lived CR flies, including decreased insulin-like signaling, lipid storage, weight gain, and resistance to starvation as well as an increase in spontaneous physical activity. We conclude that Indy and CR interact to affect longevity and that a decrease in Indy may induce a CR-like status that confers life span extension.

Calorie restriction and the nutrient sensing signaling pathways.

Calorie restriction (CR) is the most potent regimen known to extend the life span in multiple species. CR has also been shown to ameliorate several age-associated disorders in mammals and perhaps humans. CR induces diverse metabolic changes in organisms, and it is currently unclear whether and how these metabolic changes lead to life span extension. Recent studies in model systems have provided insight into the molecular mechanisms by which CR extends life span. In this review, we summarize and provide recent updates on multiple nutrient signaling pathways that have been connected to CR and longevity regulation. The roles of highly conserved longevity regulators--the Sirtuin family--in CR are also discussed.

Sirtuins in Aging and Disease

Sirtuin genes function as anti-aging genes in yeast, Caenorhabditis elegans, and Drosophila. The NAD requirement for sirtuin function indicates a link between aging and metabolism, and a boost in sirtuin activity may in part explain how calorie restriction extends life span. In mammals, one of the substrates of the SIR2 ortholog, SIRT1, is a regulator of mitochondrial biogenesis, PGC-1alpha. Indeed, the putative SIRT1 activator resveratrol has been shown to stimulate mitochondrial biogenesis and deliver health benefits in treated mice. I explore here how mitochondrial biogenesis may have beneficial effects on aging and, perhaps, diseases of aging. In particular, I speculate that SIRT1-mediated mitochondrial biogenesis may reduce the production of reactive oxygen species, a possible cause of aging, and offer two possible mechanisms for this effect. An understanding of how calorie restriction works may lead to novel drugs to combat diseases of aging.

Mitochondria and NO for Longer Life

Calorie restriction extends life span in organisms ranging from yeast to mammals. Nisoli et al. find that when mice are subjected to calorie restriction, endothelial nitric oxide synthase (eNOS) expression and 3′,5′-cyclic guanosine monophosphate formation are increased. This change is accompanied by mitochondrial biogenesis, increased oxygen consumption, adenosine triphosphate production, and expression of sirtuin 1, a protein previously implicated in mediating the effects of calorie restriction on life span. These effects are strongly attenuated in mutant mice lacking eNOS. Thus, NO may play a role in the processes induced by calorie restriction and in life-span expansion in mammals. E. Nisoli, C. Tonello, A. Cardile, V. Cozzi, R. Bracale, L. Tedesco, S. Falcone, A. Valerio, O. Cantoni, E. Clementi, S. Moncada, M. O. Carruba, Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310 , 314-317 (2005). [Abstract] [Full Text]

Calorie Restriction Promotes Mitochondrial Biogenesis by Inducing the Expression of eNOS

Calorie restriction extends life span in organisms ranging from yeast to mammals. Here, we report that calorie restriction for either 3 or 12 months induced endothelial nitric oxide synthase (eNOS) expression and 3',5'-cyclic guanosine monophosphate formation in various tissues of male mice. This was accompanied by mitochondrial biogenesis, with increased oxygen consumption and adenosine triphosphate production, and an enhanced expression of sirtuin 1. These effects were strongly attenuated in eNOS null-mutant mice. Thus, nitric oxide plays a fundamental role in the processes induced by calorie restriction and may be involved in the extension of life span in mammals.

Sir2 mediates longevity in the fly through a pathway related to calorie restriction

Calorie restriction can extend life span in a variety of species including mammals, flies, nematodes, and yeast. Despite the importance of this nearly universal effect, little is understood about the molecular mechanisms that mediate the life-span-extending effect of calorie restriction in metazoans. Sir2 is known to be involved in life span determination and calorie restriction in yeast mother cells. In nematodes increased Sir2 can extend life span, but a direct link to calorie restriction has not been demonstrated. We now report that Sir2 is directly involved in the calorie-restriction life-span-extending pathway in Drosophila. We demonstrate that an increase in Drosophila Sir2 (dSir2) extends life span, whereas a decrease in dSir2 blocks the life-span-extending effect of calorie reduction or rpd3 mutations. These data lead us to propose a genetic pathway by which calorie restriction extends life span and provides a framework for genetic and pharmacological studies of life span extension in metazoans.

The mitochondrial plasmid pAL2-1 reduces calorie restriction mediated life span extension in the filamentous fungus Podospora anserina

Calorie restriction is the only life span extending regimen known that applies to all aging organisms. Although most fungi do not appear to senesce, all natural isolates of the modular filamentous fungus Podospora anserina have a limited life span. In this paper, we show that calorie restriction extends life span also in Podospora anserina. The response to glucose limitation varies significantly among 23 natural isolates from a local population in The Netherlands, ranging from no effect up to a 5-fold life span extension. The isolate dependent effect is largely due to the presence or absence of pAL2-1 homologous plasmids. These mitochondrial plasmids are associated with reduced life span under calorie restricted conditions, suggesting a causal link. This has been substantiated using three combinations of isogenic isolates with and without plasmids. A model is proposed to explain how pAL2-1 homologues influence the response to calorie restriction.

How does calorie restriction work?

For almost 70 years, calorie restriction has been known to extend life span. Despite the extensive physiological characterization of this dietary regimen, the molecular basis for the slowing in aging remains unsolved. Recent findings have pinpointed a few molecular pathways that appear to regulate the aging process. In this review, we propose a molecular model for how calorie restriction works that incorporates these recent findings. Calorie restriction (CR) refers to a dietary regimen low in calories without undernutrition. It was first noted in the 1930s that food restriction significantly extends the life span of rodents (McCay et al. 1935). This longevity results from the limitation of total calories derived from carbohydrates, fats, or proteins to a level 25%–60% below that of control animals fed ad libitum (Richardson 1985; Weindruch et al. 1986). The extension in life span can approach 50% in rodents (Sohal and Weindruch 1996). CR extends life span in a remarkable range of organisms, including yeast, rotifers, spiders, worms, fish, mice, and rats (Weindruch and Walford 1988). Emerging data show that its effect may also apply to nonhuman primates (Lane et al. 2001). CR delays a wide spectrum of diseases in different experimental animals; for example, kidney disease, a variety of neoplasias, autoimmune disease, and diabetes (Fernandes et al. 1976; Sarkar et al. 1982; Fernandes and Good 1984; Kubo et al. 1984; Engelman et al. 1990; Shields et al. 1991; Johnson et al. 1997). CR reduces ageassociated neuronal loss in most mouse models of neurodegenerative disorders such as Parkinson’s disease (Duan and Mattson 1999) or Alzheimer’s disease (Zhu et al. 1999). However, beneficial effects in a mouse model for amyotrophic lateral sclerosis were not observed (Pedersen and Mattson 1999). The CR regimen also prevents age-associated declines in psychomotor and spatial memory tasks (Ingram et al. 1987) and loss of dendritic spines necessary for learning (Moroi-Fetters et al. 1989) and improves the brain’s plasticity and ability for selfrepair (Mattson 2000). Why does CR exert these effects? Because CR delays reproduction and promotes survival in times of scarcity, it may have been evolutionarily adaptive during boom/ bust cycles (Harrison 1989; Holliday 1989). Despite the plausibility of this reasoning, several challenges to the significance of CR studies in the laboratory have been made. Perhaps the restricted animals live longer simply because controls are overfed to the point of ill health. However, regimens in which animals are fed controlled amounts of food rather than ad libitum still show beneficial effects of low calories (Weindruch and Walford 1988). Another objection is that inbred strains of rodents are not representative of animals in the wild. For example, lab strains are selected for rapid reproduction and large litters (Miller et al. 1999). It has been argued that these animals may accordingly have shorter life spans than wild strains. By this reasoning, CR may simply correct a defect that has been created by domestication. However, the generality of CR in many different organisms, as mentioned above, supports the argument against this criticism. Even though benefits of CR have been known for many years, the mechanism(s) of its action remains unclear. Its complexity lies in multiple effects including metabolic, neuroendocrine, and apoptotic changes, which vary in intensity and exhibit striking differences among specific organ systems. Several major models to explain CR exist, but none satisfactorily integrates all of CR’s effects. In this review, we address the question of how CR might function to extend life span. We begin with a summary of several aging theories and classical views about the action of CR. Then we discuss how CR extends the life span in Saccharomyces cerevisiae. We extrapolate these findings from yeast to mammals and consider metabolic, neuroendocrine, and apoptotic shifts that may trigger longevity in the higher organisms. We conclude with a model of CR that integrates its effects on mammals.