Caloric restriction does not enhance longevity in all species and is unlikely to do so in humans

Calorie restriction is known to increase lifespan in many but not all species and may perhaps not do so in humans. Exceptions to life extension have been identified in the laboratory and others are known in nature. Given the variety of physiological responses to variation in food supply that are possible, evolutionary life history theory indicates that an increased investment in maintenance in response to resource shortage will not always be the strategy that maximises Darwinian fitness. Additionally, for the well-studied species in which life extension is observed, there is considerable variation in the response. This suggests that it is not an ancient ancestral response, which has been conserved across the species range. Although calorie restriction does not increase lifespan in all species, it remains a fascinating and valuable tool to study ageing at the whole organism level.     

Role of starvation in production of creatinuria in experimental hyperthyroidism

Since thyroid hormone accelerates energy-requiring processes, a negative caloride balance often exists in the hyperthyroid state. To assess the role of this induced calorie deficit in the production of thyrotoxic myopathy, we have examined the effect of calorie deprivation on creatine excretion in experimental hyperthyroidism. Since food restriction decreases fecal excretion of thyroid hormone, a low-residue glucose-supplemented diet has been used to produce calorie-replete hyperthyroid animals having circulating thyroid hormone levels comparable to half-starved hyperthyroid animals. Calorie-deprived hyperthyroid animals have a 2–4-fold increase in creatine excretion when compared to fully fed hyperthyroid animals having comparable thyroid hormone levels. Although a negative calorie balance greatly enhances creatinuria in experimental hyperthyroidism, it is not a necessary condition for thyroid hormone-induced creatinuria. Calorie-replete hyperthyroid animals consistently gained weight, indicating a positive calorie balance. Nevertheless, these animals manifested increased creatinuria when compared to euthyroid controls. Therefore, excess thyroid hormone appears to cause muscle damage as reflected in creatinuria by a mechanism other than mobilization of muscle protein to provide endogenous calories. A study of the effect of triiodothyronine (T₃) on creatine and urea excretion in fasting rats led to the same conclusion. T₃ plus fasting produced a much more marked creatinuria than fasting alone. During the first 48 hr of fasting, the rate of weight loss and urea excretion were comparable in T₃-treated and control animals. Nevertheless, the rate of creatine excretion during this interval was 10–12-fold increased in the T₃-treated group. In these experiments, there was clearly a dissociation between T₃ stimulation of urea excretion and the magnitude of creatinuria induced. Although a negative calorie balance appears to hasten the development of thyrotoxic myopathy, accelerated muscle proteolysis to supply an induced calorie deficit is not an adequate model to account for muscle involvement in hyperthyroidism.     

Recent advances in calorie restriction research on aging

The extension of both median and maximum lifespan and the suppression of age-related diseases in laboratory animals by reduced food intake, i.e., calorie restriction (CR) are regarded as hallmarks of CR's anti-aging action. The diverse efficacy of CR to counteract aging effects and its experimental reproducibility has made it the gold standard of many aging intervention studies of recent years. Although CR originally was used as a tool to perturb the aging process of laboratory animals as to uncover clues of underlying mechanisms of aging processes, current CR research interests have shifted to the retardation of aging-related functional decline and the prevention of age-related diseases. Advances in CR research on non-human primates and recent endeavors using human subjects offer a promising outlook for CR's beneficial effects in healthy human aging.     

Linking sirtuins, IGF-I signaling, and starvation

Our studies in yeast have shown that the down-regulation of major signal transduction mediators increases stress resistance and causes an up to 10 fold chronological life span extension. Whereas other laboratories have proposed that sirtuins (Sir2 and its homologs), a family of conserved proteins which are NAD(+)-dependent histone deacetylases, can extend longevity in various model organisms, we propose that one sirtuin, i.e., Sir2, can also accelerate cellular aging and death. In Saccharomyces cerevisiae (yeast), the deletion of Sir2 increases DNA damage but in combination with longevity mutations in principal intracellular signal transduction mediators, or in combination with calorie restriction it causes a further increase in the chronological lifespan as well as an increase in the stress resistance and a major reduction in age-dependent genomic instability. Our recent results also provide evidence for a role of the mammalian Sir2 ortholog SirT1 in the activation of a highly conserved neuronal pathway and in the sensitization of neurons to oxidative damage. However, the mean lifespan of the SirT1(+/-) mice is not different from that of wild type animals, and the survival of SirT1(-/-) mice was reduced under both normal and calorie restricted conditions. Here, I review the studies linking SirT1, IGF-I signaling and starvation in various model organisms with a focus on the post-mitotic cells, which indicate that sirtuins can play both protective and pro-aging roles.     

Calorie Restriction for Optimal Cardiovascular Aging: The Weight of Evidence

The epidemic of obesity and overweight is spreading worldwide. Excessive adiposity is associated with a myriad of adverse health outcomes, leading to increased health care expenditures and shortened life expectancy. In contrast to overeating, calorie restriction (CR), defined as a reduction in food intake without malnutrition, increases both mean and maximum lifespan in a variety of species by reducing the incidence of several chronic degenerative diseases, including cardiovascular disease. The constellation of health benefits brought about by CR results from biological and physiologic changes affecting fundamental processes underlying aging and age-related pathologies. Despite the beneficial properties of CR, it is likely that most people will not engage in such a dietary regimen for the long-term. Supplementation with specific compounds mimicking CR may represent a more feasible means to improve health and prolong life. However, evidence on long-term effectiveness and safety of these compounds is not yet available in humans.     

Downregulation of plasma insulin levels and hepatic PPARgamma expression during the first week of caloric restriction in mice

Calorie restriction extends lifespan by decreasing the rate of tumor formation, an effect occurring within 8 weeks of initiating a restricted diet. Our goal was to define how the first weeks of a calorie restricted diet (60% of ad libitum calories) affects putative mediators of the calorie restriction phenotype, focusing on regulators of fatty acid biosynthesis. In C57Bl/6 mice, insulin decreased over 50% (p<0.05) during the first week of calorie restriction whereas IGF-1 was unaffected. In the liver, PPARgamma mRNA fell to 13% of baseline after 1 week of calorie restriction (p<0.05), whereas hepatic SREBP-1c and SIRT1 mRNA levels were unaffected. No changes in abdominal or subcutaneous adipose tissue were observed until after 4 weeks of caloric restriction. We conclude that calorie restriction-induced decreases in insulin and hepatic PPARgamma are rapid enough to support a role for these molecules in triggering the initial phase of the calorie restriction phenotype.     

Resveratrol vs. calorie restriction: Data from rodents to humans

Calorie restriction extends lifespan and confers metabolic benefits similar to the effect of lifestyle interventions. Poor compliance to long-term dietary restriction, however, hinders the success of this approach. Evidence is now persuasive for a role of resveratrol supplementation (a polyphenol in red grapes) as potential alternative to calorie restriction. This review summarizes the latest literature on the effects and the molecular mechanisms by which calorie restriction and resveratrol confer health benefits. Resveratrol activates SIRT1 and the associated improvement in energy utilization and insulin sensitivity closely resembles the benefits of calorie restriction. Current data largely support resveratrol as a potential calorie restriction mimetic to improve metabolic and probably functional health. Future studies which characterize the bioavailability and efficacy of resveratrol supplementation are critical to provide evidence for its long-term health benefits.     

Hormesis does not make sense except in the light of TOR-driven aging

Weak stresses (including weak oxidative stress, cytostatic agents, heat shock, hypoxia, calorie restriction) may extend lifespan. Known as hormesis, this is the most controversial notion in gerontology. For one, it is believed that aging is caused by accumulation of molecular damage. If so, hormetic stresses (by causing damage) must shorten lifespan. To solve the paradox, it was suggested that, by activating repair, hormetic stresses eventually decrease damage. Similarly, Baron Munchausen escaped from a swamp by pulling himself up by his own hair. Instead, I discuss that aging is not caused by accumulation of molecular damage. Although molecular damage accumulates, organisms do not live long enough to age from this accumulation. Instead, aging is driven by overactivated signal-transduction pathways including the TOR (Target of Rapamycin) pathway. A diverse group of hormetic conditions can be divided into two groups. "Hormesis A" inhibits the TOR pathway. "Hormesis B" increases aging-tolerance, defined as the ability to survive catastrophic complications of aging. Hormesis A includes calorie restriction, resveratrol, rapamycin, p53-inducing agents and, in part, physical exercise, heat shock and hypoxia. Hormesis B includes ischemic preconditioning and, in part, physical exercise, heat shock, hypoxia and medical interventions.     

Maintaining good hearing: Calorie restriction,Sirt3, and glutathione

Reducing calorie intake extends the lifespan of a variety of experimental models and delays progression of age-related hearing loss (AHL). AHL is a common feature of aging and is characterized by age-related decline of hearing associated with loss of sensory hair cells, spiral ganglion neurons, and/or stria vascularis degeneration in the cochlea. Sirtuins are a family of NAD⁺-dependent enzymes that regulate lifespan in lower organisms and have emerged as broad regulators of cellular fate. Our recent study indicated that mitochondrial Sirt3, a member of the sirtuin family, mediates the anti-aging effects of calorie restriction (CR) on AHL in mice. Interestingly, we also found that weight loss alone may not be sufficient for maintaining normal hearing. How does CR slow the progression of AHL through regulation of Sirt3? Here we review the evidence that during CR, Sirt3 slows the progression of AHL by promoting the glutathione-mediated mitochondrial antioxidant defense system in mice. A significant reduction in food consumption in one's daily life may not be a desirable and realistic option for most people. Therefore, identification/discovery of compounds that induce the activation of SIRT3 or glutathione reductase, or that increase mitochondrial glutathione levels has potential for maintaining good hearing through mimicking the anti-aging effects of CR in human inner ear cells.     

Calorie restriction in primates: will it work and how will we know?

Dietary caloric restriction is the most robust and reproducible means of slowing aging and extending lifespan and healthspan in short-lived mammals and lower organisms. Numerous aspects of this paradigm have been investigated in laboratories around the world since its inception more than 60 years ago. However, two questions about calorie restriction remain unanswered to this day: (1) By what mechanism does it work? and (2) Will it work in humans? This review will focus on the latter with particular emphasis on evaluation criteria, current studies in primate models, available data, and plans for actual human caloric restriction interventions.