Dr. James Manos (MD)
21 February 2016
Longevity TIPS!
Calorie restriction (CR) theory & substances that may increase lifespan!
I. Calorie restriction (CR) theory
Calorie restriction (CR) theory supports a restricted calorie intake dietary regimen. It is not related to malnutrition but is supposed to improve age-related health and longevity by slowing aging. In calorie restriction, energy intake is decreased. However, consuming vitamins, minerals, elements, and other essential nutrients is sufficient. Western diet is hypercaloric. The CR theory is supported by research on many animals (such as fish, dogs, and rodents) and some fungi (such as yeast). Research on primitives, amongst them on humans, is promising. An investigation started in 1934 when Mary Crowell and Clive McCay of Cornell University noticed that calorie-restricted rats had increased lifespans up to twice. Since then, a similar finding has been ascertained in several animals and fungi (1).
Calorie restriction (CR) is the only experimental manipulation known to extend the lifespan of some organisms, including yeast, worms, flies, rodents, and perhaps non-human primates. Also, CR has been shown to reduce the incidence of age-related disorders (for example, diabetes, cancer, and cardiovascular diseases) in mammals. The mechanisms through which this occurs have been unclear. CR induces metabolic changes, improves insulin sensitivity, and alters animal neuroendocrine function. CR results in longevity and robust health, which might open new avenues of therapy for diseases of aging (7).
Caloric restriction, decreasing caloric intake by 20-30%, was first shown to extend life in rats nearly 80 years ago. Since then, limiting food intake for longevity has been investigated in species from yeast to humans. In yeast and lower animals, caloric restriction has repeatedly been demonstrated to lengthen the lifespan. Studies of caloric restriction in non-human primates and humans are ongoing, and initial results suggest prolonging life and preventing age-related disease. There is also data in rodents suggesting that short-term caloric restriction has beneficial effects on fertility. Although caloric restriction has many positive effects on health and longevity, quality of life on a restricted diet and the ability to maintain that diet long-term are concerns that humans must consider (13).
Calorie restriction (CR), a reduction of 10–40% in intake of a nutritious diet, is often reported as the most robust non-genetic mechanism to extend lifespan and health span. CR is frequently used to understand the mechanisms of aging and age-associated diseases. In addition to increasing lifespan, CR has been reported to delay or prevent the occurrence of many chronic diseases in various animals. Beneficial effects of CR on outcomes such as immune function, motor coordination, and resistance to sarcopenia in rhesus monkeys have recently been reported. The authors state that a CR regimen implemented in young and older rhesus monkeys at the National Institute on Aging (NIA) has not improved survival outcomes. These findings contrast with an ongoing study at the Wisconsin National Primate Research Center (WNPRC), which reported improved survival associated with 30% CR initiated in adult rhesus monkeys (7–14 years) and a preliminary report with a small number of CR monkeys (14).
Calorie restriction (CR) (consumption of a diet with fewer calories but containing all the essential nutrients) is the most robust genetic or environmental manipulation to extend longevity and improve health parameters in laboratory animals. However, outside of the protected laboratory environment, the effects of CR are much less specific. Understanding the molecular mechanisms of CR may lead to developing novel therapies to combat diseases of aging and improve the quality of life. Sirtuins, a family of NAD (+)-dependent enzymes, mediate some metabolic and behavioral responses to CR and are intriguing targets for pharmaceutical interventions (20).
Studies demonstrated a longevity gene called Sir2 (silent information regulator 2), a sirtuin, in baker's yeast cells. This gene expands lifespan by suppressing DNA instability. In mammals, a similar gene is known as SIRT1. Many researchers support the idea that the Sir2 gene is expressed in CR, increasing longevity. Similarly, in mammals, a CR diet ends up in the increased activity of the SIRT1 gene. It is suggested that a low-calorie diet that requires less nicotinamide adenine dinucleotide to metabolize may allow SIRT1 to be more active in its life-extending processes. Attempts are being made to develop CR mimetics. Resveratrol has been reported to activate Sir2/SIRT1 and extend the lifespan of yeast, nematode worms, fruit flies, and mice consuming a high-calorie diet. However, it does not seem to extend the lifespan in normal mice (1).
Calorie restriction (CR) extends the lifespan of various species. Previously, the authors showed that calorie restriction increases the replicative life span in yeast by activating Sir2, a highly conserved NAD-dependent deacetylase. In a new study, the authors tested whether CR activates Sir2 by increasing the NAD/NADH ratio or by regulating the level of nicotinamide, a known inhibitor of Sir2. They showed that CR decreases NADH levels and that NADH is a competitive inhibitor of Sir2. A genetic intervention that decreases NADH levels explicitly increases lifespan, validating the model that NADH regulates yeast longevity in response to CR (17).
Caloric restriction extends the lifespan of numerous species. This effect in the budding yeast Saccharomyces cerevisiae requires Sir2, a member of the sirtuin family of NAD+-dependent deacetylases. Sirtuin-activating compounds (STACs) can promote human cells' survival and extend yeast's replicative lifespan. A study showed that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans (a nematode (roundworm)) and Drosophila melanogaster (fruit fly) and extend the lifespan of these animals without reducing fecundity. Lifespan extension depends on functional Sir2 and is not observed when nutrients are restricted. Together, these data indicate that STACs slow metazoan aging by mechanisms that may be related to caloric restriction (16).
Sirtuin 1-7 (SIRT1-7) are deacetylases dependent on NAD (+) for their activity. SIRT1 down-regulates p53 activity, increasing lifespan, cell survival, and neuroprotection; it also deacetylates peroxisome proliferator-activated receptor-gamma and its coactivator 1alpha, promoting fat mobilization, increasing mitochondrial size and number, and positively regulating insulin secretion. Sirtuins link nutrient availability and energy metabolism. Calorie restriction, which increases lifespan and is beneficial in age-related disorders, activates sirtuin. To date, resveratrol is the most potent natural compound able to activate SIRT1, mimicking the positive effect of calorie restriction. Resveratrol might help in the treatment or prevention of obesity and in preventing the aging-related decline in heart function and neuronal loss. Resveratrol has low bioavailability and interacts with multiple molecular targets. So, developing new molecules with better bioavailability and targeting sirtuin at lower concentrations is a promising field of medicinal chemistry. New SIRT1 activators are up to 1,000 times more effective than resveratrol have recently been identified. These improve the response to insulin and increase the number and activity of mitochondria in obese mice (18).
Resveratrol (RESV) exerts critical pharmacological effects on human health. In addition to its beneficial effects on type 2 diabetes and cardiovascular diseases, it modulates neuronal energy homeostasis and shows anti-aging properties. Although it has free radical scavenger properties, the mechanisms involved in these beneficial effects are not fully understood. In this regard, one area of significant interest concerns the impact of RESV on the activity of sirtuin 1 (SIRT1), a NAD (+)-dependent histone deacetylase implicated in aging. Indeed, the role of SIRT1 is currently the subject of intense research due to the anti-aging properties of RESV, which increases lifespan in various organisms ranging from yeast to rodents. Also, when RESV is administered in experimental animal models of neurological disorders, it has similar beneficial effects to caloric restriction. SIRT1 activation could thus constitute a potential strategic target in neurodegenerative diseases and in disorders involving disturbances in glucose homeostasis, as well as in dyslipidemias (high blood lipids, i.e., fats) or cardiovascular diseases. Therefore, small SIRT1 activators such as SRT501, SRT2104, and SRT2379, currently undergoing clinical trials, could be potential drugs for treating type 2 diabetes, obesity, and metabolic syndrome, among other disorders (19).
It has been widely known that slow metabolism induced by calorie restriction (CR) can extend the lifespan of model organisms. Notwithstanding, the underlying mechanism remains poorly understood. Accumulated evidence suggests that SIRT1 may be actively involved in CR-induced signaling pathways. As a putative activator of SIRT1, resveratrol, known as the French paradox, can partially mimic the physiological effects of CR. While the deacetylase activity of SIRT1 is essential for the beneficial effects of resveratrol, resveratrol-induced SIRT1 activation has recently been challenged by the observations that resveratrol could not induce SIRT1-mediated deacetylation of native substrates in vitro (25).
Calorie restriction (CR) is a known intervention that delays most aging processes. Most of the beneficial effects of CR are mediated by improved maintenance of mitochondrial performance in aged individuals. The control of mitochondrial biogenesis, apoptosis (programmed cell death), and protein turnover is required for healthy aging. CR can induce molecular mechanisms that preserve oxidative capacity and decrease oxidative damage. Published data indicate that peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) is activated in old animals under CR conditions compared to ad libitum counterparts, enhancing mitochondrial biogenesis. The molecular regulation of PGC-1α has recently attracted significant research interest. The master regulators of energy metabolisms, such as AMP-activated protein kinase and sirtuin 1, have been demonstrated to activate mitochondrial biogenesis through increased PGC-1α activity at transcriptional and post-translational levels. The latest findings explain how CR promotes mitochondrial efficiency and decreases mitochondrial-derived oxidative damage (21).
Whether the well-known metabolic switch AMP-activated protein kinase (AMPK) is involved in the insulin-sensitizing effect of calorie restriction (CR) is unclear. A study investigated the role of AMPK in the insulin-sensitizing effect of CR in skeletal muscle. Wild-type (WT) and AMPK-α2 (-/-) mice received ad libitum (at their pleasure) (AL) or CR (8 weeks at 60% of AL) feeding. The results suggest that AMP-activated protein kinase (AMPK) may be modulated by calorie restriction (CR) in a ubiquitylation-dependent manner and acts as a chief dictator for the insulin-sensitizing effects of CR in skeletal muscle (23).
Calorie restriction (CR) extends the lifespan in a broad spectrum of organisms and is the only regimen known to lengthen the lifespan of mammals. In a study, they established a model of CR in the budding yeast Saccharomyces cerevisiae. This system's lifespan can be extended by limiting glucose or reducing the glucose-sensing cyclic-AMP-dependent kinase (PKA) activity. Lifespan extension in a mutant with reduced PKA activity requires Sir2 and NAD (nicotinamide adenine dinucleotide (NAD)). The study explored how CR activates Sir2 to extend lifespan and showed that the shunting of carbon metabolism toward the mitochondrial tricarboxylic acid cycle and the concomitant increase in respiration play a central part in this process (2).
Calorie restriction may work by reducing the levels of reactive oxygen species (ROS) produced during respiration. In a study, they mimicked calorie restriction in yeast by physiological or genetic means and showed a substantial extension in lifespan. This extension was not observed in strains mutant for SIR2 (which encodes the silencing protein Sir2p) or NPT1 (a gene in a pathway in the synthesis of NAD, the oxidized form of nicotinamide adenine dinucleotide (NAD)). The study concluded that the increased longevity induced by calorie restriction requires the activation of Sir2p by NAD (nicotinamide adenine dinucleotide) (3).
In the budding yeast Saccharomyces cerevisiae, lifespan extension by calorie restriction (see above) requires the NAD1-dependent histone deacetylase, Sir2. It has been recently shown that Sir2 and its closest human homolog SIRT1, a p53 deacetylase, are strongly inhibited by the vitamin B3 precursor nicotinamide2. A study showed that increased expression of PNC1 (pyrazinamidase/ nicotinamidase 1), which encodes an enzyme that deaminates nicotinamide, is both necessary and sufficient for lifespan extension by calorie restriction and low-intensity stress. PNC1, in the study, is identified as a longevity gene responsive to all stimuli that extend lifespan. The study showed that nicotinamide depletion is sufficient to activate Sir2 and that this is the mechanism by which PNC1 regulates longevity. The study concluded that yeast lifespan extension by calorie restriction results from an active cellular response to low-intensity stress and speculated that nicotinamide might regulate critical cellular processes in higher organisms (2).
Obesity is a complex disease resulting from a chronic and long-term positive energy balance involving genetic and environmental factors. Weight-reduction methods are focused on dietary changes and increased physical activity. However, responses to nutritional intervention programs show a wide range of inter-individual variation, which is importantly influenced by genetic determinants. In this sense, subjects carrying several obesity-related single-nucleotide polymorphisms (SNPs) show differences in response to calorie restriction programs. Furthermore, there is evidence indicating that dietary components not only fuel the body but also participate in the modulation of gene expression. Thus, the expression pattern and nutritional regulation of several obesity-related genes have been studied, and those differentially expressed by caloric restriction (15).
A randomized controlled trial examined the effects of 6 months of calorie restriction, with or without exercise, in overweight, non-obese (body mass index, 25 to less than 30) men and women. The study concluded that 2 biomarkers of longevity (fasting insulin level and body temperature) are decreased by prolonged calorie restriction in humans and support the theory that metabolic rate is reduced beyond the level expected from reduced metabolic body mass (4).
Human studies have shown that calorie restriction reduces atherosclerosis risk factors.CR lowers cholesterol (and especially LDL cholesterol (΄΄bad΄΄ cholesterol) and total cholesterol), triglycerides, fasting insulin, fasting glucose levels, CRP levels (an acute-phase protein, it is increased, e.g., in heart problems) and also lowers BP (blood pressure), PDGF (Platelet Derivative Growth Factor) AB, BMI (Body Mass Index) and body fat percentage (1).
A study evaluated the effect of calorie restriction (CR) on risk factors for atherosclerosis (hardening of the arteries) in individuals restricting food intake to slow aging. In the study participated 18 individuals who had been on CR for an average of 6 years and 18 age-matched healthy individuals on the typical American diet. The results showed that carotid artery intima-media thickness (IMT) was about 40% less in the CR group than in the comparison group. The study concluded that long-term calorie restriction (CR) has a powerful protective effect against atherosclerosis. This interpretation is supported by the finding of a low carotid artery intima-media thickness (IMT) (12).
Calorie restriction (CR) prolongs life in animals but may reduce plasma HDL (high-density lipoprotein cholesterol; ΄΄good΄΄ cholesterol), which is important in reverse cholesterol transport (RCT). The effect of CR, 60% of an ad libitum (AL) diet, on cholesterol removal from rectus femoris muscle injected with cationized LDL was studied in C57BL male mice. The study concluded that CR (calorie restriction) did not interfere with reverse cholesterol transport (RCT) in vivo, so it could possibly be beneficial to patients at risk for coronary heart disease (11).
Calorie restriction (CR) extends lifespan and reduces the incidence and age of onset of age-related disease in several animal models. The National Institute on Aging (NIA), to determine if this nutritional intervention has similar actions in a long-lived primate species, initiated a study in 1987 to investigate the effects of a 30% CR in male and female rhesus macaques (Macaca mulatta) monkeys of a broad age range. The results showed physiological effects of CR that were parallel with rodent studies and may be predictive of an increased lifespan. Specifically, results from the NIA study demonstrated that CR decreases body weight and fat mass, improves glucoregulatory (blood glucose regulation) function, decreases blood pressure and blood lipids, and decreases body temperature. Although 81% of the monkeys in the study are still alive, preliminary evidence suggests that calorie restriction (CR) will benefit morbidity and mortality (5).
A prospective 16-year follow-up study investigated the independent associations and the possible interaction of body mass index (BMI), leisure–time physical activity (LTPA), and perceived physical fitness and functional capability with the mortality risk. A regionally representative cohort of 35 – 63 years old Finnish men (n= 1,090 subjects) and women (n= 1122 subjects) participated. The study concluded that although BMI did not prove to be an independent risk factor for mortality from CVD (cardiovascular disease), CHD (coronary heart disease), or from all causes combined, perceived physical fitness and functional capability did. An increase in LTPA (leisure-time physical activity) seems to have a similar beneficial effect on the mortality risk of obese and non-obese men and women. The effect also seems to be similar to fit and unfit subjects (10).
Recent studies suggest that calorie restriction (CR) may benefit Alzheimer’s disease (AD) by preventing amyloid-beta (Abeta) neuropathology in mouse models of AD. A study explored the role of CR in AD-type brain amyloidosis in Squirrel monkeys (Saimiri sciureus). In the study, the monkeys were maintained on regular and CR diets throughout their entire lifespan until they died of natural causes. The study showed that 30% of Squirrel monkeys with CR diets had reduced contents of Abeta1-40 and Abeta1-42 peptides in the temporal cortex, relative to control (CON) fed monkeys. The decreased contents of cortical Abeta peptide inversely correlated with SIRT1 protein concentrations in the same brain region. The study concluded that investigation of the role of calorie restriction (CR) in non-human primates may provide a valuable approach for further clarifying the role of CR in Alzheimer’s disease (AD) (9).
Aging is the major known risk factor for the onset of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Mitochondria play a vital role in aging as mitochondrial dysfunction increases with age and produces harmful levels of reactive oxygen species, leading to cellular oxidative stress (free radical theory of aging). Oxidative stress is highly damaging to cellular macromolecules and is also a significant cause of the loss and impairment of neurons in neurodegenerative disorders. A growing body of evidence suggests that modulation of sirtuin activity and restricting calorie intake has a robust neuroprotective effect. SIRT1 induction using pharmacological activators or by calorie restriction (CR) diet regimen has been shown to protect against neuronal loss and impairment in the cellular and animal models of Alzheimer's disease (AD) and Parkinson's disease (PD) (22).
A study investigated the effects of calorie restriction (CR) on behavioral performance and expression of SIRT1 and SIRT5 in rat cerebral tissues. Beginning at 18 months of age, 60 rats were randomly divided into a CR group (n = 30 subjects) and a group that remained fed ad libitum (at their pleasure) (AL; n = 30 subjects). CR rats were restricted to a diet of 60% of their daily food consumption. The results showed that after 6 months of CR, CR rats displayed a maximum 50% reduction in escape latency and a 3.2 s decrease in time and distance to target when evaluated in Morris's water maze tests. The SIRT1 and SIRT5 protein levels in the cerebral tissues of CR rats were elevated compared to AL rats. CR retarded declines in cognitive ability and enhanced the expression of both SIRT1 and SIRT5 proteins in the cerebral tissue of CR rats compared with AL rats (24).
Calorie restriction (CR) increases longevity in many organisms. However, it is unclear if calorie restriction/dieting contributes to cognitive impairment (6).
A study assessed the effects of CR versus ad-lib feeding on cognitive function in male Brown Norway x Fisher344 rats across ages (8 – 38 months), using two tasks differentially sensitive to age-related cognitive decline: object recognition and Morris water maze (MWM). The results showed that all ages performed equally in object recognition, whereas, as a group, CR rats were impaired. On the contrary, there was an age-related impairment in the Morris water maze (MWM) that was attenuated by CR as measured by time in proximity with and latency to reach the platform. Distance to the platform, a more sensitive measure, was not affected by CR. Also, calorie restriction (CR) resulted in an overall increase in physical activity (8).
A randomized controlled trial on 48 participants assessed the effect of 6 months of calorie restriction on cognitive functioning. The study concluded that calorie restriction/dieting was not associated with a consistent pattern of cognitive impairment. Previous reports of cognitive impairment might reflect sampling biases or information processing biases (6).
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