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Over the last seven decades evidence from insect and animal studies has pointed to the restriction of calorie intake resulting in increase in life span. These findings have led to interest developing for a better understanding of the molecular mechanisms of calorie restriction that bestow the health directed benefits and translating these benefits to human beings, as a means of overcoming life threatening diseases and conditions for better quality of life and increase in life spans (Koubova & Gurante, 2003).
Koubova and Gurante, 2003, p.313 defines calorie restriction as "a dietary regimen low in calories without malnutrition". Therefore, in calorie restriction though energy giving food intake is minimized to essential requirement, other required important nutrients and vitamins and minerals in adequate quantities are provided for. Lower cholesterol levels, lower fasting glucose levels and blood pressure are considered to be biomarkers for aging, since there is a correlation between these markers and those diseases normally associated with advancing age or ageing itself. Calorie restriction studies in animals has shown to reduce these biomarkers associated with aging and hence the holding out of the promise for the use of calorie restriction with the therapeutic potential to improve the treatment of diseases and conditions associated with aging to increase life span in humans (Brown, 2008).
The modern interest in calorie restriction can be traced back to 1930s and the research of the nutritionist Clive McKay. McKay and his team conducting cancer research discovered that severe calorie restriction up to 60% ad Librium levels resulted in a measurable increase in life span in rats. This interesting finding remained in cold storage for nearly three decades, as the findings were not found to be relevant to cancer research as such. Michael Ross took up this thread of investigation in the 1960s using Sprague-Dawley rats, to study the incidence of tumours and its age relation. The results of increased life span in rats caused by calorie restriction sparked interest among gerontologists and gerontology research. In the 1970s two groups of research investigation on calorie started, one under Roy Walford at UCLA and the other led by Edward Masoro and B.P. Yu at the University of Texas (Sprott & Austad, 2006).
Walford and his team, with particular emphasis on Richard Weindruch focused on the impact of calories restriction on different models that ranged from mice to rhesus monkeys to humans. Some of these investigations continue even today and has led to general acceptance that calorie restriction has turned to be the only intervention that results in life span extension among mammals. The Masoro group on the other hand concentrated their work on F344 rats investigating the physiological basis of the calorie restriction effect, which has been further extended by Richard McCarter at Pennsylvania State University on to the mechanism of action of calorie restriction in F344 rats and transgenic and non-transgenic C57BL/6 mice. The results of this research activity are a body of literature on the benefits of calorie restriction in rats and mice that is not limited to mere extension of lifespan (Sprott & Austad, 2006).
The body of literature that has emerged from research on the beneficial effects of calorie restriction from studies on a range of living beings that include yeast, flies, fish, mice and monkeys has led to the consideration that calorie restriction holds out promise for benefits in humans too. Preliminary evidence gives hope to this promise. Early evidence from human studies have indicated that calorie restriction is associated with several beneficial markers like increased span of life, lower insulin levels, lower body temperatures, reduction in malignant tumor development and lower chromosomal damage. It is these benefits seen from calorie restriction that makes a promising medical intervention in several threatening diseases and conditions (Cousens & Rainoshek, 2008).
The published study of Eduardo Arias Vallejo is considered by several leading figures in the study of calorie restriction as laying the basis for the benefits of calorie restriction for humans, by studying good nutritional practices in human beings. The study however finds criticisms in that calorie restriction was not applied, but rather followed an up and down nutritional pattern in normal elderly subjects, ensuring that there was no weight gain. Nevertheless the findings of this study and the evidence from other studies conducted on animals in laboratories and preliminary evidence from short term calorie restriction studies on elderly humans has led to the hypothesis that in addition to the observed health benefits in terms of insulin resistance, asthma, viral infections, bacterial infections, fungal infections, autoimmune disorders, osteoarthritis, CNS inflammatory lesions, cardiac arrhythmias and hot flashes in menopause, other areas of health related benefits include Alzheimer's Disease, Parkinson's Disease, multiple sclerosis, stroke, malignant tumors, NIDDM and cardiac conditions. This has led to interest demonstrated among scientists in calorie restriction in these health related areas, with particular emphasis on some areas of deeper concern like aging, cancer, diabetes, neurodegenerative diseases, heart diseases and obesity or overweight issues (Johnson, Laub & John, 2006).
However, the exact mechanisms involved in calorie restriction still remain elusive because of its complex nature that derives from its multiplicity. The multiple effects of calorie restriction that have been observed include metabolic, neuroendocrine and apoptic effects that are expresses with remarkable differences in the different organ systems. This relative low understanding on the mechanisms of the effects of calorie restriction coupled with the many of these benefits being observed only in laboratory animals and not in natural terms has restricted the universal acceptance calorie restriction as a part of standard medical therapies for health improvement. The rationale behind calorie restriction lies in calorie restriction acting as a moderating factor on reproduction while promoting survival during times of scarcity. Calorie restriction by promoting survival may act as a deterrent coming to aid of humans to provide the hope in several areas of medical benefits. For example in its role as promoting longevity of life, calorie restriction is believed to restrict the oxidative damage that occurs, thereby reducing the cumulative oxidative, which is theoretically believed to be cause of aging (Koubova & Gurante, 2003). Though there is limited direct evidence of the health benefits on humans parallel experiences in humans have been observed. For example, residents of the Island of Okinawa in Japan consume 20% fewer calories and maintain a healthy diet in comparison with the other regions of Japan. These residents show elongated life spans of up to 40 fold increase in age span compared to residents in other regions of Japan. Again, the Biosphere experiment in 1990s in U.S.A involving eight participants between the ages of 25 years and 67 years for two years on calorie restriction demonstrated physiological changes that were similar to the physiological changes in rodents and monkeys in laboratory conditions with calorie restriction. These changes were reduction in blood glucose, insulin, cholesterol, blood pressure and a more potent immune system (Berk, 2007).
Nevertheless, there is the need for more research to remove the existing enigma in calorie restriction. The multiple effects of calorie restriction have led to several health and research organizations ranging from the World Health Organization to cancer research organizations, diabetes research organizations and neurology research organizations being involved in ongoing research activity in calorie restriction. However, among all these organizations die credit has to be extended to the National Institute of Aging for being the pioneer in research activity in calorie restriction as support for its gerontology role (Sprott & Austad, 2006).
1.2. Area to Which Calorie Restriction Extends
1.2.1. Calorie Restriction and Aging
Based on evidence from studies the current studies aging is not a process that happens on a random basis, but is controlled through a genetically-regulated network. Aging can be decelerated by therapies like calorie restriction that influence this genetically-regulated network (Blagosklonny et al, 2010).
Review of the currently available literature on calorie restriction shows that it is the only intervention that has demonstrated consistently the ability to significantly slow done the rate of ageing and thereby extend life span in short lived species. However, there still remains gaps in understanding the real effect of long term calorie restriction in longer living species like primates and humans, though some short term and long term studies on humans have pointed to similar benefits. The main area of concern with calorie restriction in humans is posed by the lack of evidence from properly conducted studies on the possible quality of life issues and side effects of long term calorie restriction in humans, to make it a suitable intervention to retard the ageing process (Dirks & Leeuwenburgh, 2006).
1.2.2. Calorie Restriction and Lifespan
Lifespan of living organisms have been show to be extended by manipulating the cellular processes like histone acetylation, the insulin IGF-1 pathway or the p53 system and calorie restriction is one such manipulative regimen. Removal of damage at the cell level through autophagy is considered the common denominator in all the manipulative regimens. Studies involving yeast and insects have led to the identification of conserved genes that act to extend life span. Among such life span extending genes is Sirtuin 1, which is a phytogenetically conserved NAD+-dependent histone deacytelase. Sirtuin 1 has shown to increase life span in yeast and insects and reduce apoptosis in mammalian cells. This has led to the hypothesis that it is epigenetic deacetylation of histones that is the critical pathway in the physiological aging of several living organisms and that by genetic manipulation of histone acetylation status it is possible to influence cellular lifespan and through that extend the lifespan of the organism. Of remarkable interest from this perspective is that the transgenic expression of Sirtuin 1 induces autophagy in mammalian cells in vitro (Madeo, Tavernakis & Kroemer, 2010).
The dose-response phenomenon of hormesis is marked by low-dose stimulation and high-dose inhibition. Hormesis is the overcompensation to environmental stress experienced by living cells and is the adaptive response to harmful external stimuli. An external stimulus that brings about a beneficial response is termed as mild stress. Calorie restriction is a stimulus that results in mild stress. Mild stress has shown to be able to increase lifespan and also the resistance to more harmful stresses. Experiments on insects and mammals have shown considerable increase in life span through the stimulus of calorie restriction. Other disease and condition related benefits have also been observed due to the adaptive response to harmful stimuli brought about by calorie restriction. Life span extension through calorie restriction as observed in insects and animals may also occur in humans (Kouda & Iki, 2010).
1.2.3. Calorie Restriction and Diabetes
Skriperchenko et al, 2002, investigated the impact of calorie restriction of 1350 kcal/day on the clinical and biochemical parameters of patients with type 2 diabetes over a period of two weeks. The investigation team found that calorie restriction in the type 2 diabetes patients resulted in a significant reduction in body weight, hyperglycemia and hypercholesterolemia (Skriperchenko et al, 2002). During the month of Ramadan Muslims observe fasting for 40 days between sunrise and sunset. This opportunity was used to investigate whether Ramadan fasting improved the metabolic control of serum fructosamine and beta hydroxybutirate in patients with type 2 diabetes mellitus. The study found that in patients with well-controlled or medium controlled type 2 diabetic patients' calorie restriction through Ramadan fasting resulted in reduction in serum fructosamine and does not result in the formation of beta hydroxybutirate (Gustaviani et al, 2004).
1.2.4. Calorie Restriction and Heart Diseases
Current knowledge on heart diseases extends to most of the risk factors for heart disease. Though age, sex genetic make up represent three risk factors that cannot be modified there are nine other modifiable risk factors. Of these modifiable risk factors eight are influenced by dietary intake. Interventions based on diet in heart diseases in general target atherogenosis by influencing, at the cellular scene, the pro-inflammatory processes that cause endothelial dysfunction, plaque formation and plaque rupture. The effect of calorie restriction on risk factors for heart disease was evaluated by a comparison study between individuals who were practicing restricted diet for six years with age-matched healthy individuals consuming a typical American high calorie diet. It was found that the calorie restriction group showed lower BMI and body fat percentages and also total serum cholesterol concentrations, LDL-cholesterol concentrations, tryacylglycerol concentrations, fasting glucose, fasting insulin, C-reactive protein, platelet-derived growth factors and blood pressure were significantly lower, while HDL was higher. In addition carotid artery intima-media thickness was lower in the calorie restricted group (De Caterina et al, 2006).
Fat loss as a result of negative energy balance is known to have a positive influence on metabolic heart disease risk factors. Fontana et al, 2007, compared the effects of fat loss in non-obese humans induced through long-term calorie restriction or by enhanced energy expenditure through exercise on heart disease risk factors. The findings of the study show that the negative energy balance achieved through calorie restriction or exercise produced substantial and similar positive influence on all the major risk factors for heart disease (Fontana et al, 2007).
Calorie Restriction and Neurodegenerative Diseases
Evidence emerging from recent studies on mouse models indicates that calorie restriction may be a useful intervention in Alzheimer's disease through its prevention of amyloid beta neuropathology. Extending these studies by a 30% calorie restriction into Squirrel monkeys demonstrated a reduction in the AB (1-40) and AB (1-42) peptides in the temporal cortex in these monkeys in comparison to the control monkeys. In addition, it was found that the reduction in contents of cortical AB peptide was inversely correlated to the SIRT 1 proteins in the same area of the brain. It may be useful to extend such studies into non-human primates to further evaluate the benefits of calorie restriction in Alzheimer's disease (Qin et al, 2006).
Maswood et al 2004 evaluated the effect of calorie restriction in a primate model of Parkinson's disease. Adult male rhesus monkeys were kept on a reduced 30% calorie diet for a period of six months and then treated with a neurotoxin to create a hemiparkinson condition. Comparison between the calorie-restricted monkeys and the control monkeys showed that the calorie-restricted monkeys demonstrated elevated levels of locomotor activity and levels of dopamine and dopamine metabolites in the striatal region. It was also noted in the calorie restricted monkeys that there were increased levels of survival of dopamine neurons in the substantia nigra and were capable of greater manual dexterity than the control. Furthermore, it was found that the levels of glial cell line-derived neurotrophic factor were also higher in the caudate nucleus of the calorie restricted monkeys. These findings point to positive neurotrophic effects from calorie restriction in Parkinson's disease (Maswood et al, 2004).
1.2.6. Calorie Restriction and Obesity/Weight Problems
Excessive calorie intake has the consequences of obesity with its accompanying risk of the development of chronic diseases. Studies on rodents have shown that calorie restriction without affecting the intake of adequate nutrients reduces the risk of chronic diseases and lengthening span of life. Review of literature on the effect of calorie restriction in humans, shows beneficial metabolic, functional and hormonal changes accruing from calorie restriction in both men and women. However, the precise amount of calorie restriction and the body fat associated in bringing out optimal health benefits is still elusive and raises the possibility that calorie restriction may be harmful in individuals with minimal fat deposits in the body (Fontana & Klein, 2007).
Coker et al, 2009, investigated the effect of weight loss from calorie restriction or exercise on hepatic and peripheral insulin resistance in obese human subjects. They found that weight loss from exercise was more beneficial in reducing visceral fat and suppression of glucose production, while in the case of insulin-stimulated glucose disposal both calorie restriction and exercise demonstrated similar benefits (Coker et al, 2009).
Findings of the Literature Review
Author & Year
Type of Study
Blagosklonny et al, 2010
To evaluate the available literature on calorie restriction
Aging is not a random occurrence, but rather the result of a genetically regulated network and that aging can be restricted by therapies like calorie restriction.
All current evidence on the effect of calorie restriction on aging is essentially based on short lived insects and animals.
Dirks & Leeuwenburgh, 2006
To evaluate the available literature on calorie restriction
Calorie restriction is the only intervention that has consistently shown the ability to slow down the rate of aging in short lived species.
Lack of evidence on the effect of calorie restriction on aging in long living species like primates and humans and thus no knowledge of any possible side effects of calorie restriction on humans.
Madeo, Tavernakis & Kroemer, 2010
Focus on autophagy
Sirtuin 1 has shown to increase life span in yeast and insects and reduce apoptosis in mammalian cells. transgenic expression of Sirtuin 1 induces autophagy in mammalian cells in vitro
Mammalian evidence of increase in lifespan limited to in vitro studies.
Kouda & Iki, 2010
Beneficial effects of mild stress through calorie restriction
Experiments on insects and mammals have shown considerable increase in life span through the stimulus of calorie restriction. Other disease and condition related benefits have also been observed due to the adaptive response to harmful stimuli brought about by calorie restriction.
Lack of adequate evidence of increase in life span in humans.
Skriperchenko et al, 2002
Impact of calorie restriction of 1350 kcal/day on the clinical and biochemical parameters of patients with type 2 diabetes
Calorie restriction in the type 2 diabetes patients resulted in a significant reduction in body weight, hyperglycemia and hypercholesterolemia
Short duration study. No evaluation of side effects.
Gustaviani et al, 2004
To investigate whether Ramadan fasting improved the metabolic control of serum fructosamine and beta hydroxybutirate in patients with type 2 diabetes mellitus
Ramadan fasting resulted in reduction in serum fructosamine and does not result in the formation of beta hydroxybutirate.
Not a controlled study. Reliability limited.
De Caterina et al, 2006
To evaluate the effect of calorie restriction on risk factors for heart disease
It was found that the calorie restriction group showed lower BMI and body fat percentages and also total serum cholesterol concentrations, LDL-cholesterol concentrations, tryacylglycerol concentrations, fasting glucose, fasting insulin, C-reactive protein, platelet-derived growth factors and blood pressure were significantly lower, while HDL was higher. In addition carotid artery intima-media thickness was lower in the calorie restricted group
Limited controls in the study, limiting its reliability.
Fontana et al, 2007
To compare the benefits of exercise and calorie restriction on metabolic risk factors for heart disease
The negative energy balance achieved through calorie restriction or exercise produced substantial and similar positive influence on all the major risk factors for heart disease
Small and short duration study. Larger study on long term basis is required to corroborate the findings of this study
Qin et al, 2006
Experimental Study on Squirrel Monkeys
Evaluation of the benefits of calorie restriction on Alzheimer's Disease
Reduction in the AB (1-40) and AB (1-42) peptides in the temporal cortex. Reduction in contents of cortical AB peptide was inversely correlated to the SIRT 1 proteins in the same area of the brain
Further studies in non-primates required to confirm these findings.
Maswood et al 2004
Experimental Study on Rhesus Monkeys
To evaluate the effect of calorie restriction in a primate model of Parkinson's disease
Elevated levels of locomotor activity and levels of dopamine and dopamine metabolites in the striatal region. Increased levels of survival of dopamine neurons in the substantia nigra and were capable of greater manual dexterity than the control. Levels of glial cell line-derived neurotrophic factor were also higher in the caudate nucleus
Still to be translated for benefits in humans.
Fontana & Klein, 2007
Review of literature on the effect of calorie restriction in humans
Beneficial metabolic, functional and hormonal changes accruing from calorie restriction in both men and women
No understanding on the precise amount of calorie restriction and the body fat associated in bringing out optimal health benefits is still elusive
Coker et al, 2009
To the effect of weight loss from calorie restriction or exercise on hepatic and peripheral insulin resistance in obese human subjects
Weight loss from exercise was more beneficial in reducing visceral fat and suppression of glucose production, while in the case of insulin-stimulated glucose disposal both calorie restriction and exercise demonstrated similar benefits
Findings need to be substantiated through further studies.
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Cousens, G. & Rainoshek, D. 2008, There is a Cure for Diabetes, North Atlantic Books, Berkeley, CA.
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Fontana, L., Vilareal, D. T., Weiss, E. P., Racette, S. B., Steger-May, K., Klein, S. & Holloszy, J. O. 2007, 'Calorie restriction or exercise: effects on coronary heart disease risk factors. A randomized, controlled trial', American Journal of physiology, endocrinology and metabolism, vol.293, no.1, pp.197-202.
Gustaviani, R., Soewondo, P., Semiardii, G. & Sudoyo, A. W. 2004, 'The influence of calorie restriction during the Ramadan fast on serum fructosamine and the formation of beta hydroxybutirate in type 2 diabetes mellitus patients', Acta medica Indonesiana, vol.36, no.3, pp.136-141.
Johnson, J. B. Laub, D. R. & John, S. 2006, 'The Effect on Health of Alternate Day Calorie Restriction: Eating Less and More than Needed on Alternate Day's Prolongs Life, Medical Hypothesis, vol.67, pp.209-211.
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Madeo, F., Tavernakis, N. & Kroemer, G. 2010, 'Can Autophagy Promote Longevity?', Nature Cell Biology, vol.12, no.9, pp.842-846.
Maswood, N., Young, J., Tilmont, E., Zhang, Z., Gash, D. M., Gerhardt, D. A., Grondin, R., Roth, G. S., Mattison, J., Lane, M. A., Carson, R. E., Cohen, R. M., Mouton, P. R., Quigley, C., Mattison, M. P. & Ingram, D. K. 2004, 'Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson's disease, Proceedings of the National Academy of Sciences of the United States of America, vol.101, pp.18171-18176.
Qin, W., Chachich, M., Lane, M., Roth, G., Bryant, M., de Cabo, R., Ottinger, M. A., Mattison, J., Ingram, D., Gandy, S. & Pasinetti, G. M. 2006, 'Calorie restriction attenuates Alzheimer's disease type brain amyloidosis in Squirrel monkeys (Saimiri sciureus), Journal of Alzheimer's Disease, vol.10, no.4, pp.417-422.
Skriperchenko, N. D., Sharafetdinov, K. K., Plotinova, O. A. & Mescheriakova, V. A. 2002, 'Influence of caloric restriction diet on clinical and biochemical parameters in patients with type 2 diabetes mellitus', Vopr Pitan, vol.71, no.4, pp.13-17.
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