2005

Mech Ageing Dev. 2005 May 10.
Toward a unified theory of caloric restriction and longevity regulation.
Sinclair DA.
Department of Pathology, Harvard Medical School, 77 Avenue Louis Paster, Boston, MA 02115, USA.

The diet known as calorie restriction (CR) is the most reproducible way to extend the lifespan of mammals. Many of the early hypotheses to explain this effect were based on it being a passive alteration in metabolism. Yet, recent data from yeast, worms, flies, and mammals support the idea that CR is not simply a passive effect but an active, highly conserved stress response that evolved early in life's history to increase an organism's chance of surviving adversity. This perspective updates the evidence for and against the various hypotheses of CR, and concludes that many of them can be synthesized into a single, unifying hypothesis. This has important implications for how we might develop novel medicines that can harness these newly discovered innate mechanisms of disease resistance and survival.

Cardiovasc Res. 2005 May 1;66(2):205-12.
Gene expression profiling studies of aging in cardiac and skeletal muscles.
Park SK, Prolla TA.
Department of Genetics and Medical Genetics, University of Wisconsin, Madison, WI 53706, USA.

To examine transcriptional alterations associated with aging in skeletal muscle and the heart, we and others have used DNA microarrays to compare the gene expression profile of young and old animals. Aging results in a differential gene expression pattern specific to each tissue, and most alterations can be completely or partially prevented by caloric restriction (CR) in both heart and skeletal muscle. Transcriptional patterns of tissues from calorie-restricted animals suggests that CR retards the aging process by reducing endogenous damage and by inducing metabolic shifts associated with specific transcriptional profiles. These studies demonstrate that DNA microarrays can be used in cardiovascular aging research to generate panels of hundreds of transcriptional biomarkers, providing a new tool to measure biological age of cardiac and skeletal muscles and to test interventions designed to retard aging in these tissues.

Physiol Res. 2005;54(1):33-9.
Short-term very low calorie diet reduces oxidative stress in obese type 2 diabetic patients.
Skrha J, Kunesova M, Hilgertova J, Weiserova H, Krizova J, Kotrlikova E.
Third Department of Internal Medicine, First Faculty of Medicine, Charles University, U nemocnice 1, 128 08 Prague 2, Czech Republic.

Oxidative stress is higher in obese diabetic than in non-diabetic subjects. This pilot study evaluates oxidative stress during short-term administration of a very low calorie diet in obese persons. Nine obese Type 2 diabetic patients (age 55+/-5 years, BMI 35.9+/-1.9 kg/m2) and nine obese non-diabetic control subjects (age 52+/-6 years, BMI 37.3+/-2.1 kg/m2) were treated by a very low calorie diet (600 kcal daily) during 8 days stay in the hospital. Serum cholesterol, triglycerides, non-esterified fatty acids (NEFA), beta-hydroxybutyrate (B-HB), ascorbic acid (AA), alpha-tocopherol (AT), plasma malondialdehyde (MDA) and superoxide dismutase (SOD) activity in erythrocytes were measured before and on day 3 and 8 of very low calorie diet administration. A decrease of serum cholesterol and triglyceride concentrations on day 8 was associated with a significant increase of NEFA (0.30+/-0.13 vs. 0.47+/-0.11 micromol/l, p<0.001) and B-HB (0.36+/-.13 vs. 2.23+/-1.00 mmol/l, p<0.001) in controls but only of B-HB (1.11+/-0.72 vs. 3.02+/-1.95 mmol/l, p<0.001) in diabetic patients. A significant decrease of plasma MDA and serum AT together with an increase of SOD activity and AA concentration (p<0.01) was observed in control persons, whereas an increase of SOD activity (p<0.01) was only found in diabetic patients after one week of the very low calorie diet. There was a significant correlation between NEFA or B-HB and SOD activity (p<0.01). We conclude that one week of a very low calorie diet administration decreases oxidative stress in obese non-diabetic but only partly in diabetic persons. Diabetes mellitus causes a greater resistance to the effects of a low calorie diet on oxidative stress.

2004

Acta Med Indones. 2004 Jul-Sep;36(3):136-41.
The influence of calorie restriction during the Ramadan fast on serum fructosamine and the formation of beta hydroxybutirate in type 2 diabetes mellitus patients.
Gustaviani R, Soewondo P, Semiardji G, Sudoyo AW.
Department of Internal Medicine, Faculty of Medicine, University of Indonesia-Dr. Cipto Mangunkusumo General Hospital, Jakarta.

AIM: To determine whether the Ramadan fasting can improve metabolic control evaluated from serum fructosamine and beta hydroxybutirate in patients with Type 2 diabetes mellitus. METHODS: This was a prospective one group before and after study (self-controlled study). Twenty four patients from the outpatient clinic of the Metabolic Endocrinology Division of the Department of Internal Medicine, Faculty of Medicine, University of Indonesia/ Cipto Mangunkusumo General Hospital who were well under control underwent assessment for serum fructosamine at weeks -1, 4, and 6 (2 weeks after the Ramadan fast) and beta hydroxybutirate formation at week 4. RESULTS: The mean serum fructosamine on weeks -1, 4, and 6 were 334.2 +/-45.7; 303.9 +/-34.5 dan 313.6 +/-45.9 umol/L. The beta hydroxybutirate level was 0.3 mmol/L. CONCLUSION: The Ramadan fasting in patients with well-controlled and medium-controlled type 2 diabetes mellitus could cause a reduction in serum fructosamine and does not cause formation of beta hyroxybutirate.

Curr Opin Clin Nutr Metab Care. 2004 Nov;7(6):615-22.
Energy restriction and aging.
Smith JV, Heilbronn LK, Ravussin E.
Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA.

PURPOSE OF REVIEW: The focus of this review is on current research involving long-term calorie restriction and the resulting changes observed in possible biomarkers of aging. Special emphasis will be given to the basic and clinical science studies which are currently investigating the effects of controlled, high-quality energy-restricted diets on both biomarkers of longevity and on the development of chronic diseases related to age and obesity in humans. RECENT FINDINGS: Prolonged calorie restriction has been shown to extend both the median and maximal lifespan in a variety of lower species such as yeast, worms, fish, rats, and mice. Mechanisms of this lifespan extension via calorie restriction are not fully elucidated, but possibly involve significant alterations in energy metabolism, oxidative damage, insulin sensitivity, and functional changes in both the neuroendocrine and sympathetic nervous systems. Ongoing studies of prolonged energy restriction in humans are now making it possible to analyze changes in these aging biomarkers to unravel some of the mechanisms of its antiaging phenomenon. SUMMARY: With the incremental expansion of research endeavors in the area of energy or calorie restriction, data on the effects of calorie restriction in animal models and humans are becoming more accessible. Detailed analyses from controlled human trials involving long-term calorie restriction will allow investigators to link observed alterations in body composition down to changes in molecular pathways and gene expression, with their possible effects on the biomarkers of aging.

2003

Southeast Asian J Trop Med Public Health. 2003;34 Suppl 3:198-201.
An introduction to nutritional treatment in inborn errors of metabolism--different disorders, different approaches.
Wilcken B.
The Children's Hospital at Westmead, Sydney, Australia.

Treatment of metabolic disease aims to restore homeostasis, where possible. This can be achieved in a number of ways. For disorders of intermediary metabolism, treatment involves a thorough understanding of the disorder and the pathogenesis of the deleterious effects The various approaches indicated may involve substrate restriction, replacement of deficient products, removal of toxic metabolites or stimulation of residual enzymes. Newer therapies include enzyme replacement and gene therapy. Often, the cornerstone of treatment is dietary. Substrate restriction includes not only a diet low in the substrate indicated by the disorder, but also strict calorie support in times of illness to avoid catabolism. Useful levels of substrate restriction may require the use of supplements of "medical foods", for example amino acid mixtures. Provision of the deficient products is important in disorders affecting energy metabolism. To understand the problems involved in nutritional treatment it is helpful to consider examples of different types of disorders. In Maple syrup urine disease (MSUD), treatment with a very strict low-protein diet, supplemented by a branched-chain-free amino acid mixture is successful, but each intercurrent illness is hazardous, regimens for sick days vital, and strict lifelong treatment is needed. Treatment for phenylketonuria is similar in restricting a substrate but there is no tendency for systemic illness if the phenylalanine levels are too high. Disorders of the urea cycle are difficult dietary challenges because while a very low-protein diet is required, no specific amino acid needs to be avoided and there is a fine line between adequate protein intake and chronic catabolism. Fatty acid oxidation disorders affect energy production and can be detected by newborn screening using tandem mass spectrometry. For long-chain fatty acid disorders, long chain fats must largely be avoided and medium-chain fats must be substituted while strictly avoiding catabolism. Glycogen storage disorders require strict attention to providing carbohydrate, at all times including throughout the night. Many patients with inborn errors do not need any specific dietary therapy, (eg those with storage or neurodegenerative disorders), although all children benefit from an optimal diet, and sick children need this especially.

Annu Rev Med. 2003;54:131-52. Epub 2001 Dec 03
Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans.
Hursting SD, Lavigne JA, Berrigan D, Perkins SN, Barrett JC.
Laboratory of Biosystems and Cancer, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.

Calorie restriction (CR) is the most effective and reproducible intervention for increasing lifespan in a variety of animal species, including mammals. CR is also the most potent, broadly acting cancer-prevention regimen in experimental carcinogenesis models. Translation of the knowledge gained from CR research to human chronic disease prevention and the promotion of healthy aging is critical, especially because obesity, which is an important risk factor for several chronic diseases, including many cancers, is alarmingly increasing in the Western world. This review synthesizes the key biological mechanisms underlying many of the beneficial effects of CR, with a particular focus on the insulin-like growth factor-1 pathway. We also describe some of the opportunities now available for investigations, including gene expression profiling studies, the development of pharmacological mimetics of CR, and the integration of CR regimens with targeted, mechanism-based interventions. These approaches will facilitate the translation of CR research into strategies for effective human chronic disease prevention.

2002

J Gerontol A Biol Sci Med Sci. 2002 Sep;57(9):B333-8
Is there an antiaging medicine?
Butler RN, Fossel M, Harman SM, Heward CB, Olshansky SJ, Perls TT, Rothman DJ, Rothman SM, Warner HR, West MD, Wright WE.
International Longevity Center-USA, New York, New York, USA.

In spite of considerable hype to the contrary, there is no convincing evidence that currently existing so-called "antiaging" remedies promoted by a variety of companies and other organizations can slow aging or increase longevity in humans. Nevertheless, a variety of experiments with laboratory animals indicate that aging rates and life expectancy can be altered. Research going back to the 1930s has shown that caloric restriction (also called dietary restriction) extends life expectancy by 30-40% in experimental animals, presumably at least partially by delaying the occurrence of age-dependent diseases. Mutations that decrease production of insulin growth factor I in laboratory mammals, and those that decrease insulin-like signaling in nematodes and fruit flies, have increased life expectancy as well. Other general strategies that appear promising include interventions that reduce oxidative stress and/or increase resistance to stress; hormone and cell replacement therapies may also have value in dealing with specific age-related pathologies. This article reports the findings of a consensus workshop that discussed what is known about existing and future interventions to slow, stop, or reverse aging in animals, and how these might be applied to humans through future research.

2001

J Gerontol A Biol Sci Med Sci. 2001 Mar;56 Spec No 1:34-44
Neuroendocrine and pharmacological manipulations to assess how caloric restriction increases life span.
Mobbs CV, Bray GA, Atkinson RL, Bartke A, Finch CE, Maratos-Flier E, Crawley JN, Nelson JF.
Department of Neurobiology, Mt. Sinai School of Medicine, New York City, NY 10029, USA.

As part of an effort to review current understanding of the mechanisms by which caloric restriction (CR) extends maximum life span, the authors of the present review were requested to develop a list of key issues concerning the potential role of neuroendocrine systems in mediating these effects. It has long been hypothesized that failure of specific neuroendocrine functions during aging leads to key age-related systemic and physiological failures, and more recently it has been postulated that physiological neuroendocrine responses to CR may increase life span. However, although the acute neuroendocrine responses to fasting have been well studied, it is not clear that these responses are necessarily identical to those observed in response to the chronic moderate (30% to 50% reduction) CR that increases maximum life span. Therefore the recommendations of this panel fall into two categories. First, further characterization of neuroendocrine responses to CR over the entire life span is needed. Second, rigorous interventional studies are needed to test the extent to which neuroendocrine responses to CR mediate the effects of CR on life span, or alternatively if CR protects the function of essential neuroendocrine cells whose impairment reduces life span. Complementary studies using rodent models, nonhuman primates, and humans will be essential to assess the generality of elucidated mechanisms, and to determine if such mechanisms might apply to humans.

Evolutional theories of aging and caloric restriction (CR) in animals predict the presence of neuroendocrine signals to divert the limited energy resources from energy-costly physiologic processes such as reproduction to those essential for survival in response to food shortage. The diversion of energy and subsequent molecular mechanisms might extend the lifespan. A growing body of evidence indicates that leptin, a peptide hormone secreted from adipocytes, has a key role in neuroendocrine adaptation against life-threatening stress such as fasting. The present review discusses the potential role of leptin in the anti-aging action of CR. Although several alternative signaling pathways might also mediate the anti-aging action of CR, leptin signaling could be a substantial pathway in the CR action. Research on neuroendocrine mechanisms of CR is warranted, because such efforts might provide clues to the regulation of the aging process in humans.

1992

Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11533-7
The calorically restricted low-fat nutrient-dense diet in Biosphere 2 significantly lowers blood glucose, total leukocyte count, cholesterol, and blood pressure in humans.
Walford RL, Harris SB, Gunion MW.
Space Biospheres Ventures, Oracle, AZ 85623.

Biosphere 2 is a 3.15-acre space containing an ecosystem that is energetically open (sunlight, electric power, and heat) but materially closed, with air, water, and organic material being recycled. Since September 1991, eight subjects (four women and four men) have been sealed inside, living on food crops grown within. Their diet, low in calories (average, 1780 kcal/day; 1 kcal = 4.184 kJ), low in fat (10% of calories), and nutrient-dense, conforms to that which in numerous animal experiments has promoted health, retarded aging, and extended maximum life span. We report here medical data on the eight subjects, comparing preclosure data with data through 6 months of closure. Significant changes included: (i) weight, 74 to 62 kg (men) and 61 to 54 kg (women); (ii) mean systolic/diastolic blood pressure (eight subjects), 109/74 to 89/58 mmHg (1 mmHg = 133 Pa); (iii) total serum cholesterol, from 191 +/- 11 to 123 +/- 9 mg/dl (mean +/- SD; 36% mean reduction), and high density lipoprotein, from 62 +/- 8 to 38 +/- 5 (risk ratio unchanged); (iv) triglyceride, 139 to 96 mg/dl (men) and 78 to 114 mg/dl (women); (v) fasting glucose, 92 to 74 mg/dl; (vi) leukocyte count, 6.7 to 4.7 x 10(9) cells per liter. We conclude that drastic reductions in cholesterol and blood pressure may be instituted in normal individuals in Western countries by application of a carefully chosen diet and that a low-calorie nutrient-dense regime shows physiologic features in humans similar to those in other animal species.