Cell. 2005 Feb 25;120(4):473-82.
Calorie restriction--the SIR2 connection.
Guarente L, Picard F.
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

A nutritious diet low in calories improves the health and extends the life span of rodents. Recent studies identified a gene, SIR2, which encodes an NAD-dependent deacetylase and may mediate the effects of calorie restriction. In this review, we discuss SIR2 genes and calorie restriction in the lower organisms yeast and Drosophila. We then describe the physiological changes in mammals during calorie restriction and how they may lead to the observed health benefits. We summarize the roles of mammalian Sirt1 in mediating these changes in tissues and endocrine systems and propose that Sirt1 regulates calorie restriction by sensing low calories and triggering physiological changes linked to health and longevity.

Endocrinology. 2005 May 26.
The Role of Oxidative Stress in relation to Caloric Restriction and Longevity.
Gredilla R, Barja G.
Department of Animal Physiology-II, Faculty of Biology, Complutense University, Madrid 28040, Spain.

Reduction of the caloric intake without malnutrition is one of the most consistent experimental interventions increasing mean and maximum life span in different species. For over seventy years caloric restriction has been studied, and during the last years the number of investigations on such nutritional intervention and aging has dramatically increased. Since caloric restriction decreases the aging rate, it constitutes an excellent approach to better understand the mechanisms underlying the aging process. Different investigations have reported reductions in steady-state oxidative damage to proteins, lipids and DNA in animals subjected to restricted caloric intake. Most interestingly, several investigations have reported that these decreases in oxidative damage are related to a lowering of mitochondrial free radical generation rate in different tissues of the restricted animals. Thus, similarly to what has been described for long-lived animals in comparative studies, a decrease in mitochondrial free radical generation has been suggested to be one of the main determinants of the extended life span observed in restricted animals. Here we review recent studies on caloric restriction and longevity, focusing on mitochondrial oxidative stress and the proposed mechanisms leading to an extended longevity in caloric restricted animals.

Ann N Y Acad Sci 2000 Jun;908:180-98.
Calorie restriction and age-related oxidative stress.
Merry BJ.
School of Biological Sciences, University of Liverpool, United Kingdom.

Calorie restriction (CR) in mammals has been recognized as the best characterized and most reproducible strategy for extending maximum survival, retarding physiological aging, and delaying the onset of age-related pathologic conditions in mammals. The overwhelming majority of studies using CR have used short-lived rodent species, although current work using rhesus and squirrel monkeys will determine whether this paradigm is also relevant to manipulating the rate of primate aging. The mechanism by which restricted calorie intake modifies the rate of aging and pathology has been the subject of much controversy, although an attenuation in the lifetime accumulation of oxidative damage appears to be a central feature. Although the majority of studies have focused on the ability of cells from calorie-restricted animals to scavenge free radicals to explain the slower accrual of oxidative damage with age, it is not established that CR has a consistent effect to upregulate the activity of these enzymes in all tissues. A major effect of calorie-restricted feeding now appears to be on the rate of production or leak of free radicals from the mitochondria. The details of the adaptation and the signaling pathway that induces this effect are currently unknown.

J Nutr Health Aging 2000;4(3):182-186.
Effects of Age and Dietary Restriction on Lifespan and Oxidative Stress of SAMP8 Mice with Learning and Memory impairments.
Choi J, Kim D.
Faculty of Food Science and Biotechnology, Pukyong National University; 599-1 Daeyeon-Dong, Nam-Gu, Pusan 608-737, Korea.

This study was to evaluate the effect of dietary restriction (DR) on lifespan and oxidative stress of dementia mouse model SAMP8 with impaired learning and memory. SAMP8 female mice were fed either ad libitum (AL) or fed 60% of food intake of AL. Results showed that basal metabolic rates (BMR) were significantly lower (15 to 22%) in DR with increased median and maximum lifespans, suggesting feed and gross efficiencies were significantly lower in DR than in AL. Grading score of senescence resulted in a marked improvement about 2-fold by DR compared with AL. The amounts of lipofuscin at 12 months were significantly lowered 16% in DR than that of AL. Median and maximal lifespans significantly increased (28.5% and 16.4%, respectively) by DR, and also lowered superoxide radical about 15~45% in DR compared with AL at 4, 8 and 12 months of age. On the other hand, superoxide dismutase (SOD) activities were higher (about 15~30%) in DR than those in AL group of SAMP8 except for 4 months of age. Our results suggest that 40% calorie restricted SAMP8 can effectively suppress dementia-related abnormalities during aging.

J Nutr 1995 Feb;125(2):195-201.
Activities of antioxidant enzymes in various tissues of male Fischer 344 rats are altered by food restriction.
Xia E; Rao G; Van Remmen H; Heydari AR; Richardson A.
Geriatric Research, Education and Clinical Center, Audie L. Murphy Memorial Veterans Hospital, San Antonio, TX.

ABSTRACT: The objective of this study was to determine how food restriction (40% restriction of food intake) altered the age-related changes in the activities of Cu,Zn superoxide dismutase, catalase and glutathione peroxidase in liver, brain cortex, heart, kidney and intestinal mucosa obtained from 6-, 16- and 26-mo-old male Fischer 344 rats. Food restriction increased the activity of one or more of the antioxidant enzymes in the liver, brain cortex, heart and kidney of the rats. However, the magnitude of the effect and the antioxidant enzyme(s) affected by food restriction varied from tissue to tissue, and food restriction had no significant effect on the activities of these enzymes in intestinal mucosa. Interestingly, the four tissues in which food restriction increased the activity of one or more of the antioxidant enzymes showed reduced lipid peroxidation as measured by thiobarbituric acid-reactive material. These data suggest that food restriction might enhance the survival of rodents by altering the levels of the antioxidant enzymes and hence reducing free radical damage.