J Assoc Physicians India. 2004 Oct;52:794-804.
Free radicals and antioxidants in human health: current status and future prospects.
Devasagayam TP, Tilak JC, Boloor KK, Sane KS, Ghaskadbi SS, Lele RD.
Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400 085.

Free radicals and related species have attracted a great deal of attention in recent years. They are mainly derived from oxygen (reactive oxygen species/ROS) and nitrogen (reactive nitrogen species/RNS), and are generated in our body by various endogenous systems, exposure to different physicochemical conditions or pathophysiological states. Free radicals can adversely alter lipids, proteins and DNA and have been implicated in aging and a number of human diseases. Lipids are highly prone to free radical damage resulting in lipid peroxidation that can lead to adverse alterations. Free radical damage to protein can result in loss of enzyme activity. Damage caused to DNA, can result in mutagenesis and carcinogenesis. Redox signaling is a major area of free radical research that is attracting attention. Nature has endowed us with protective antioxidant mechanisms- superoxide dismutase (SOD), catalase, glutathione, glutathione peroxidases and reductase, vitamin E (tocopherols and tocotrienols), vitamin C etc., apart from many dietary components. There are epidemiological evidences correlating higher intake of components/ foods with antioxidant abilities to lower incidence of various human morbidities or mortalities. Current research reveals the different potential applications of antioxidant/free radical manipulations in prevention or control of disease. Natural products from dietary components such as Indian spices and medicinal plants are known to possess antioxidant activity. Newer and future approaches include gene therapy to produce more antioxidants in the body, genetically engineered plant products with higher level of antioxidants, synthetic antioxidant enzymes (SOD mimics), novel biomolecules and the use of functional foods enriched with antioxidants.

Ann N Y Acad Sci. 2004 Jun;1019:333-42.
Short-term caloric restriction and sites of oxygen radical generation in kidney and skeletal muscle mitochondria.
Gredilla R, Phaneuf S, Selman C, Kendaiah S, Leeuwenburgh C, Barja G.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, 28040 Madrid, Spain.

Mitochondrial free radical generation is believed to be one of the principal factors determining aging rate, and complexes I and III have been described as the main sources of reactive oxygen species (ROS) within mitochondria in heart, brain, and liver. Moreover, complex I ROS generation of heart and liver mitochondria seems especially linked to aging rate both in comparative studies between animals with different longevities and in caloric restriction models. Caloric restriction (CR) is a well-documented manipulation that extends mean and maximum longevity. One of the factors that appears to be involved in such life span extension is the reduction in mitochondrial free radical generation at complex I. We have performed two parallel investigations, one studying the effect of short-term CR on oxygen radical generation in kidney and skeletal muscle (gastrocnemius) mitochondria and a second one regarding location of mitochondrial ROS-generating sites in these same tissues. In the former study, no effect of short-term caloric restriction was observed in mitochondrial free radical generation in either kidney or skeletal muscle. The latter study ruled out complex II as a principal source of free radicals in kidney and in skeletal muscle mitochondria, and, similar to previous investigations in heart and liver organelles, the main free radical generators were located at complexes I and III within the electron transport system.

Biol Rev Camb Philos Soc. 2004 May;79(2):235-51.
Aging in vertebrates, and the effect of caloric restriction: a mitochondrial free radical production-DNA damage mechanism?
Barja G.
Department of Animal Biology-II (Animal Physiology), Faculty of Biology, Complutense University, Madrid 28040, Spain.

Oxygen is toxic to aerobic animals because it is univalently reduced inside cells to oxygen free radicals. Studies dealing with the relationship between oxidative stress and aging in different vertebrate species and in caloric-restricted rodents are discussed in this review. Healthy tissues mainly produce reactive oxygen species (ROS) at mitochondria. These ROS can damage cellular lipids, proteins and, most importantly, DNA. Although antioxidants help to control this oxidative stress in cells in general, they do not decrease the rate of aging, because their concentrations are lower in long- than in short-lived animals and because increasing antioxidant levels does not increase vertebrate maximum longevity. However, long-lived homeothermic vertebrates consistently have lower rates of mitochondrial ROS production and lower levels of steady-state oxidative damage in their mitochondrial DNA than short-lived ones. Caloric-restricted rodents also show lower levels of these two key parameters than controls fed ad libitum. The decrease in mitochondrial ROS generation of the restricted animals has been recently localized at complex I and the mechanism involved is related to the degree of electronic reduction of the complex I ROS generator. Strikingly, the same site and mechanism have been found when comparing a long- with a short-lived animal species. It is suggested that a low rate of mitochondrial ROS generation extends lifespan both in long-lived and in caloric-restricted animals by determining the rate of oxidative attack and accumulation of somatic mutations in mitochondrial DNA.

J Appl Physiol 2003 Mar;94(3):947-52
Modulations by dietary restriction on antioxidant enzymes and lipid peroxidation in developing mice.
Wu A, Sun X, Wan F, Liu Y.
Departments of Nutrition and Food Hygiene and Environmental Toxicology, Tongji Medical University, Wuhan, Hubei 430030, China.

The effects of dietary restriction (DR) on the activities of liver superoxide dismutase (SOD), catalase (Cat), and glutathione peroxidase (GPX) and the level of lipid peroxidation (LP) in developing mice were investigated in this study. Male and female Kunmin mice were fed a standard rodent diet ad libitum (AL), 80% of AL food intake (20% DR), or 65% of AL food intake (35% DR) for 12 or 24 wk. Both 12 and 24 wk of DR resulted in retarded body weight gain in male and female mice. The activities of SOD, Cat, and GPX and the content of LP in DR male and female mice were not different (P > 0.05) from those in controls after 12 wk of DR. However, the SOD activity was increased at 24 wk in 20% DR (P < 0.05) and 35% DR (P < 0.01) male, but not in DR female, mice. The Cat activity was elevated at 24 wk in both DR male (P < 0.05 for 20% DR, P < 0.01 for 35% DR) and female (P < 0.01) mice with a greater increase in DR female (P < 0.05) than in DR male animals. GPX activity was also increased at 24 wk in DR male (P < 0.01) and female (P < 0.01) mice with a greater elevation in DR females (P < 0.05) than in DR males. Furthermore, LP was decreased at 24 wk in both DR male (P < 0.01) and female (P < 0.01) animals with a greater reduction in DR females (P < 0.01) compared with DR males. These findings indicated that 24 wk, but not 12 wk, of DR led to differential effects on liver SOD, Cat, and GPX activities and LP content in male and female mice during development, suggesting sex-associated modulations of DR on antioxidant systems in developing animals.

J Gerontol A Biol Sci Med Sci 1998 May;53(3):B161-7.
Effects of aging and food restriction on the antioxidant enzyme activity of rat livers.
Gomi F, Matsuo M.
Tokyo Metropolitan Institute of Gerontology, Faculty of Science, Konan University, Hyogo, Japan.

The effects of aging and food restriction on the activities and mRNA levels of antioxidant enzymes in rat livers were examined. Rats were fed ad libitum every day (AL) or ad libitum on every other weekday (FR). At 30 months of age, the catalase and glutathione peroxidase activities were lower, whereas the thiobarbituric acid (TBA) value, an index of lipid peroxidation of the AL rats, was higher than that at younger ages. At 33 months of age, copper/zinc superoxide dismutase (CuZnSOD), catalase, and glutathione peroxidase activities increased, and the TBA value of the FR rats remained unchanged as compared with those at younger ages. Until old age, food restriction gave rather decreasing effects on antioxidant enzyme activities. Furthermore, antioxidant enzyme activities and the TBA values of the FR rats were higher at the end of a fasting period than those at the end of a feeding period.