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Dietary restriction (DR) or caloric restriction (CR) is the well-established means to retard aging, leading to prolongation of mean and maximum life span in many animal models. We have been interested in the possibility of extending the span of health of elderly people rather than increasing longevity, and therefore studied the effects of DR/CR initiated late in life in rodent models. We restricted food for 2-3.5 months in mice or rats of middle or old ages, which would perhaps be equivalent to 50-70 years of age in humans. We found that: (1) Potentially harmful altered proteins were reduced in the animals' tissues. (2) Extended half-life of protein in aged animals was shortened in mouse hepatocytes, suggesting improved protein turnover. (3) Reduced proteasome activity was upregulated in rat liver and skeletal muscle. (4) Protein carbonyls were decreased in rat liver mitochondria and skeletal muscle cytoplasm, and also oxidative DNA damage was reduced in rat liver nucleus, suggesting amelioration of oxidative stress. (5) Reduced apo A-IV and C-III metabolism in aged mouse was restored, suggesting increase in reduced fatty acid mobilization. (6) The carbonyl modification in histones that was paradoxically reduced in aged rat was increased to the level of a young animal, suggesting restoration of reduced transcription. These findings in rodents suggest a possibility that DR/CR is beneficial if applied in middle-aged or early senescent obese people. We argue, however, that application of late life DR/CR can be harmful if practiced in people who are already eating modestly.

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Dietary restriction (DR) increases the resistance to different stresses, retards various age-related diseases and extends life span in a variety of animals. Here we have investigated the effect of DR (alternate days of feeding for 3 months) on glucocorticoid receptors (GRs) in the liver of adult (5 months) and old (20 months) male mice. A significant decrease was observed in the level of receptors in old mice (25%) as compared to the adult ones. DR subjected mice of both age groups showed a marked increase in the GR concentration (37% in adult and 31% in old mice) as compared to the ad libitum (AL) fed mice, whereas the affinity remained the same in both groups of animals at both ages. Scatchard analyses and the protein slot blot experiment confirmed the increase in the receptor level in AL and DR fed animals for both age groups. The magnitude of heat and salt activation of GR was higher in the adult mice as compared to the old mice who were fed AL. DR, however, significantly increased (40%) the magnitude of activation of GR in the older mice as compared to the AL fed animals, whereas no such change was observed in the adult animals. Further, DNase I digestion and extraction of nuclear bound GR-complexes showed a higher degree of extraction in adult animals (57%-59%) as compared to the old (31%-33%) animals. Mice subjected to DR revealed no significant change at either age. These findings indicate that DR regulates GR in an age-dependent manner and that it may allow animals to better adapt to metabolic regulation in older ages.

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Oxidative modification alters the function of proteins and is thought to play an important role in the decline of cellular functions during aging. Reactive oxygen species generated as by-products of oxidative metabolism frequently damage cellular macromolecules such as DNA, lipids and proteins. Protein carbonyls are commonly used as a marker of protein oxidation in cells and tissues. The brain is a highly oxidative organ consuming 20% of the body's oxygen despite accounting for only 2% of the total body weight. In the present study, we have evaluated the levels of free radicals and protein carbonyls in the cerebral hemispheres of young and old mice. Dimethylsulphoxide treatment to the mice has been shown to cause a reduction in reactive oxygen species and protein carbonylation. In this study, we have also investigated the combined effect of dimethylsulphoxide and curcumin on free radicals and protein oxidation. Curcumin (90mg/kg body weight) dissolved in dimethylsulphoxide was administered to the mice for three consecutive days. A significant reduction in the level of reactive oxygen species and protein carbonylation was seen with co-supplementation of the two antioxidants. The present study, thus demonstrated the antioxidative effects of dimethylsulphoxide and curcumin in the brain which may help in preventing free-radical-induced damage to the proteins during the later stages of life.

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