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Aging, The Molecular Concepts


Since McCay et al. (28) first reported that dietary restriction increased the lifespan of rats more than 60 years ago, numerous studies have demonstrated that life spans of rats, mice and hamsters can be extended significantly using various restriction regimens (29-31).

Fig. 7.3.
Fig. 7.3.Effect of aging and dietary restriction on UDS in rat hepatocytes and kidney cells. Hepatocytes (A) and kidney cells (B) were isolated from male Fisher 344 rats fed ad libidum (•) or calorie-restricted diet (o). UV-induced UDS was measured 24 hours after UV-irradiation. Data are taken from Weraarchakul et al. (37).

At the present time, it is generally accepted that restriction of total calories increases the lifespan of rodents by retarding the aging process. For example, it has been shown that dietary restriction in rodents maintains important physiological processes in a youthful state for a longer period of life. These effects range from gene expression to organ functions (29, 31). Dietary restriction also prevents or delays the occurrence of most age-associated diseases (29, 31).

Investigators also have studied if dietary restriction plays a role in preserving the integrity of the genome. Dempsey et al. (32) observed that the frequency of mutations in the hypoxanthine phosphoribosyltransferase (hprt) gene was significantly reduced in splenic lymphocytes of calorie-restricted mice compared to the mice fed ad libitum. More recently, Casciano et al. (33) reported that dietary restriction significantly lowered the frequency of spontaneous and chemically induced mutations in the hprt gene of rat lymphocytes. Studies in Yu's laboratory (34) showed that rats fed a calorie-restricted diet exhibited a lower level of 8-hydroxydeoxyguanosine (a DNA oxidative product) in liver DNA than rats fed ad libitum. In addition, Djuric et al. (35) showed that the level of 5-hydroxymethyluracil (another oxidative product of DNA) in DNA from liver and mammary gland of rats was significantly decreased by caloric restriction. More recently, Sohal et al. (36) reported that dietary restriction reduced the level of 8-hydroxydeoxyguanosine in all tissues studied, e.g. skeletal muscle, brain, heart, liver and kidney.

There are only a limited number of studies on the effect of dietary restriction on DNA repair. Richardson et al. showed that UV-induced UDS in the hepatocytes and kidney cells isolated from rats fed a calorie-restricted diet was higher than in cells from rats fed ad libitum at all ages studied (37), and these data are shown in Fig. 7.3. Several other laboratories have also shown that cells from rodents fed a calorie-restricted diet have enhanced DNA repair. In 1988, Licastro et al. (38) reported that dietary restriction significantly increased the levels of UDS after UV-irradiation in lymphocytes obtained from the spleens of mice. Subsequently, Lipman et al. (39) observed that cultured skin fibroblasts obtained from rats fed a calorie-restricted diet exhibited higher levels of UDS induced by UV-irradiation or methyl methanesulfonate than the fibroblasts from rats fed ad libitum. More recently, Srivastava et al. (40) and Tilley et al. (41) compared UDS in hepatocytes and lung fibroblasts isolated from rats fed either ad libitum or a calorie-restricted diet. Results from these studies support the view that caloric restriction enhances the ability of cells to repair the UV-induced DNA damage.

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