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December 2001

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Short-term calorie restriction improves disease-related markers in older male rhesus monkeys (Macaca mulatta).

Calorie restriction (CR) is widely known for its effects on life span, physiological aging and age-related disease in laboratory rats and mice. Emerging data from CR studies in rhesus monkeys suggest that this nutritional intervention paradigm may also have beneficial effects in long-lived mammals. Studies from our laboratory and others have suggested that young- or adult-onset CR might have beneficial effects on cardiovascular disease and diabetes. For example, long-term CR reduced body fat and serum triglycerides, and increased a subfraction of HDL cholesterol associated with decreased cardiovascular disease risk. These studies suggested that long-term CR begun in young or adult animals might have important effects on markers relevant to age-related disease. Few studies have examined the effects of CR initiated in older animals (rodents or monkeys), and the temporal nature of some potentially beneficial effects of CR is unknown. The present study examined several markers related to diabetes and cardiovascular disease in thirteen older adult (> 18 year) non-obese (body fat < 22%), male rhesus monkeys during a short-term CR paradigm. Specifically, we collected these data at baseline (ad libitum feeding), 10, 20, and 30% CR, and at 6 and 12 months on 30% CR. Fasting and peak insulin were significantly reduced as were the acute and second-phase insulin responses. CR also marginally reduced triglycerides (50% reduction), but had no effect on total serum cholesterol or blood pressure. Interestingly, the observed glucoregulatory changes emerged prior to any evidence of a change in body composition suggesting that certain effects of CR may not be wholly dependent on changes in body composition in older monkeys.

Mech Ageing Dev 2000 Jan 10;112(3):185-96

Controlling caloric consumption: protocols for rodents and rhesus monkeys.

One approach for investigating biological aging is to compare control-fed animals with others restricted in calorie intake by 20% or more. Caloric restriction (CR) is the only intervention shown to extend the maximum life span of several invertebrates and vertebrates including spiders, fish, rats and mice. The capacity of CR to retard aging in nonhuman primates is now being explored. The rodent studies show that CR opposes the development of many age-associated pathophysiological changes, including changes to the brain and changes in learning and behavior. One goal of studying CR in rodent is to determine the mechanisms by which it retards aging to design interventions that duplicate those effects. The methods that we use for conducting CR studies on mice and rhesus monkeys are described. We employ procedures designed to achieve a high degree of caloric control for all animals in the study. As used in our studies, this control includes the following features: 1) animals are individually housed, and 2) all individuals in the control group eat the same number of calories (i.e., they are not fed ad lib). Although this method results in strict caloric control for all animals, there seems to be considerable procedural flexibility for the successful conduct of CR studies.

Neurobiol Aging 1999 Mar-Apr;20(2):157-65

The effects of aging and calorie restriction on plasma nutrient levels in male and female Emory mice.

We examined the effect of diet, age (4.5, 13 and 23 months), and sex on plasma levels of retinol, tocopherol, ascorbate, cholesterol, glucose and glycohemoglobin in male and female Emory mice which were fed control (C) and 50% calorie restricted (R) diets. Results showed that C fed animals tended to have higher levels of plasma ascorbate (50-71%), cholesterol (23-71%), glucose (38-81%) and glycohemoglobin (50%). However, these diet differences varied with the age and sex of the animals. Plasma retinol levels were lower only in R males vs. C males (50%). Novel sex-related differences in levels of plasma retinol (2-fold higher in C male mice than in C or R female mice) are described. Aging was associated with trends towards lower levels of plasma ascorbate (14-25%), glucose (34-36%) and glycohemoglobin (47-57%) from 4.5 to 23 months of age. However, these age differences depended upon the diet and sex of the animals. These data suggest that lower plasma levels of glucose, glycosylated hemoglobin and cholesterol may be causally related to the life extension noted in R animals since elevated levels of these moieties have been related to aging. Since oxidative stress is thought to be causally related to aging it appears unlikely that retinol, tocopherol and ascorbate are causally related to R-induced life extension.

Mech Ageing Dev1998 Sep 15;105(1-2):31-44

Antioxidant enzyme activities in lens, liver and kidney of calorie restricted Emory mice.

Dietary calorie restriction extends both mean and maximum life span and retards age-related diseases, including eye lens cataract in Emory mice. The beneficial effects of calorie restriction have been hypothesized to reflect enhanced tissue antioxidant capacity. As a test of this hypothesis, we reared male and female Emory mice on control (C) or 40% calorie-restricted (R) diets. We then determined activities of total superoxide dismutase (T-SOD), Cu/Zn-SOD, Mn-SOD, glutathione peroxidase (GPx), glutathione reductase (GR) and catalase (CAT) in eye lens, liver and kidney of young (4.5 or 6 months), mature (11 or 12 months) and old (22 months) animals. Effects of diet, age and sex were evaluated by multi-factor ANOVA. Only kidney GR activities (mean +/- S.E.M.) were significantly enhanced with the R diet (R, 61 +/- 2 vs. C, 54 +/- 3 U/mg protein; P = 0.03). More frequently, we noted reduced antioxidant enzyme activity in R as compared with C animals, including reduced activities of T-SOD in lens, liver and kidney, Cu/Zn-SOD in liver and kidney, liver Mn-SOD and liver CAT (P < 0.05). Effects of age on antioxidant enzyme activity in C mice included age-dependent decreases in lens and kidney CAT and in liver Mn-SOD. There was also an age-dependent increases in liver and kidney Cu/Zn-SOD and liver GR. None of these age-dependent alterations in antioxidant enzyme function were attenuated in tissues of mice fed the R diet. Values for liver CAT were significantly lower in females than in males (P = 0.05). These results indicate that antioxidant enzyme activities in Emory mouse tissues are influenced by diet, age and sex. However, it is unlikely that increased lifespan and attenuation of cataract (and perhaps other age-dependent debilities), which are associated with the R diet in the Emory mouse, are due to enhanced antioxidant enzyme capabilities.

Mech Ageing Dev 1997 Dec 30;99(3):181-92

Effects of changes in calorie intake on intestinal nutrient uptake and transporter mRNA levels in aged mice.

In aged, chronically calorie-restricted (CR) mice, intestinal nutrient uptake is significantly higher than in same-age ad libitum controls. Can this chronic restriction-induced enhancement of uptake be reversed by ad libitum feeding? We addressed this question by switching 32-mo-old chronically CR mice to ad libitum feeding for 4 wk (CRAL). Intestinal transport rate and total intestinal absorptive capacity for D-sugars and several nonessential L-amino acids decreased significantly in CRAL mice. In contrast, switching CR mice to an ad libitum regimen for only 3 d had no effect on intestinal nutrient transport, indicating that the negative effects of ad libitum feeding require a duration longer than the 3-d lifetime of most enterocytes. Permeability of the intestinal mucosa to L-glucose was independent of the switches in diet. Levels of the brushborder glucose transporter SGLT1, brushborder fructose transporter GLUT5, and basolateral sugar transporter GLUT2 mRNA as determined by reverse transcriptase-polymerase chain reaction in 6-, 24- and 32-mo-old mice were each apparently independent of caloric restriction and age. We conclude that the high rates of intestinal nutrient uptake exhibited by chronically CR mice can be reversed by ad libitum feeding of only 1 month duration. These decreases in uptake were due mainly to specific decreases in transport per unit weight of intestine and not to nonspecific decreases in intestinal mass. Changes in rates of sugar uptake induced by chronic CR and age are apparently not accompanied by changes in steady-state levels of mRNA coding for those transporters.

J Gerontol A Biol Sci Med Sci 1997 Nov;52(6):B300-10

Effects of dehydroepiandrosterone and calorie restriction on the Bcl-2/Bax-mediated apoptotic pathway in p53-deficient mice.

Modulation of apoptosis through altered expression of Bcl-2 and/or Bax may be a mechanism by which dehydroepiandrosterone (DHEA) administration and calorie restriction (CR) exert their chemopreventive effects in p53-deficient (p53-/-) mice. Using immunohistochemical detection we found that treatment with both DHEA and CR resulted in decreased expression of the PCNA proliferation marker in the thymus. In addition, treatment with DHEA also increased the rate of apoptosis in the thymus, resulting in marked thymic atrophy. Thus, both DHEA and CR appear to shift cell number homeostasis by favoring apoptosis. To further understand the molecular mechanisms by which DHEA and CR exert their effects, we examined two components of the apoptotic pathway, Bcl-2 and Bax. We found that p53-/- mice have much higher levels of Bcl-2 mRNA in the thymus than wild-type (p53+/+) mice. Treatment of p53-/- animals with DHEA resulted in decreased Bcl-2 but not Bax mRNA levels in the thymus. In contrast, CR did not change either Bcl-2 or Bax mRNA expression. The present study provides molecular evidence that DHEA and CR may modulate tumorigenesis through alterations in the apoptotic and/or proliferative pathways.

Cancer Lett 1997 Jun 3;116(1):61-9

Calorie restriction inhibits the age-related dysregulation of the cytokines TNF-alpha and IL-6 in C3B10RF1 mice.

TNF-alpha and IL-6 are generally increased in the sera of aged humans and mice. The dysregulation of these cytokines may be critical in autoreactivity and immune dysfunction. In earlier studies we demonstrated that production of TNF-alpha and IL-6 following in vitro stimulation of peritoneal macrophages by LPS was reduced in old compared to young mice, and that dietary caloric restriction (CR) had no effect on the induction of TNF-alpha in this system. In the present study we examined the effects of age and calorie restriction on the constitutive production of both TNF-alpha and IL-6. Serum levels of both cytokines were significantly higher in old versus young mice. However, in old mice subjected to long term CR the serum levels were comparable to those of young mice. The potential involvement of normalization of TNF-alpha and IL-6 levels in the life extension effect of CR are discusse.

Mech Ageing Dev 1997 Feb;93(1-3):87-94

Effects of calorie restriction and aging on the expression of antioxidant enzymes and ubiquitin in the liver of Emory mice.

We studied the effect of age and calorie restriction on the expression of genes involved in antioxidant defenses in livers of young (4.5 to 6 months) and old (22 months) Emory mice fed a control (C) or restricted (R) diet. Specifically examined were catalase (CAT), glutathione peroxidase (Gpx), Cu/Zn and Mn superoxide dismutase (Cu/ZnSOD and MnSOD). As an indicator of oxidative damage to the tissues we measured lipid peroxidation. As indicators of oxidative stress we determined ubiquitin mRNA levels and endogenous high molecular weight (HMW) ubiquitin conjugates. Lower mRNA levels of ubiquitin (P < 0.05), CAT (P < 0.01) and Gpx (P < 0.01) were observed in tissues from young R versus C animals. The old C group had a lower CAT mRNA level (P < 0.0001) compared with young C. In the R group, age did not affect the CAT mRNA levels or Gpx mRNA levels; however, ubiquitin mRNA levels were higher (P < 0.05). No significant changes in Cu/Zn or MnSOD mRNA were observed with age or diet. Cu/ZnSOD protein levels were lower in the young R at 4.5 months (P < 0.05) than young C, and higher in the old R group versus old C (P < 0.05). CAT protein levels were higher in the old C versus old R (P < 0.05). Changes of HMW ubiquitin conjugates with age r diet were not significant. Of the four groups, the old R group showed the highest levels of lipid peroxidation.

Mech Ageing Dev 1996 Oct 25;91(2):115-29