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Caloric restriction (CR) retards diseases and aging in laboratory rodents and is now being tested in nonhuman primates. One way to apply these findings to human health is to identify and test agents that may mimic critical actions of CR. Panel 2 focused on two outcomes of CR, reduction of oxidative stress and improved glucoregulation, for which candidate metabolic mimics exist. It was recommended that studies on oxidative stress should emphasize mitochondrial function and to test the efficacy of nitrone and other antioxidants in mimicking CR's effects. Studies should also focus on the long-term effects of compounds known to lower circulating glucose and insulin concentrations or to increase insulin sensitivity. Also, four other developing areas were identified: intermediary metabolism, response to infection, stress responses, and source of dietary fat. These areas are important because either they hold promise for the discovery of new mimetics or they need to be explored prior to initiation of CR trials in humans. Other recommendations were that transgenic approaches and adult-onset CR should be emphasized in future studies. [ABSTRACT FROM AUTHOR]

Long-term caloric restriction (CR) retards aging processes and increases maximum life span. We investigated the influence of CR on mitochondrial proton leaks in rat skeletal muscle. Because CR lowers oxidative damage to mitochondrial membrane lipids and proteins, we hypothesized that leak would be lower in mitochondria from old CR rats than in age-matched controls. Three groups (n = 12) were studied: 4-month-old "young" control rats (body weight: 404 g +/- 7 SEM), 33-month-old CR rats (body weight: 262 g +/- 3), and 33-month-old control rats (body weight: 446 g +/- 5). CR rats received 67% of the energy intake of old control rats, with adequate intakes of all essential nutrients. Maximum leak-dependent O2 consumption (State 4) was 23% lower in CR rats than in age-matched controls, whereas protonmotive force values were similar, supporting our hypothesis. The overall kinetics of leak were similar between the two groups of old rats; in the young, kinetics indicated higher protonmotive force values. The latter indication is consistent with aging-induced alterations in proton leak kinetics that are independent of dietary intervention. There was no influence of age or diet on serum T4 level, whereas T3 was lower in young than in old control rats. These results support and extend the oxidative stress hypothesis of aging. [ABSTRACT FROM AUTHOR]

Caloric restriction (CR), which increases longevity and retards age-associated diseases in laboratory rodents, is being evaluated in nonhuman primate trials. CR reduces oxidative stress in rodents and appears to improve risk factors for cardiovascular disease in nonhuman primates. We tested the hypothesis that low-density lipoprotein (LDL) oxidizability is reduced in two monkey species (rhesus and cynomolgus) subjected to chronic CR. In both species, no significant differences occurred between CR and control animals on total, LDL, or high-density lipoprotein (HDL) cholesterol. In rhesus monkeys, triglycerides were higher in controls than CR (139 +/- 23 vs 66 +/- 8 mg/dl,p < .01, respectively). LDL from CR rhesus monkeys was reduced in triglyceride content and molecular weight compared to controls, whereas LDL composition in cynomolgus monkeys was similar in CR and control animals. In keeping with minor deviations in lipids, antioxidants, and LDL composition, no consistent differences in in vitro LDL oxidizability were apparent between CR and controls in either species. [ABSTRACT FROM AUTHOR]

Caloric restriction (CR) has been shown to retard aging processes in many species. We investigated effects of CR on plasma low density lipoproteins (LDL), a major risk factor for the age-associated process of atherosclerosis. Studies emphasized effects of CR on LDL composition and their interaction with arterial proteoglycans (PG). Rhesus monkeys were fed a control diet (n=13) or subjected to CR (n=12 fed 30% less calories) for > 5 years. Plasma LDL cholesterol concentrations were similar for control and CR groups (82+/-8 vs 72+/-6 mg/dL, mean+/-SEM). LDL was isolated by ultracentrifugation and HPLC. LDL particles from CR animals had a lower molecular weight (2.9+/-0.1 vs 3.2+/-0.1 g/micromol, p < .05) and were depleted in triglyceride (249+/-16 vs 433+/-49 mol/particle, p < .005) and phospholipid (686+/-20 vs 837+/-33 mol/particle, p <.001). Lower PG binding was measured for LDL from CR animals (10.1+/-0.8 vs 15.6+/-1.1 microg LDL cholesterol/microg PG, p <.005). This was associated with the lower triglycerides (r=.76, p < .0005) and phospholipids (r=.48, p < .01). Thus, a dietary intervention which may retard aging inhibits a proposed mechanism of atherogenesis. [ABSTRACT FROM AUTHOR]

Caloric and fat intake may have important skeletal consequences. To evaluate this possibility, skeletal effects of adult-onset caloric restriction (CR) at differing fat intakes were assessed in male Lobund-Wistar rats. At age 17 months, two groups of animals received an anti-obesity diet, restricted approximately 35% from individual ad libitum baseline calorie consumption, and two groups received a diet approximately 50% restricted. Dietary fat concentrations were 5, 15, 15, and 25% by weight, respectively. At ages 20, 24, 28, 30, and 32 months, ex vivo femoral bone densitometry and serum biochemical analyses were performed. Body weight (BW) decreased with time on CR in each group (p < .005), declining faster at the more severe restriction (p = .001). Femoral bone mineral contents (BMC) were also reduced. After adjusting for bone area and BW differences among groups, the only significant difference was a reduction in distal femur BMC in the 25% fat group subjected to more severe CR (p = .02). No differences were observed in serum parathyroid hormone, calcium, phosphorus, or creatinine. Femoral bone loss occurred with CR. This was entirely accounted for by reduction in BW. Higher dietary fat content did not affect BW in CR animals, but did result in lower distal femur BMC. [ABSTRACT FROM AUTHOR]

Dietary restriction (DR) has emerged as a major paradigm in experimental gerontology. The effects of DR on rodents are numerous and include reduced rates of immunologic aging, delayed morbidity, and increases in longevity. The effects of DR on primate species remain largely unknown. We began a randomized trial of long-term, adult-onset DR in rhesus monkeys (Macaca mulatta) in 1989. This report describes some early differences in immunologic function after two to four years of DR. Peripheral blood mononuclear cells were studied for mitogen-induced proliferation, natural killer (NK) cell lysis, and expression of cell surface antigens. Antibody response to influenza vaccine and the number of peripheral blood lymphocytes were also measured. Unexpectedly, concanavalin A and pokeweed mitogen response measures were reduced in restricted monkeys compared to controls (p < or = .01). NK activity and antibody responses were also reduced (p < .05). Neither cell surface antigens nor peripheral blood lymphocyte counts appear affected by DR thus far. [ABSTRACT FROM AUTHOR]