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Genetic disruption of insulin and insulin-like signaling pathways may extend lifespan. Hyperinsulinemia and insulin resistance may accelerate aging. The hypothesis was tested that a once-a-week life-long inhibition of insulin secretion by the administration of anti-lipolytic drugs might have anti-aging effects. Groups of 3-month-old male Sprague-Dawley rats were (a) given standard laboratory food ad libitum (AL); (b) fed AL 6 days and fasted 1 day every week (FW); (c) fed AL every other day (EOD), (d) fed like FW and given Acipimox (50 mg/kg b.w.) on the day of fasting (FWA) by the gastric tube. The AL, FW and EOD groups received saline intragastrically. Treatment with ACIPIMOX transiently decreased plasma free fatty acids, glucose and insulin and increased valine plasma levels, and had no long-term effect on food consumption and body weight. By age 6, 12 and 24 months subgroups were taken and the age-related changes in liver dolichol and autophagic proteolysis—which are correlated with life-expectancy—were measured. Liver dolichol levels increased and autophagic proteolysis decreased in mature and older AL rats; EOD and FWA fully counteracted these changes; FW rats had significant but smaller beneficial effects. It is concluded that life-long weekly-repeated transient inhibition of insulin secretion by antilipolytic drugs may have an anti-aging effect, additive to the anti-aging effect of a milder caloric restriction. Speculation is that transiently lower plasma insulin levels might stimulate the anti-aging cell-repair mechanism autophagy, which has longer lasting effects on cell housekeeping. [Copyright &y& Elsevier]

Abstract: 8-Hydroxy-deoxyguanosine adducts (8-OHdG), indices of oxidative DNA damage, were measured by immunohystochemistry with diaminobenzidine detection in the brain, skeletal muscle, heart, liver, tenuum mucosa and lymphocytes from young (4 months) and aged (24 months) Sprague–Dawley rats fed ad libitum or held on two different caloric restriction diets (alternate day ad libitum feeding or daily feeding with 40% reduced calories). In the absence of caloric restriction the levels of oxidative DNA damage increased as a function of age in all tissues examined, with a maximum ∼3-fold increase being detected in the peripheral lymphocytes and the heart and a minimum ∼2-fold increase being detected in the liver and brain tissues. Caloric restriction regimens effectively reduced age-dependent increase of oxidative DNA damage in all tissues examined; in particular, the brain and small intestine did not exhibit any age-related increase of oxidative DNA damage. We propose that the levels of 8-OHdG in peripheral lymphocytes may serve a biochemical index of age-related whole organism oxidative DNA damage. Immunohistochemistry might be exploited as a rapid and simple techniques for measuring lymphocytes oxidative DNA damage in large scale studies. [Copyright &y& Elsevier]