No abstract

Aging denotes a postmaturational deterioration of cells and organisms with the passage of time, an increased vulnerability to challenges and prevalence of age-associated diseases, and a decreased ability to survive. Causes of this deterioration may be found in an enhanced production of reactive oxygen species (ROS) and oxidative damage and incomplete "housekeeping." Caloric restriction is the most robust anti-aging intervention known so far. Similar beneficial effects on median and maximum life span were obtained by feeding animals a 40%-reduced diet or by every-other-day ad libitum feeding. In both instances, animals are forced to spend a great part of their time in a state of fasting and activated autophagy. Autophagy is a highly conserved process in eukaryotes, in which the cytoplasm, including excess or aberrant organelles, is sequestered into double-membrane vesicles and delivered to the lysosome/vacuole, for breakdown and eventual recycling of the resulting macromolecules. This process has an essential role in adaptation to fasting and changing environmental conditions, cellular remodeling during development, and accumulation of altered ROS-hypergenerating organelles in older cells. Several pieces of evidence show that autophagy is involved in aging and is an essential part of the anti-aging mechanism of caloric restriction. As an application, intensification of autophagy by the administration of an antilipolytic drug rescued older cells from accumulation of altered mtDNA in less than 6 hours. It is concluded that the pharmacologic intensification of autophagy (PISA treatment) has anti-aging effects and might prove to be a big step toward retardation of aging and prevention of age-associated diseases in humans.

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Autophagy is a process that sequesters and degrades organelles and macromolecular constituents of cytoplasm for cellular restructuring and repair and as a source of nutrients for metabolic use in early starvation. The effects of two antiaging dietary regimens (initiated in rats at the age of 2 months), namely, 40% dietary restriction (DR) and every-other-day ad-libitum feeding, that exhibited different effects on metabolism and similar effects on longevity on the age-related changes in the regulation of autophagic proteolysis were studied by monitoring the rate of valine release in the incubation medium from isolated liver cells of male albino Sprague-Dawley rats aged 2, 6, 12, 18, 24, and 27 months. (The liver cells were incubated in vitro with added amino acids and 10(-7) M insulin or glucagon.) Age-matched male albino Sprague-Dawley rats fed ad libitum served as a control. Results show that in ad-libitum-fed rats, after a transient increase by age 6 months, autophagic proteolysis and regulation by amino acid exhibit a dramatic age-related decline, and that the age-related changes are prevented by dietary antiaging intervention. A comparison shows that the protective effects of DR and every-other-day ad-libitum feeding are partially different in 24-month-old rats (but the beneficial effects of the two diets on regulation of autophagic proteolysis are always similar). With regard to endocrine regulation, results confirm that the liver cell response to glucagon (but not to insulin) declines with increasing age, and they show that antiaging DRs significantly improve the effects of glucagon (and have no effect on the response to insulin). The interactions of age by diet, glucagon (and in older rats, insulin), and amino acids are significant. It is concluded that DR significantly improves the susceptibility of liver cells to lysosomal degradation, and it prevents decline with increasing age. It is suggested that improved liver autophagy and lysosomal degradation might be part of the antiaging mechanisms of DR.

During intervals between meals, autophagy is a major source of nutrients and may remove damaged organelles and membranes. Age-related changes in the regulation of autophagic proteolysis were studied by monitoring the rate of valine release from liver cells of 2-, 6-, 12-, 18-, and 24-month-old male Sprague-Dawley rats fed ad libitum, and incubated in vitro with added amino acids and 10(-7) M of insulin or glucagon. The maximum rate of proteolysis and its maximum inhibition by amino acids were reached at 6 months and declined thereafter. In contrast, the rate of protein degradation in the presence of high concentrations of amino acids was not affected by aging. The inhibitor effect of insulin was additive to that of amino acids and was not altered significantly by age. The conclusion is that altered regulation of autophagic proteolysis decreases susceptibility of older cells to lysosomal degradation, and it may lead to the accumulation of altered organelles and membranes.