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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. [ABSTRACT FROM AUTHOR]

Comments on the article 'Is There an Antiaging Medicine?,' which was published in the 2002 issue of 'The Journals of Gerontology.' Theme of the article; Background on autophagy; Description of the treatment developed by the Pharmacological Intensification of Suppression of Aging.

8-Hydroxy-2-deoxyguanosine (8OHdG) excreted into the urine is considered a marker of oxidative stress effect on DNA, and it is reported to be mainly produced by the DNA repair system. In previous works, we showed that autophagy was also involved in 8OHdG disposal through the degradation of oxidatively altered mitochondria. Here, we show that aging in Sprague-Dawley male rats is associated with a decline in the in vitro function of liver autophagy and a slight and not significant decrease in the urinary excretion of 8OHdG. In addition, we demonstrate that anti-aging caloric restriction maintains levels of both liver autophagy and urinary excretion of 8OHdG at very high levels throughout life. Finally, we show the in vivo stimulation of autophagy by the administration of an antilipolytic agent or everolimus, which rescues rats from the accumulation of 8OHdG in the liver mtDNA, also causes a dramatic increase in the urinary excretion of 8OHdG. The intensification of autophagy by the administration of the antilipolytic drugs to fasting rats faded progressively with increasing age, together with a reduced increase in 8OHdG output into the urine. It is concluded that the process of autophagy may play a major role in the disposal of 8OHdG with urine, and that the assay of 8OHdG levels in the urine before and after the stimulation of autophagy may provide a novel, non-invasive and safe procedure to monitor the in vivo functioning of the process. [ABSTRACT FROM AUTHOR]

Autophagy is a process that sequesters and degrades altered organelles and macromolecular cytoplasmic constituents for cellular restructuring and repair, and as a source of nutrients for metabolic use in early starvation it may be involved in anti-aging mechanisms of caloric restriction. The effects of 40% daily dietary restriction (DR) and intermittent feeding (EOD) on the age-related changes in the endocrine regulation of autophagic proteolysis were studied by monitoring the rate of valine release from isolated rat liver cells. Results show that in ad libitum-fed rats sensitivity of autophagy to glucagon and insulin declines by one order of magnitude in older rats. Both DR and EOD maintain the sensitivity to glucagon at juvenile levels, whereas only EOD can fully maintain response to insulin. It is concluded that changes in the sensitivity to glucagon may have a role in the aging process. [ABSTRACT FROM AUTHOR]