The Role of Autophagy in Aging

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.

Autophagy-Derived Alzheimer’s Pathogenesis

“…Therefore it is reasonable to propose that the autophagylysosomal machinery likely shifts from a functional and protective status to a pathological and deleterious status during brain aging. Consistent with this, autophagic function is known to decline with age (Bergamini et al, 2007). Taken together, either brain aging or Aβ 1-42 proteotoxicity contributes to the chronic deterioration of the neuronal autophagylysosomal system.…”

Autophagy: Regulation and role in disease

“…289 Because autophagy, which declines with age, 290,291 can eliminate damaged intracellular structures, including mitochondria, it is not surprising that activating autophagy can increase longevity. Indeed, the ability of calorie restriction to increase longevity may be due not only to decreased ROS production because of diminished pressure on the respiratory chain but also to activation of autophagy, 288,292 particularly of mitochondria. 293 Direct evidence that maintaining appropriate autophagic activity throughout the life span slows down the functional organ failure associated with aging was provided by recent experiments with transgenic mice encoding Lamp-2A that was expressed in the liver only.…”

Diet, Autophagy, and Cancer: A Review

“…In vitro data and a limited number of animal studies suggest that the mechanism by which caloric restriction may extend the life span is by stimulating autophagy along with reducing insulin and glucose levels and decreasing growth hormone-insulin-like growth factor-I axis signaling (157,158). In this regard, ketone bodies (such as h-hydroxybutyrate), which are elevated during prolonged starvation in humans, have been shown to induce autophagy (159).…”