Towards an understanding of the anti-aging mechanism of caloric restriction.

Accumulation of oxidatively altered cell components may play a role in the age-related cell deterioration and associated diseases. Caloric restriction is the most robust anti-aging intervention that extends lifespan and retards the appearance of age-associated diseases. Autophagy is a highly conserved cell-repair process in which the cytoplasm, including excess or aberrant organelles, is sequestered into double-membrane vesicles and delivered to the degradative vacuoles.

The role of autophagy in aging: its essential part in the anti-aging mechanism of caloric restriction.

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.

3-Hydroxy-3-methylglutaryl coenzyme A reductase deregulation and age-related hypercholesterolemia: a new role for ROS.

The microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR) is the rate-limiting enzyme in cholesterol synthesis and is highly regulated by a variety of factors. We have recently reported increased reductase activity during ageing, attributed to a higher activation state and impaired degradation of the hepatic enzyme. One of the widely recognized causes of age-related metabolic modifications is the large increase of reactive oxygen species (ROS).

Accumulation of dolichol in older tissues satisfies the proposed criteria to be qualified a biomarker of aging.

Criteria for defining biomarkers have been suggested. Accumulation of dolichol in tissues of older animals meets the following criteria: (a) levels of dolichol exhibit a quantitative correlation with age in all tissues and are not altered by several age-dependent diseases in the same direction as that of aging; (b) accumulation is not secondary to metabolic changes of aging and is altered appropriately by factors that modulate the aging rate like caloric restriction and physical exercise; (c) biomarker is applicable to different tissues across mammalian species, including humans, and to trisomy 21 and its hypothalamic digoxin-mediated model. Reliable changes in tissue dolichol levels are seen in relatively short intervals of time compared to over a life span, and levels can be tested on a small amount of tissue without causing death of the animal.

Mechanisms underlying the impaired regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in aged rat liver.

As the main risk factor for cardiovascular disease, hypercholesterolemia is one of the most studied age-related metabolic alterations. In the liver, cholesterol homeostasis is strictly regulated through the modulation of the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), the key enzyme of cholesterol biosynthesis. With ageing, hepatic HMG-CoA reductase becomes completely activated and cholesterol content increases in the blood.