Age-related changes of isoprenoid biosynthesis in rat liver and brain.

The physiological role of dolichol is not yet known but its accumulation in several tissues has been extensively reported in various physiological states or pathological conditions. Increased dolichol concentration in mammalian tissues during ageing has been also reported; in particular, we have previously indicated dolichol accumulation in liver as a new biomarker of ageing. However, the mechanism and the role of this accumulation is unknown. The aim of this work was to study the mechanism of the age-dependent dolichol accumulation analysing, in the liver and in the brain, the activity of the rate-limiting enzyme of isoprenoid biosynthesis, the 3-hydroxy 3-methylglutaryl CoA reductase, the dolichol and cholesterol synthesis on aged rats both fed ad libitum and caloric restricted. Furthermore, the dolichol and cholesterol levels in the plasma were assayed. The data shows that during ageing, the tissue dolichol accumulation is connected with the increase of 3-hydroxy 3-methylglutaryl CoA reductase activity and only in liver affected by diet restriction. In addition the aged rats maintain the capability to regulate their tissue cholesterol content by modifying cholesterol delivery into the blood. The amount of the 3-hydroxy 3-methylglutaryl CoA reductase enzyme detectable in liver and brain by Western blot analysis does not show significant changes during ageing. The presented data show that the accumulation of dolichol is related to the loss of enzymatic regulation characteristic of ageing. In fact, a higher mevalonate availability deriving from an increased expressed activity of HMGCoA-R could cause an increased production of dolichol.