Age-associated alterations in cholesterol homeostasis: evidence from a cross-sectional study in a Northern Italy population

Abstract

BackgroundThe modifications of cholesterol metabolism associated with aging are ill-defined. The objective of this study was to define age-associated alterations of the different metabolic pathways controlling cholesterol homeostasis by analyzing circulating sterols.MethodsWe analyzed serum samples collected from 201 adult (75 male, 126 female) subjects within the epidemiological MICOL study (Multicentrica Italiana Colelitiasi). The age range was 38–79 years; 103 had evidence of gallstones. The concentrations of the different sterols, recognized as markers of the main pathways of cholesterol homeostasis, were analyzed by gas chromatography-mass spectrometry, including lathosterol (synthesis), campesterol and sitosterol (absorption), and 7α-hydroxy-4-cholesten-3-one (degradation to bile acids).ResultsA significant direct correlation was detected between age and cholesterol levels (r =0.34, P<0.01). The lathosterol/cholesterol ratio was lower in older age quartiles (P<0.05 by analysis of variance), with an inverse correlation between the lathosterol/cholesterol ratio and age (r=−0.32, P<0.01). Such correlation was particularly evident in females. The campesterol/cholesterol and sitosterol/cholesterol ratios were inversely correlated with aging in control, but not in gallstone patients. The levels of 7α-hydroxy-4-cholesten-3-one were not correlated with age.ConclusionThese data show a reduction of cholesterol synthesis with aging which is associated with increased circulating cholesterol levels. The finding might be related to a reduced metabolic need for cholesterol in advancing age, leading to a downregulation of the main mechanisms of cholesterol intake in the liver. A different age-related behavior was observed in gallstone-free versus gallstone patients regarding cholesterol absorption. The possible implications in terms of the pharmacological management of hypercholesterolemia in the elderly remain to be defined.

Biochemical Alterations during the Obese-Aging Process in Female and Male Monosodium Glutamate (MSG)-Treated Mice

“…It is important to mention that aging’s effect on cholesterol homeostasis is poorly defined. A number of epidemiological studies suggest that serum cholesterol levels tend to increase in adults, but subsequently decrease in the very elderly [43]. Similarly, it has been found that obese young and older patients showed significantly higher cholesterol and TG plasma levels compared with their control age matched groups [44].…”

Management of high cholesterol levels in older people

“…Data in humans largely derive from the analysis of plasma levels of hydroxylated sterols, which are currently regarded as reliable markers of cholesterol absorption efficiency, such as sitosterol and campesterol. The ratios of sitosterol to cholesterol and campesterol to cholesterol were found to be either unaffected or reduced with aging; therefore, it seems unlikely that changes in intestinal absorption might underlie the observed increase in plasma cholesterol.…”

“…In humans, circulating levels of biosynthetic precursors of cholesterol, in particular the lathosterol to cholesterol ratio, were utilized as markers of cholesterol synthesis. The evidence in the literature is conflicting, bringing either evidence of a reduction of synthesis markers or no change with aging. Once again, the changes in this metabolic process tend to be less pronounced in the oldest strata.…”

“…Data in humans, mainly obtained in vivo , have shown a reduced degradation of cholesterol to bile acids, possibly mediated by alterations in the hepatic expression of cholesterol 7α‐hydroxylase, the limiting enzyme, and of its transcriptional coactivators . Evidence on the circulating levels of 7α‐hydroxylated precursors has not always been consistent with this view, perhaps due to different patient settings …”

Role of diet on non-alcoholic fatty liver disease: An updated narrative review

“…Finally, production of free oxygen radicals is generated by the cytochrome P450 4A and 2E1 isoenzymes-lypoxygenases [12] . Age-related data even though still undefined might reveal some connection of alterations in cholesterol synthesis in patients with NAFLD [13] . Finally this lipid peroxidation leads to the release of malondial-dehyde and 4-hydroxynonenal, which causes cell death and protein cross-linkage, resulting in the formation of Mallory's hyaline in the hepatocyte [14] .…”