Mortality and Cholesterol Metabolism in Subjects Aged 75 Years and Older: The Helsinki Businessmen Study.

BACKGROUND/OBJECTIVES: In many studies, low serum cholesterol is paradoxically associated with a higher mortality risk among older adults. Therefore, we studied whole-body cholesterol metabolism and its role in all-cause mortality of older men in two subcohorts of different ages. DESIGN: Prospective long-term cohort. SETTING: Home-dwelling men of the Helsinki Businessmen Study. PARTICIPANTS: Two partly overlapping subcohorts were recruited, in 2003 (n = 660; mean age = 76 years) and in 2011 (n = 398; mean age = 83 years). The younger subcohort was followed up after 3 and 11 years, and the older subcohort was followed up after 3 years. MEASUREMENTS: Cholesterol metabolism was assessed via serum noncholesterol sterol-cholesterol ratios, and quantification was performed by gas-liquid chromatography with flame ionization detection. All statistical analyses were performed with age and statin treatment as covariates. RESULTS: At the end of the 3-year follow-up, 10% of the younger and 13% of the older subcohort had died; and at the end of the 11-year follow-up, 40% of the younger subcohort had died. Serum total and low-density lipoprotein (LDL) cholesterol and cholesterol precursors reflecting cholesterol synthesis were lower in the older than in the younger subcohort (P < .001 for all). In the older subcohort, low serum campesterol and sitosterol, reflecting decreased cholesterol absorption efficiency, predicted all-cause mortality (P < .05). This was supported by a trend toward low serum campesterol and sitosterol predicting mortality (P = .088 and P = .079, respectively) in the younger subcohort after 11 years. Cholesterol synthesis did not predict mortality, but in the older subcohort, decreased cholesterol absorption was less efficiently compensated for by decreased cholesterol synthesis. CONCLUSIONS: Low cholesterol absorption efficiency predicted all-cause mortality, especially in men aged 83 years on average, and cholesterol synthesis was lowered. These metabolic changes could contribute to the lowering of serum total and LDL-cholesterol in older men. J Am Geriatr Soc 68:281-287, 2020.

Serum noncholesterol sterols in Alzheimer's disease: the Helsinki Businessmen Study.

Cerebral cholesterol metabolism is perturbed in late-onset Alzheimer's disease (AD), but whether also the extracerebral cholesterol metabolism is perturbed is not known. Thus, we studied whole-body cholesterol synthesis and absorption with serum noncholesterol sterols in men without AD (n = 114) or with (n = 18) "pure" AD (no concomitant atherosclerotic cardiovascular disease) in a long-term cohort (the Helsinki Businessmen Study) of home-dwelling older men without lipid-lowering drugs and on their habitual home diet. Serum lipids did not differ between AD and controls, but age was higher (78 ± 1 vs 74 ± 0.3 years, mean ± standard error, P < 0.001), age-adjusted plasma glucose concentration was lower (4.8 ± 0.3 vs 5.7 ± 0.1 mmol/L, P = 0.011), and APOE ε4 allele and frailty were more frequent in AD than in controls. Of the age and frailty-adjusted serum noncholesterol sterols desmosterol and lathosterol ratios to cholesterol reflecting cholesterol synthesis were lower in AD than in controls (eg, lathosterol 114 ± 12 vs 137 ± 5 102 µmol/mmol cholesterol, P = 0.004). Cholestanol ratio to cholesterol was higher in AD than in controls suggesting increased cholesterol absorption. lathosterol/sitosteroll ratio reflecting cholesterol metabolism was lower in AD than in controls (0.95 ± 0.28 vs 1.52 ± 0.11 102 µmol/mmol cholesterol, P = 0.027). In AD, plasma glucose correlated negatively with cholesterol synthesis, whereas in controls the correlation was positive. In conclusion, extracerebral cholesterol metabolism was altered in AD. This finding along with the low plasma glucose concentration and its paradoxical interaction with cholesterol synthesis opens new perspectives in the regulation of cholesterol metabolism and glucose homeostasis in AD.

Determining the mechanisms of dietary turnip rapeseed oil on cholesterol metabolism in men with metabolic syndrome.

We have earlier reported the reduction of total cholesterol, low-density lipoprotein (LDL) cholesterol and oxidized LDL caused by short-term modification of diet with cold-pressed turnip rapeseed oil (CPTRO) instead of butter. The aim of this supplementary study was to determine whether the beneficial effects resulted from altered cholesterol metabolism during the intervention.Thirty-seven men with metabolic syndrome (MetS) completed an open, randomized and balanced crossover study. Subjects' usual diet was supplemented with either 37.5 g of butter or 35 mL of CPTRO for 6-8 weeks. Otherwise normal dietary habits and physical activity were maintained without major variations. Serum non-cholesterol sterols were assayed with gas-liquid chromatography and used as surrogate markers of whole-body cholesterol synthesis and absorption efficiency. Serum proprotein convertase subtilisin/kexin type 9 (PCSK9) concentration was analyzed with Quantikine ELISA Immunoassay. Serum cholesterol synthesis markers and serum cholestanol (absorption marker), all as ratios to cholesterol, did not differ between the periods. Serum campesterol and sitosterol ratios to cholesterol were significantly increased after the administration of CPTRO resulting from the increased intake of 217 mg/day of plant sterols in CPTRO. Serum PCSK9 concentration did not differ between CPTRO and butter periods.The reduction in serum cholesterol by 7.2% after consumption of rapeseed oil could not be explained by changes in cholesterol absorption, synthesis or PCSK9 metabolism in MetS.ClinicalTrials.gov NCT01119690.

Cholesterol metabolism and non-cholesterol sterol distribution in lipoproteins of type 1 diabetes: the effect of improved glycemic control.

In type 1 diabetes, the ratios to cholesterol of serum absorption markers, e.g., cholestanol, are elevated and those of synthesis markers, e.g., lathosterol, are reduced suggesting perturbed cholesterol metabolism. We studied 17 subjects with type 1 diabetes in poor glycemic control at baseline to assess whether improvement of glycemic control affects lathosterol and cholestanol ratios to cholesterol and their distribution in lipoproteins. Cholesterol and the non-cholesterol sterols were assayed directly from serum, and free and ester fractions after thin-layer chromatographic separation of lipoprotein sterols with gas-liquid chromatography. After the 2-6 months follow-up, the mean value of HbA1(c) decreased from 10.8% to 8.6% (p=0.001). Even though the concentrations of serum and lipoprotein cholesterol remained unchanged, the serum lathosterol to cholesterol ratio increased by 28% (p<0.05) and the lathosterol/cholestanol proportion by 23% (p<0.05). The ratios of total and esterified lathosterol to cholesterol in serum, chylomicrons and LDL, and free lathosterol to cholesterol in serum and IDL, were negatively associated with HbA1(c) at baseline and after follow-up, suggesting that the better glycemic control, the higher was cholesterol synthesis. The absorption markers were less consistently associated with HbA1(c). About half of the serum lathosterol and cholestanol was carried in LDL and one-fourth to one-fifth in HDL, but the lathosterol ratios were roughly similar in all lipoproteins. In contrast, cholestanol accumulated in chylomicrons and HDL. Glycemic control did not affect the distributions of lathosterol and cholestanol. In conclusion, improvement in glycemic control increased cholesterol synthesis, but had no effect on cholesterol absorption as measured by the serum or lipoprotein cholestanol to cholesterol ratio. From a clinical point of view, the better the glycemic control, the more antiatherogenic cholesterol metabolism may be in type 1 diabetes.