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Phenotypes and genotypes of high density lipoprotein cholesterol in exceptional longevity.

ABSTRACT: A change in the lipoprotein profile is a metabolic hallmark of aging and has been the target for modern medical developments. Although pharmaceutical interventions aimed at lipid lowering substantially decrease the risk of cardiovascular disease, they have much less impact on mortality and longevity. Moreover, they have not affected death from other age-related diseases. In this review we focus on high density lipoprotein (HDL) cholesterol, the levels of which are either elevated or do not decrease as would be expected with aging in centenarians, and which are associated with lower prevalence of numerous age-related diseases; thereby, suggesting a potential HDL-mediated mechanism for extended survival. We also provide an update on the progress of identifying longevity-mediating lipid genes, describe approaches to discover longevity genes, and discuss possible limitations. Implicating lipid genes in exceptional longevity may lead to drug therapies that prevent several age-related diseases, with such efforts already on the way.

SUBMITTER: Milman S

PROVIDER: S-EPMC4087084 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Phenotypes and genotypes of high density lipoprotein cholesterol in exceptional longevity.

Milman Sofiya S Atzmon Gil G Crandall Jill J Barzilai Nir N

Current vascular pharmacology 20140101 5

A change in the lipoprotein profile is a metabolic hallmark of aging and has been the target for modern medical developments. Although pharmaceutical interventions aimed at lipid lowering substantially decrease the risk of cardiovascular disease, they have much less impact on mortality and longevity. Moreover, they have not affected death from other age-related diseases. In this review we focus on high density lipoprotein (HDL) cholesterol, the levels of which are either elevated or do not decre ...[more]

PMID: 24350928

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Project description:Adipose harbors a large depot of free cholesterol. However, a role for adipose in cholesterol lipidation of high-density lipoprotein (HDL) in vivo is not established. We present the first evidence that adipocytes support transfer of cholesterol to HDL in vivo as well as in vitro and implicate ATP-binding cassette subfamily A member 1 (ABCA1) and scavenger receptor class B type I (SR-BI), but not ATP-binding cassette subfamily G member 1 (ABCG1), cholesterol transporters in this process.Cholesterol efflux from wild-type, ABCA1(-/-), SR-BI(-/-), and ABCG1(-/-) adipocytes to apolipoprotein A-I (apoA-I) and HDL3 were measured in vitro. 3T3L1 adipocytes, labeled with (3)H-cholesterol, were injected intraperitoneally into wild-type, apoA-I transgenic, and apoA-I(-/-) mice, and tracer movement onto plasma HDL was monitored. Identical studies were performed with labeled wild-type, ABCA1(-/-), or SR-BI(-/-) mouse embryonic fibroblast adipocytes. The effect of tumor necrosis factor-alpha on transporter expression and cholesterol efflux was monitored during adipocyte differentiation. Cholesterol efflux to apoA-I and HDL3 was impaired in ABCA1(-/-) and SR-BI(-/-) adipocytes, respectively, with no effect observed in ABCG1(-/-) adipocytes. Intraperitoneal injection of labeled 3T3L1 adipocytes resulted in increased HDL-associated (3)H-cholesterol in apoA-I transgenic mice but reduced levels in apoA-I(-/-) animals. Intraperitoneal injection of labeled ABCA1(-/-) or SR-BI(-/-) adipocytes reduced plasma counts relative to their respective controls. Tumor necrosis factor-alpha reduced both ABCA1 and SR-BI expression and impaired cholesterol efflux from partially differentiated adipocytes.These data suggest a novel metabolic function of adipocytes in promoting cholesterol transfer to HDL in vivo and implicate adipocyte SR-BI and ABCA1, but not ABCG1, in this process. Furthermore, adipocyte modulation of HDL may be impaired in adipose inflammatory disease states such as type 2 diabetes mellitus.

Project description:Background and objectiveKlotho is a protein that is closely related to human aging. Soluble Klotho (S-Klotho) is a circulating protein, and its level decreases in response to systemic inflammation. The relationship between the platelet/high-density lipoprotein cholesterol ratio (PHR), an emerging inflammatory index, and S-Klotho concentrations is still unclear. In addition, the mean platelet volume has been confirmed to have a significant negative association with S-Klotho concentrations, but the relationship between the platelet count (PC) and S-Klotho concentrations has not yet been reported.MethodsData from individuals who participated in the National Health and Nutrition Examination Survey (NHANES) during the five cycles from 2007 to 2016 were retrieved for analysis. Linear regression, two-piecewise linear regression, and restricted cubic spline (RCS) methods were used to analyze the associations of the PHR index and its components with S-Klotho concentrations. In addition, subgroup analysis and effect modification tests were conducted.ResultsA total of 11,123 participants (5463 men (48.17%)), with an average age of 56.2 years, were included. After full adjustment, the S-Klotho levels of participants in the highest quartile group of PHR (β: -51.19, 95% CI: -75.41 to -26.97, P < 0.001) and the highest quartile group of PC (β: -72.34, 95% CI: -93.32 to -51.37, P < 0.0001) were significantly lower than those in their respective lowest quartile groups, and a significant downward trend was presented among the four groups (P for trend < 0.05, respectively). However, high-density lipoprotein cholesterol (HDL-C) concentrations were not significantly associated with S-Klotho concentrations. RCS revealed that the PHR and PC were nonlinearly associated with S-Klotho concentrations; two-piecewise linear regression revealed that the inflection points were 175.269 and 152, respectively, and that these associations slightly weakened after the inflection point. According to the subgroup analysis, liver disease status enhanced the association between the PC and S-Klotho concentrations.ConclusionsBoth the PHR and PC were significantly negatively associated with S-Klotho concentrations, and these associations were nonlinear. There was no significant association between HDL-C and S-Klotho concentrations. Liver disease status enhances the negative association between the PC and S-Klotho concentrations, and the specific mechanism deserves further exploration.

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Phenotypes and genotypes of high density lipoprotein cholesterol in exceptional longevity.

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Phenotypes and genotypes of high density lipoprotein cholesterol in exceptional longevity.

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