Abstract

Alteration of single genes involved in nutrient and lipoprotein metabolism increases longevity in several animal models. Because exceptional longevity in humans is familial, it is likely that polymorphisms in genes favorably influence certain phenotypes and increase the likelihood of exceptional longevity. A group of Ashkenazi Jewish centenarians ( n = 213), their offspring ( n = 216), and an age-matched Ashkenazi control group ( n = 258) were genotyped for 66 polymorphisms in 36 candidate genes related to cardiovascular disease (CVD). These genes were tested for association with serum lipoprotein levels and particle sizes, apolipoprotein A1, B, and C-3 levels and with outcomes of hypertension, insulin resistance, and mortality. The prevalence of homozygosity for the −641C allele in the APOC3 promoter (rs2542052) was higher in centenarians (25%) and their offspring (20%) than in controls (10%) ( p = 0.0001 and p = 0.001, respectively). This genotype was associated with significantly lower serum levels of APOC3 and a favorable pattern of lipoprotein levels and sizes. We found a lower prevalence of hypertension and greater insulin sensitivity in the −641C homozygotes, suggesting a protective effect against CVD and the metabolic syndrome. Finally, in a prospectively studied cohort, a significant survival advantage was demonstrated in those with the favorable −641C homozygote ( p < 0.0001). Homozygosity for the APOC3 −641C allele is associated with a favorable lipoprotein profile, cardiovascular health, insulin sensitivity, and longevity. Because modulation of lipoproteins is also seen in genetically altered longevity models, it may be a common pathway influencing lifespan from nematodes to humans.

Highlights

  • Manipulation of single genes can confer longevity in lower organisms, supporting the notion that understanding pathways for exceptional longevity may be possible in humans

  • We studied 66 single nucleotide polymorphisms (SNP) in 36 candidate genes in pathways related to lipoprotein metabolism and other risk factors for cardiovascular disease (CVD)

  • Analysis of the frequency trend with age for polymorphisms in apolipoprotein C3 (APOC3) and cholesterol ester transfer protein (CETP) (Figure 1), revealed a highly significant (p, 0.0006; b 1⁄4 1.89 [95% CI, 0.2–3.6]) monotonically increasing frequency trend f or ho m oz y go s it y fo rtheA PO C3 À641 C allele (CC)(rs2542052), and near-significance (b 1⁄4 3.06 [95% CI, 0.33–5.8, p 1⁄4 0.069]) for homozygosity for the CETP codon 405 valine allele (VV)(rs5882)

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Summary

Introduction

Manipulation of single genes can confer longevity in lower organisms, supporting the notion that understanding pathways for exceptional longevity may be possible in humans. Given that the extreme old age of the probands precludes the use of a proper age-matched control group for analysis of traits that may be related to exceptional longevity, (e.g., lipoprotein levels), we recruited their offspring, many of whom presumably inherited longevity gene variants and should manifest the longevity phenotype. We reasoned that this approach would permit comparison of the offspring to agematched controls who would not be expected to be enriched

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