Lipoprotein Genotype and Conserved Pathway for Exceptional Longevity in Humans

1,2[ 3[ 2,4,6 8 1,5,6 7 Atzmon , Marielisa Rincon , Clyde B. Schechter , Alan R. Shuldiner , Richard B. Lipton , Aviv Bergman , 1,2* Barzilai

1 Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York, United States of America, 2 Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York, United States of America, 3 Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, United States of America, 4 Department of Family and Social Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America, 5 Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, United States of America, 6 Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, United States of America, 7 Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America, 8 University of Maryland School of Medicine, and the Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, Maryland, United States of America

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 ¼ 213), their offspring (n ¼ 216), and an age-matched Ashkenazi control group (n ¼ 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 (cid:1)641C allele in the APOC3 promoter (rs2542052) was higher in centenarians (25%) and their offspring (20%) than in controls (10%) (p¼ 0.0001 and p¼0.001, 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(cid:1)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(cid:1)641C homozygote (p , 0.0001). Homozygosity for the APOC3 (cid:1)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.

Citation: Atzmon G, Rincon M, Schechter CB, Shuldiner AR, Lipton RB, et al. (2006) Lipoprotein genotype and conserved pathway for exceptional longevity in humans. PLoS Biol 4(4): e113.

Citation: Atzmon G, Rincon M, Schechter CB, Shuldiner AR, Lipton RB, et al. (2006) Lipoprotein genotype and conserved pathway for exceptional longevity in humans. PLoS

increases the likelihood of survival. Here we test if poly- morphisms in certain candidate genes are significantly more frequent in centenarians than in younger participants. 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 also recruited their offspring, many of whom presumably inherited longevity gene variants and thus should also manifest the longevity phenotype. We reasoned that this approach would permit comparison of the offspring to age- matched controls who would not be expected to be enriched

Introduction

Manipulation of single genes can confer longevity in lower organisms, supporting the notion that understanding path- ways for exceptional longevity may be possible in humans. Because the contribution of genetics to lifespan is estimated to be only ;20%, a way to enhance the odds of identifying genetic factors is to study those with very exceptional survival [1]. Favorable modulation of aging processes and disease susceptibility is strongly inherited in families with excep- tional longevity [2,3]. Current centenarians have survived to more than double their life expectancy at birth, and have often been spared from age-related diseases, specifically cardiovascular disease (CVD), Alzheimer disease, diabetes mellitus (DM), and cancer [4]. Furthermore, evidence suggests that the offspring of centenarians may inherit protection against major causes of mortality, because they have approximately 50% lower prevalence of these major diseases than control groups [5].

DOI: 10.1371/journal.pbio.0040113

Copyright:  2006 Atzmon et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Because of the strong heritability of this survival we began a search for gene variants that could explain extended life of centenarians and their families among genetically homogeneous population of Ashkenazi Crucial to our approach is the knowledge that only survives to 100 y, while the average lifespan in the US is y. Thus, enrichment in the frequency of certain gene at extreme old age probably reflects a selection effect