Lipoprotein Genotype and Conserved Pathway for Exceptional Longevity in Humans

Atzmon, Gil; Rincon, Marielisa; Schechter, Clyde B; Shuldiner, Alan R; Lipton, Richard B.; Bergman, Aviv; Barzilai, Nir

doi:10.1371/journal.pbio.0040113

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Lipoprotein Genotype and Conserved Pathway for Exceptional Longevity in Humans

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Author(s): Gil Atzmon ¹ ^, ² , Marielisa Rincon ³ , Clyde B Schechter ² ^, ⁴ ^, ⁶ , Alan R Shuldiner ⁸ , Richard B Lipton ¹ ^, ⁵ ^, ⁶ , Aviv Bergman ⁷ , Nir Barzilai ¹ ^, ² ^,

Editor(s): Simon Melov

Publication date (Electronic): 4 April 2006

Journal: PLoS Biology

Publisher: Public Library of Science

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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.

Abstract

An allele of apolipoprotein C3 (which regulates lipoprotein metabolism) is more prevalent in centenarian humans than controls. This genotype is associated with a favorable lipoprotein profile, cardiovascular health, insulin sensitivity, and longevity.

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Most cited references 43

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Banting lecture 1988. Role of insulin resistance in human disease.

G M Reaven (1988)

Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in approximately 25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the beta-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration. Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulin-stimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one.(ABSTRACT TRUNCATED AT 400 WORDS)

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A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.

Y Miki, J. Swensen, D Shattuck-Eidens … (1994)

A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods. Probable predisposing mutations have been detected in five of eight kindreds presumed to segregate BRCA1 susceptibility alleles. The mutations include an 11-base pair deletion, a 1-base pair insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. The BRCA1 gene is expressed in numerous tissues, including breast and ovary, and encodes a predicted protein of 1863 amino acids. This protein contains a zinc finger domain in its amino-terminal region, but is otherwise unrelated to previously described proteins. Identification of BRCA1 should facilitate early diagnosis of breast and ovarian cancer susceptibility in some individuals as well as a better understanding of breast cancer biology.

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The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews.

Jeffery P Struewing, Patricia Hartge, Sholom Wacholder … (1997)

Carriers of germ-line mutations in BRCA1 and BRCA2 from families at high risk for cancer have been estimated to have an 85 percent risk of breast cancer. Since the combined frequency of BRCA1 and BRCA2 mutations exceeds 2 percent among Ashkenazi Jews, we were able to estimate the risk of cancer in a large group of Jewish men and women from the Washington, D.C., area. We collected blood samples from 5318 Jewish subjects who had filled out epidemiologic questionnaires. Carriers of the 185delAG and 5382insC mutations in BRCA1 and the 6174delT mutation in BRCA2 were identified with assays based on the polymerase chain reaction. We estimated the risks of breast and other cancers by comparing the cancer histories of relatives of carriers of the mutations and noncarriers. One hundred twenty carriers of a BRCA1 or BRCA2 mutation were identified. By the age of 70, the estimated risk of breast cancer among carriers was 56 percent (95 percent confidence interval, 40 to 73 percent); of ovarian cancer, 16 percent (95 percent confidence interval, 6 to 28 percent); and of prostate cancer, 16 percent (95 percent confidence interval, 4 to 30 percent). There were no significant differences in the risk of breast cancer between carriers of BRCA1 mutations and carriers of BRCA2 mutations, and the incidence of colon cancer among the relatives of carriers was not elevated. Over 2 percent of Ashkenazi Jews carry mutations in BRCA1 or BRCA2 that confer increased risks of breast, ovarian, and prostate cancer. The risks of breast cancer may be overestimated, but they fall well below previous estimates based on subjects from high-risk families.

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Author and article information

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: Role: Academic Editor

Journal

Journal ID (nlm-ta): PLoS Biol

Journal ID (publisher-id): pbio

Title: PLoS Biology

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Print): 1544-9173

ISSN (Electronic): 1545-7885

Publication date (Print): April 2006

Publication date (Electronic): 4 April 2006

Volume: 4

Issue: 4

Electronic Location Identifier: e113

Affiliations

[1] 1Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York, United States of America

[2] 2Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York, United States of America

[3] 3Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, United States of America

[4] 4Department of Family and Social Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America

[5] 5Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, United States of America

[6] 6Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, United States of America

[7] 7Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America

[8] 8University of Maryland School of Medicine, and the Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, Maryland, United States of America

Buck Institute United States of America

Article

DOI: 10.1371/journal.pbio.0040113

PMC ID: 1413567

PubMed ID: 16602826

SO-VID: cd34b82b-abb4-4fef-967d-fbfbe638fbb8

Copyright © 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.

Lipoprotein Genotype and Conserved Pathway for Exceptional Longevity in Humans

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Most cited references 43

Banting lecture 1988. Role of insulin resistance in human disease.

A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.

The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews.

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