Unique Lipoprotein Phenotype and Genotype Associated with Exceptional Longevity

Nir Barzilai, Gil Atzmon, Clyde B. Schechter, Ernst J. Schaefer, Adrienne L. Cupples, Richard B. Lipton, Suzanne Cheng, Alan R. Shuldiner

Research output: Contribution to journalArticle

441 Citations (Scopus)

Abstract

Context: Individuals with exceptional longevity have a lower incidence and/or significant delay in the onset of age-related disease, and their family members may inherit biological factors that modulate aging processes and disease susceptibility. Objective: To identify specific biological and genetic factors that are associated with or reliably define a human longevity phenotype. Design, Setting, and Participants: In a case-control design, 213 Ashkenazi Jewish probands with exceptional longevity (mean [SD] age, 98.2 [5.3] years) and their offspring (n=216; mean [SD] age, 68.3 [6.7] years) were recruited from 1998 to 2002, while an age-matched control group of Ashkenazi Jews (n=258) and participants from the Framingham Offspring Study (n=589) were accepted as control groups. Main Outcome Measures: Detailed questionnaires, physical examination, and blood samples were taken, including assessment of lipids and lipoprotein subclass levels and particle sizes by proton nuclear magnetic resonance. Samples were also genotyped for the codon 405 isoleucine to valine (I405V) variation in the cholesteryl ester transfer protein (CETP) gene, which is involved in regulation of lipoprotein and its particle sizes. Results: High-density lipoprotein (HDL) and low-density lipoprotein (LDL) particle sizes were significantly higher in probands compared with both control groups (P=.001 for both), independent of plasma levels of HDL and LDL cholesterol and apolipoprotein A1 and B. This phenotype was also typical of the proband's offspring but not of the age-matched controls. The HDL and LDL particle sizes were significantly larger in offspring and controls without hypertension or cardiovascular disease, (P=.001 and P=.008, respectively). Furthermore, lipoprotein particle sizes, but not plasma LDL levels, were significantly higher in offspring and controls without the metabolic syndrome (P<.001). Probands and offspring had a 2.9- and 3.6-fold (in men) and 2.7- and 1.5-fold (in women) increased frequency, respectively, of homozygosity for the 405 valine allele of CETP (VV genotype), respectively, compared with controls (P<.001 for both). Those probands with the VV genotype had increased lipoprotein sizes and lower serum CETP concentrations. Conclusions: Individuals with exceptional longevity and their offspring have significantly larger HDL and LDL particle sizes. This phenotype is associated with a lower prevalence of hypertension, cardiovascular disease, the metabolic syndrome, and increased homozygosity for the I405V variant in CETP. These findings suggest that lipoprotein particle sizes are heritable and promote a healthy aging phenotype.

Original languageEnglish (US)
Pages (from-to)2030-2040
Number of pages11
JournalJournal of the American Medical Association
Volume290
Issue number15
DOIs
StatePublished - Oct 15 2003

Fingerprint

Particle Size
Lipoproteins
Cholesterol Ester Transfer Proteins
Genotype
Phenotype
HDL Lipoproteins
LDL Lipoproteins
Valine
Biological Factors
Control Groups
Cardiovascular Diseases
Hypertension
Jews
Isoleucine
Apolipoprotein A-I
Disease Susceptibility
Apolipoproteins B
Age of Onset
Codon
LDL Cholesterol

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Unique Lipoprotein Phenotype and Genotype Associated with Exceptional Longevity. / Barzilai, Nir; Atzmon, Gil; Schechter, Clyde B.; Schaefer, Ernst J.; Cupples, Adrienne L.; Lipton, Richard B.; Cheng, Suzanne; Shuldiner, Alan R.

In: Journal of the American Medical Association, Vol. 290, No. 15, 15.10.2003, p. 2030-2040.

Research output: Contribution to journalArticle

Barzilai, Nir ; Atzmon, Gil ; Schechter, Clyde B. ; Schaefer, Ernst J. ; Cupples, Adrienne L. ; Lipton, Richard B. ; Cheng, Suzanne ; Shuldiner, Alan R. / Unique Lipoprotein Phenotype and Genotype Associated with Exceptional Longevity. In: Journal of the American Medical Association. 2003 ; Vol. 290, No. 15. pp. 2030-2040.
@article{74d2a9e8cceb4d4d9ee78402396062ff,
title = "Unique Lipoprotein Phenotype and Genotype Associated with Exceptional Longevity",
abstract = "Context: Individuals with exceptional longevity have a lower incidence and/or significant delay in the onset of age-related disease, and their family members may inherit biological factors that modulate aging processes and disease susceptibility. Objective: To identify specific biological and genetic factors that are associated with or reliably define a human longevity phenotype. Design, Setting, and Participants: In a case-control design, 213 Ashkenazi Jewish probands with exceptional longevity (mean [SD] age, 98.2 [5.3] years) and their offspring (n=216; mean [SD] age, 68.3 [6.7] years) were recruited from 1998 to 2002, while an age-matched control group of Ashkenazi Jews (n=258) and participants from the Framingham Offspring Study (n=589) were accepted as control groups. Main Outcome Measures: Detailed questionnaires, physical examination, and blood samples were taken, including assessment of lipids and lipoprotein subclass levels and particle sizes by proton nuclear magnetic resonance. Samples were also genotyped for the codon 405 isoleucine to valine (I405V) variation in the cholesteryl ester transfer protein (CETP) gene, which is involved in regulation of lipoprotein and its particle sizes. Results: High-density lipoprotein (HDL) and low-density lipoprotein (LDL) particle sizes were significantly higher in probands compared with both control groups (P=.001 for both), independent of plasma levels of HDL and LDL cholesterol and apolipoprotein A1 and B. This phenotype was also typical of the proband's offspring but not of the age-matched controls. The HDL and LDL particle sizes were significantly larger in offspring and controls without hypertension or cardiovascular disease, (P=.001 and P=.008, respectively). Furthermore, lipoprotein particle sizes, but not plasma LDL levels, were significantly higher in offspring and controls without the metabolic syndrome (P<.001). Probands and offspring had a 2.9- and 3.6-fold (in men) and 2.7- and 1.5-fold (in women) increased frequency, respectively, of homozygosity for the 405 valine allele of CETP (VV genotype), respectively, compared with controls (P<.001 for both). Those probands with the VV genotype had increased lipoprotein sizes and lower serum CETP concentrations. Conclusions: Individuals with exceptional longevity and their offspring have significantly larger HDL and LDL particle sizes. This phenotype is associated with a lower prevalence of hypertension, cardiovascular disease, the metabolic syndrome, and increased homozygosity for the I405V variant in CETP. These findings suggest that lipoprotein particle sizes are heritable and promote a healthy aging phenotype.",
author = "Nir Barzilai and Gil Atzmon and Schechter, {Clyde B.} and Schaefer, {Ernst J.} and Cupples, {Adrienne L.} and Lipton, {Richard B.} and Suzanne Cheng and Shuldiner, {Alan R.}",
year = "2003",
month = "10",
day = "15",
doi = "10.1001/jama.290.15.2030",
language = "English (US)",
volume = "290",
pages = "2030--2040",
journal = "JAMA - Journal of the American Medical Association",
issn = "0002-9955",
publisher = "American Medical Association",
number = "15",

}

TY - JOUR

T1 - Unique Lipoprotein Phenotype and Genotype Associated with Exceptional Longevity

AU - Barzilai, Nir

AU - Atzmon, Gil

AU - Schechter, Clyde B.

AU - Schaefer, Ernst J.

AU - Cupples, Adrienne L.

AU - Lipton, Richard B.

AU - Cheng, Suzanne

AU - Shuldiner, Alan R.

PY - 2003/10/15

Y1 - 2003/10/15

N2 - Context: Individuals with exceptional longevity have a lower incidence and/or significant delay in the onset of age-related disease, and their family members may inherit biological factors that modulate aging processes and disease susceptibility. Objective: To identify specific biological and genetic factors that are associated with or reliably define a human longevity phenotype. Design, Setting, and Participants: In a case-control design, 213 Ashkenazi Jewish probands with exceptional longevity (mean [SD] age, 98.2 [5.3] years) and their offspring (n=216; mean [SD] age, 68.3 [6.7] years) were recruited from 1998 to 2002, while an age-matched control group of Ashkenazi Jews (n=258) and participants from the Framingham Offspring Study (n=589) were accepted as control groups. Main Outcome Measures: Detailed questionnaires, physical examination, and blood samples were taken, including assessment of lipids and lipoprotein subclass levels and particle sizes by proton nuclear magnetic resonance. Samples were also genotyped for the codon 405 isoleucine to valine (I405V) variation in the cholesteryl ester transfer protein (CETP) gene, which is involved in regulation of lipoprotein and its particle sizes. Results: High-density lipoprotein (HDL) and low-density lipoprotein (LDL) particle sizes were significantly higher in probands compared with both control groups (P=.001 for both), independent of plasma levels of HDL and LDL cholesterol and apolipoprotein A1 and B. This phenotype was also typical of the proband's offspring but not of the age-matched controls. The HDL and LDL particle sizes were significantly larger in offspring and controls without hypertension or cardiovascular disease, (P=.001 and P=.008, respectively). Furthermore, lipoprotein particle sizes, but not plasma LDL levels, were significantly higher in offspring and controls without the metabolic syndrome (P<.001). Probands and offspring had a 2.9- and 3.6-fold (in men) and 2.7- and 1.5-fold (in women) increased frequency, respectively, of homozygosity for the 405 valine allele of CETP (VV genotype), respectively, compared with controls (P<.001 for both). Those probands with the VV genotype had increased lipoprotein sizes and lower serum CETP concentrations. Conclusions: Individuals with exceptional longevity and their offspring have significantly larger HDL and LDL particle sizes. This phenotype is associated with a lower prevalence of hypertension, cardiovascular disease, the metabolic syndrome, and increased homozygosity for the I405V variant in CETP. These findings suggest that lipoprotein particle sizes are heritable and promote a healthy aging phenotype.

AB - Context: Individuals with exceptional longevity have a lower incidence and/or significant delay in the onset of age-related disease, and their family members may inherit biological factors that modulate aging processes and disease susceptibility. Objective: To identify specific biological and genetic factors that are associated with or reliably define a human longevity phenotype. Design, Setting, and Participants: In a case-control design, 213 Ashkenazi Jewish probands with exceptional longevity (mean [SD] age, 98.2 [5.3] years) and their offspring (n=216; mean [SD] age, 68.3 [6.7] years) were recruited from 1998 to 2002, while an age-matched control group of Ashkenazi Jews (n=258) and participants from the Framingham Offspring Study (n=589) were accepted as control groups. Main Outcome Measures: Detailed questionnaires, physical examination, and blood samples were taken, including assessment of lipids and lipoprotein subclass levels and particle sizes by proton nuclear magnetic resonance. Samples were also genotyped for the codon 405 isoleucine to valine (I405V) variation in the cholesteryl ester transfer protein (CETP) gene, which is involved in regulation of lipoprotein and its particle sizes. Results: High-density lipoprotein (HDL) and low-density lipoprotein (LDL) particle sizes were significantly higher in probands compared with both control groups (P=.001 for both), independent of plasma levels of HDL and LDL cholesterol and apolipoprotein A1 and B. This phenotype was also typical of the proband's offspring but not of the age-matched controls. The HDL and LDL particle sizes were significantly larger in offspring and controls without hypertension or cardiovascular disease, (P=.001 and P=.008, respectively). Furthermore, lipoprotein particle sizes, but not plasma LDL levels, were significantly higher in offspring and controls without the metabolic syndrome (P<.001). Probands and offspring had a 2.9- and 3.6-fold (in men) and 2.7- and 1.5-fold (in women) increased frequency, respectively, of homozygosity for the 405 valine allele of CETP (VV genotype), respectively, compared with controls (P<.001 for both). Those probands with the VV genotype had increased lipoprotein sizes and lower serum CETP concentrations. Conclusions: Individuals with exceptional longevity and their offspring have significantly larger HDL and LDL particle sizes. This phenotype is associated with a lower prevalence of hypertension, cardiovascular disease, the metabolic syndrome, and increased homozygosity for the I405V variant in CETP. These findings suggest that lipoprotein particle sizes are heritable and promote a healthy aging phenotype.

UR - http://www.scopus.com/inward/record.url?scp=0142088521&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0142088521&partnerID=8YFLogxK

U2 - 10.1001/jama.290.15.2030

DO - 10.1001/jama.290.15.2030

M3 - Article

C2 - 14559957

AN - SCOPUS:0142088521

VL - 290

SP - 2030

EP - 2040

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0002-9955

IS - 15

ER -