Unique Lipoprotein Phenotype and Genotype Associated With Exceptional Longevity

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 suscep-

Design, Setting, and Participants In a case-control design, 213 Ashkenazi Jew- ish 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 trans- fer protein (CETP) gene, which is involved in regulation of lipoprotein and its particle

gevity have been generally spared from major age-related diseases that are responsible for most deaths in elderly persons, such as cardiovascu- lar disease (CVD), diabetes mellitus, Alzheimer disease, and cancer.1 Vari- ous studies suggest that genetic deter- minants of exceptional longevity are highly heritable.2,3 Siblings of cente- narians have an 8- to 17-fold higher probability of living past the age of 100 years, accounting for only approxi- mately 1 of 10000 individuals in the general population.2,3 The offspring of long-lived parents have an approxi- mately 50% lower prevalence of hyper- tension, diabetes mellitus, myocardial infarction, and stroke/transient ische- mic attacks compared with age- matched control groups.3 Further- more, at least 1 study linked a locus on chromosome 4 to exceptional longev- ity.4 Identification of biological mark- ers and genes that are conducive to exceptional longevity may provide in- sights into mechanisms that protect from a host of common diseases and/or slow the biological processes of aging.

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 signifi- cantly 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 homo- zygosity for the 405 valine allele of CETP (VV genotype), respectively, compared with an MeP<. 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 sig- nificantly 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. JAMA. 2003;290:2030-2040 www.jama.com

of Medicine, Boston University School of Medicine, Boston, Mass (Dr Cupples); and Department of Hu- man Genetics, Roche Molecular Systems Inc, Ala- meda, Calif (Dr Cheng). FinancialDisclosure: DrChengisemployedbyRoche

AuthorAffiliations: InstituteforAgingResearch,Dia- betes Research and Training Center (Drs Barzilai and Atzmon), Department of Neurology (Dr Lipton), and Department of Family Medicine and Community Health(DrSchechter),AlbertEinsteinCollegeofMedi- cine, New York, NY; University of Maryland School of Medicine and the Geriatrics Research and Educa- tionClinicalCenter,BaltimoreVeteransAffairsMedi- calCenter,Baltimore(DrShuldiner);JeanMayerUSDA Human Nutrition Research Center on Aging, Tufts University, Boston, Mass (Dr Schaefer); Department

of Medicine, Boston University School of Medicine, Boston, Mass (Dr Cupples); and Department of Hu- man Genetics, Roche Molecular Systems Inc, Ala- meda, Calif (Dr Cheng). Financia

isclosure: D

hengisemployedb

oche Molecular Systems. Corresponding Author and Reprints: Nir Barzilai, MD, Institute for Aging Research, Albert Einstein College of Medicine, Belfer Bldg

,

Morris Park Ave, Bronx, NY

(e-mail: barzilai@aecom .yu.edu).

Corresponding Author and Reprints: Nir Barzilai, MD, Institute for Aging Research, Albert Einstein College of Medicine, Belfer Bldg 701, 1300 Morris Park Ave, Bronx, NY 10461 (e-mail: barzilai@aecom

Longevity genes have been demon- strated in other species but the rel- evance to humans is controversial.1 In contrast, rodent models of aging and ag-

2030 JAMA, October 15, 2003—Vol 290, No. 15 (Reprinted)

Informed written consent was ob- tained in accordance with the policy of the committee on clinical investiga- tions of the Albert Einstein College of Medicine, New York, NY.