Unique Lipoprotein Phenotype and Genotype Associated With Exceptional Longevity

Individuals with exceptional longevity have a lower incidence and/or significant delay in the onset of age-related diseases, and their family members may inherit biological factors that modulate aging processes and disease susceptibility.

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. 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.

Individuals with exceptional longevity have been generally spared from major age-related diseases that are responsible for most deaths in elderly persons, such as cardiovascular disease (CVD), diabetes mellitus, Alzheimer's disease, and cancer. Various studies suggest that genetic determinants of exceptional longevity are highly heritable. Siblings of centenarians have an 8- to 17-fold higher probability of living past the age of 100 years, accounting for only approximately 1 in 10,000 individuals in the general population. The offspring of long-lived parents have an approximately 50% lower prevalence of hypertension, diabetes mellitus, myocardial infarction, and stroke/transient ischemic attacks compared with age-matched control groups. Furthermore, at least one study linked a locus on chromosome 4 to exceptional longevity. Identification of biological markers and genes that are conducive to exceptional longevity may provide insights into mechanisms that protect individuals 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 probands' 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), compared with an age-matched control group (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.

JAMA. 2003;290:2030-2040 www.jama.com

Author Affiliations: Institute for Aging Research, Diabetes Research and Training Center (Drs Barzilai and Atzmon), Department of Neurology (Dr Lipton), and Department of Family Medicine and Community Health (Dr Schechter), Albert Einstein College of Medicine, New York, NY; University of Maryland School of Medicine and the Geriatrics Research and Education Clinical Center, Baltimore Veterans Affairs Medical Center, Baltimore (Dr Shuldiner); Jean Mayer USDA 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 Human Genetics, Roche Molecular Systems Inc, Alameda, Calif (Dr Cheng). Financial Disclosure: Dr Cheng is employed by Roche Molecular Systems. 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 104Einstein College of Medicine. We followed the National Cholesterol Education Program (Adult Treatment Panel III) guidelines, defining the metabolic syndrome as the presence of 3 or more of the 5 risk factors: increased waist girth (>94 cm for women, >102 cm for men), increased blood pressure (>130/85 mm Hg or treatment for hypertension), increased fasting glucose (>110 mg/dL [6.11 mmol/L] or drug treatment for diabetes), low plasma HDL cholesterol (<40 mg/dL [1.04 mmol/L]), and elevated fasting triglyceride levels (>150 mg/dL [1.70 mmol/L]). We developed a novel study design in a genetically homogeneous founder population to identify the biological and genetic underpinnings of exceptional longevity by studying Ashkenazi Jewish families defined by long-lived probands. In addition, we recruited the offspring of probands and an age-matched control group, hypothesizing that the former may have inherited certain biological protective factors that could be more easily discerned at younger ages if compared with an age-matched control group.