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MEDICAL BIOLOGY: LIPOPROTEIN SIZE AND LONGEVITY

The following points are made by N. Barzilai et al (J. Am. Med. Assoc. 2003 290:2030):

1) 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 disease, and cancer.(1) Various studies suggest that genetic determinants of exceptional longevity are highly heritable.(2,3) Siblings of centenarians have an 8- to 17-fold higher probability of living past the age of 100 years, accounting for only approximately 1 of 10,000 individuals in the general population.(2,3) 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.(3) Furthermore, at least 1 study linked a locus on chromosome 4 to exceptional longevity.(4) Identification of biological markers and genes that are conducive to exceptional longevity may provide insights into mechanisms that protect from a host of common diseases and/or slow the biological processes of aging.

2) Longevity genes have been demonstrated in other species but the relevance to humans is controversial.(1) In contrast, rodent models of aging and aging-related diseases may be more relevant to humans. Expression of human cholesteryl ester transfer protein (CETP) in rats, a species that commonly lacks this gene, leads to combined hyperlipidemia, coronary heart disease, and decreased survival, making CETP a strong candidate gene for human aging.(5) Cholesteryl ester transfer protein is involved in the regulation of reverse cholesterol transport and high-density lipoprotein (HDL) levels. Indeed high levels of low-density lipoprotein (LDL) cholesterol and low levels of HDL cholesterol are correlated with increased incidence of CVD in humans, although other factors may contribute to accelerated aging through effects on vascular wall, cancer, or other mechanisms.(1) Although lipoprotein levels are not consistently unusual in centenarians, this does not rule out its potential role in promoting longevity, because the levels may be different at the end of life in centenarians than they were at earlier ages.

3) The authors 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 family members (probands). In addition, the authors 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.

4) From their results, the authors conclude: 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. The authors suggest these findings indicate that lipoprotein particle sizes are heritable and promote a healthy aging phenotype.

References (abridged):

1. Barzilai N, Shuldiner AR. Searching for human longevity genes: the future history of gerontology in the post-genomic era. J Gerontol. 2001;56A:M83-M87

2. Perls TT, Wilmoth J, Levenson R, et al. Life-long sustained mortality advantage of siblings of centenarians. Proc Natl Acad Sci U S A. 2002;99:8442-8447

3. Atzmon G, Schechter C, Greiner W, et al. Clinical phenotype of families with longevity. J Am Geriatr Soc. In press.

4. Puca AA, Daly MJ, Brewster SJ, et al. A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4. Proc Natl Acad Sci U S A. 2001;98:10505-10508

5. Herrera VL, Makrides SC, Xie HX, et al. Spontaneous combined hyperlipidemia, coronary heart disease and decreased survival in Dahl salt-sensitive hypertensive rats transgenic for human cholesteryl ester transfer protein. Nat Med. 1999;5:1383-1389

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