Mechanisms of Aging and Development 126 (2005) 341-345 www.elsevier.com/locate/mechagedev Evidence for Inheritance of Exceptional Longevity

Gil Atzmon, Marielisa Rincon, Pegah Rabizadeh, Nir Barzilai

a Department of Medicine, Institute for Aging Research, Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA b Pediatric Endocrinology, Children's Hospital at Montefiore, Bronx, NY 10461, USA Available online 6 November 2004

Abstract
Subjects with exceptional longevity have a lower incidence and/or significant delay in the onset of age-related diseases. Their family members may inherit biological factors that modulate aging processes and disease susceptibility. In a case-control study, we aim to determine the phenotype and genotype of exceptional longevity in a genetically homogenous population (Ashkenazi Jews) and their offspring. An age-matched control group of Ashkenazi Jews was used as a control group. We demonstrated that exceptional longevity and healthy aging in humans is an inherited phenotype across three generations. Moreover, we demonstrated that subjects with exceptional longevity and their offspring have significantly larger high-density lipoprotein (HDL) levels and particle sizes and low-density lipoprotein (LDL) levels that reflect on their health and cognitive function performance. This phenotype has led us to study candidate genes involved in lipoprotein metabolism and to the implication of homozygosity for the 405 valine (V) allele of cholesteryl ester transfer protein (CETP). A markedly higher frequency of a functional CETP variant that led to increased particle sizes of HDL and LDL and thus better health performance is the first example of a phenotype and an associated genotype in humans with exceptional longevity. Hopefully, this line of research will lead us to establish which genotype is necessary (although not necessary sufficient) for prolonged disease-free aging.

Keywords: Lipoprotein particle size; High-density lipoprotein (HDL) cholesterol; Low-density lipoprotein (LDL) cholesterol; Longevity; Centenarians; Cardiovascular disease; Cognitive function; Cholesteryl ester transfer protein (CETP); Genetics

Manipulations on lower organisms, though, provide strong support for the concept that genes can control lifespan and that cellular and metabolic pathways may mediate this phenotype (Barzilai and Shuldiner, 2001). A growing number of human longevity studies support the notion that families with exceptional longevity have a unique phenotype (Atzmon et al., 2004; Barzilai et al., 2003; Terry et al., 2003) and genotype (Barzilai et al., 2003; Geesaman et al., 2003; Perls and Terry, 2003a; Perls and Terry, 2003b). Since extreme longevity is a rare phenotype (1/10,000), efforts to collect and study such individuals are enormous. There are only a few major research groups that investigate this unique phenotype. Several approaches have been used to understand environmental and genetic variables involved in the phenotype of long-lived individuals. Selection of study populations has included isolated groups of centenarians (Lio et al., 2003), mixed population from the same area across the world (Blanche et al., 2001; Choi et al., 2003; Rosholm et al., 2002; Sikora, 2000).

Our approach was designed to overcome some of the problems in tackling the potential biological complexity of exceptional longevity. First, to avoid the task of population stratification, we gathered Ashkenazi Jews who were relatively healthy past the age of 95. This unique population originated in the Pale of Europe up to the 17th century, encountered a combination of plagues, wars, and anti-Semitic persecution, constricting the population size to an estimated few hundred thousands. This relatively small group then experienced rapid population growth, but ensuing generations stemmed from a relatively limited number of founders. The genetic makeup of Ashkenazi Jews is, therefore, comparatively homogenous, making it easier to identify important genetic differences, for example, the genes for ovarian cancer and breast cancer which were originally identified in studies done among Ashkenazi women (Lancaster et al., 1997).

Second, we argued that the phenotype that was helpful during the aging of our subjects might not be apparent at the end of their lives. Therefore, we recruited their offspring who may be enriched with longevity phenotype and genotype if it is indeed a marked one. Third, because the controls for centenarians died a few decades ago, we established an age-matched control group for their offspring. This group consists mainly of the spouses of the offspring or their neighbors who share much of their environment. Here, we will demonstrate the advantages of suchThere is a significant statistical association between genetic variation in CETP and exceptional longevity (Barzilai et al., 2003). Homozygosity for the 405V allele of CETP was significantly higher among centenarians and their offspring compared to an Ashkenazi control group (Fig. 3). Further investigation of subjects carrying the VV genotype showed lower serum CETP levels and larger lipoprotein particle sizes. Following reasonable statistical assumptions, we calculated that the attributable risk of having the VV genotype to reach exceptional old age is 18.1. We proposed a causal connection between individuals carrying the VV genotype and survival advantage, mediated by decreased levels of CETP that promote higher lipoprotein sizes and levels which we believe lead to exceptional longevity (Barzilai et al., 2003). This finding, along with the recent discovery that a common polymorphism of microsomal transfer protein (MTP), a protein involved in HDL levels and cognitive function, is associated with exceptional longevity (Geesaman et al., 2003), provides further evidence for a link between genetics and a protective lipoprotein phenotype.