Mechanisms of Ageing and Development 126 (2005) 341–345

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evidence for inheritance of exceptional longevity

a b a Gil Atzmon , Marielisa Rincon , Pegah Rabizadeh , Nir Barzilai

aDepartment of Medicine, Institute for Aging Research, Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA bPediatric 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 disease, and their family members may inherit biological factors that modulate aging processes and disease susceptibility. In a case control study, we aim to determine phenotype and genotype of exceptional longevity in a genetically homogenous population (Ashkenazi Jews), and their offspring, while an age-matched control group of Ashkenazi Jews was used as control groups.

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 have 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 a 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 a 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, provides strong support for the concept that genes can control life span 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 and there are only 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 have included isolated groups of centenarians (Lio et al., 2003), mixed population from the same area

1. Introduction

Extension of life span has been genetically achieved in lower species such as nematodes (Caenorhabditis elegans) and flies (Drosophila). One of the most remarkable life extensions (three to fivefold increase) was achieved by genetically altering the daf-16 gene of the nematode (Libina et al., 2003). A less well-defined genetic mutation (Methuselah) was induced in Drosophila (Lin et al., 1998), which increased life span by 35%. However, data in lower organisms should be cautiously applied to humans because of the complexity of human systems and because life span and causes of death in humans are different than those in lower species. Longevity induced by genetic

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3. Inheritance of longevity in centenarians’ families

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 for 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 popula- tion 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 few decades ago, we established an age-matched control group for their offspring. This group consists of mainly the spouses of the offsprings or their neighbors, sharing much of their environment. Here, we will demons- trate the advantages of such an approach.