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.

ing-related diseases may be more rel- evant to humans. Expression of hu- man cholesteryl ester transfer protein (CETP) in rats, a species that com- monly lacks this gene, leads to com- bined hyperlipidemia, coronary heart disease, and decreased survival, mak- ing CETP a strong candidate gene for human aging.5 Cholesteryl ester trans- fer protein is involved in the regula- tion of reverse cholesterol transport and high-density lipoprotein (HDL) lev- els. Indeed high levels of low-density lipoprotein (LDL) cholesterol and low levels of HDL cholesterol are corre- lated 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 lev- els are not consistently unusual in cen- tenarians, this does not rule out its po- tential role in promoting longevity, because the levels may be different at the end of life in centenarians than they were at earlier ages.

genetic homogeneity and has made this population useful for identification of several genes, the breast cancer gene being a prominent example.8 Two hun- dred thirteen probands with excep- tional longevity (157 women and 56 men; mean [SD] age, 98.2 [5.3] years; | yve range, 95-107 years; 48% were 100 years)wererecruitedtoparticipateinthe study, which was conducted from 1998 to 2002. The participants’ ages were de- finedbybirthcertificatesordatesofbirth as stated on passports. Probands were required to be living independently at 95-years-old as a reflection of good health, although at the time of recruit- ment they could be at any institution or level of dependency. In addition, pro- bands had to have a first-degree off- spring who was willing to participate in the study. The offspring group con- sisted of 122 women and 94 men (mean [SD] age, 68.3 [6.7] years; range, 51-89 years). We used 2 different control groups. The first control group con- sisted of spouses of the offspring (n=75; mean [SD] age, 70.2 [10.2] years; 53% women). Fewer spouses of offspring than offspring of probands were re- cruited because 22 spouses had died, 18 offspring were divorced or sepa- rated, 10 spouses were not Ashkenazi Jews, and 55 spouses elected not to par- ticipate. The first control group also consisted of 183 age-matched Ash- kenazi Jewish controls recruited from the Einstein Aging Study9 (mean [SD] age, 71.3 [9.1] years; 57% women) for a total of 258 participants. Of this first control group, 2 participants were ex- cluded from the analysis because their parents had lived to be 98 and 102 years. A second control group con- sisted of 589 age-matched white par- ticipants enrolled in the Framingham Offspring Study (mean [SD] age, 67.8 [3.5] years; 48% women), a commu- nity-based cohort. Given the low preva- lence of exceptional longevity in the general population, we reasoned that the Framingham controls are not likely to have a family history of exceptional longevity or to carry longevity genes or phenotypes.

Clinical Evaluation

A research nurse visited the probands in the morning to draw a venous blood sample, obtain a medical history, mea- sure height and weight, and perform a physical examination. Health histo- ries were obtained using a standard- ized questionnaire. At that visit, the off- spring and the participating spouses underwent similar evaluations, as pre- viously described.3,6,7 All blood samples were processed at the General Clinical Research Center at Albert Einstein Col- lege of Medicine.

We followed the National Choles- terol Education Program (Adult Treat- ment Panel III) guidelines,10 defining the metabolic syndrome as the pres- ence of 3 or more of the 5 risk factors: ahs(>¢ increased waist girth ( 94 cm for women, 102 cm for men), increased in(>1 blood pressure ( 130/85 mm Hg or treatment for hypertension), in- ne(1 creased fasting glucose ( 110 mg/dL Vite[>6 [ 6.11 mmol/L] or drug treatment for diabetes), low plasma HDL choles- AROS(<4 [<l terol ( 40 mg/dL [ 1.04 mmol/L]), and elevated fasting triglycericde lev- ed(1 Oo *[1 els ( 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 Jew- ish families defined by long-lived pro- bands. In addition, we recruited the offspring of probands and an age- matched control group, hypothesiz- ing that the former may have inher- ited certain biological protective factors that could be more easily discerned at younger ages if compared with an age- matched control group.

Lipids and Lipoproteins

Total plasma cholesterol, triglycer- ides, HDL, LDL, very LDL, and apoli- poprotein A-I and B concentrations for Ashkenazi participants were per- formed by standard automated meth- ods at the clinical laboratories of Mon- tefiore Medical Center, Bronx, NY. The same lipid measurements were per- formed on fasting plasma samples from the Framingham Offspring Study as previously described.11 The LDL and HDL subclass levels and mean particle sizes were determined for all partici- pants by nuclear magnetic resonance (NMR) spectroscopy at LipoScience Inc (Raleigh, NC) as previously de- scribed.12,13 Each NMR measurement produces the concentrations of 3 LDL

METHODS

Study Design and Participants

In a case-control study, Ashkenazi Jews were recruited as described else- where.3,6,7 This population derived from an undetermined small number (esti- mated to be in the several thousands) of founders. External factors, including ecclesiastical edicts prohibiting all so- cial contact with Jews, the Crusades, the establishment of the Pale of Settle- ment, numerous Pogroms, and ethnic bigotry, resulted in the social isolation and inbreeding of the Ashkenazi Jews.