Recently, we demonstrated that longevity is not an ‘‘once in a family’’ trait, since it presented in every branch of the centenarians’ ancestors (Atzmon et al., 2004). We obtained the age of death from the two pairs of centenarians’ and their spouses’ parents. We then calculated the risk ratio of survival to the age of 100 in this population that lived in the 19th century where life expectancy was 50 (Mackay, 2003). Compared to centenarians’ in-laws, centenarians’ parents risk ratio to live to extended age increased on every decade, attaining 6.9 (95% CI = 3.8–10.1) at last; furthermore, a significant threshold (p < 0.007) was seen comparing the 1960s decade (95% CI = 0.77–1.23). We then hypothesized that inheritance of such phenomenon decodes into a healthier performance. To avoid skewed results since centenarians are at the end of their life we then tested the next generation.

4. Offspring of centenarians are healthier

Following our observation that longevity is inherited, we then examined offspring of centenarians to determine whether or not they were relatively spared from age-related diseases. The assumption was that offspring who were (cid:1)33 years younger than their long-lived parents, would have inherited a favorable genotype that is reflected on their good health phenotype. In fact, we reported significantly lower prevalence of diabetes mellitus, hypertension and myocar- dial infarction, without any report of stroke in the offspring group compared to their cohort (Fig. 1), and these observations were extended to several other control groups such as NHANES and Israel Clalit Members (Atzmon et al., 2004). This finding supports the hypothesis that offspring of long-lived parents are healthier probably due to good genetic background. In addition, it could explain the notion that exceptional longevity is just a flip side of being spared from

2. Study design, data recruitment and statistical analysis

2004). This finding supports the hypothesis that offspring of long-lived parents are healthier probably due to good genetic background. In addition, it could explain the notion that exceptional longevity is just a flip side of being spared from cardiovascular disease, a potential age-related risk. To

described elsewhere (Atzmon et al., 2002; Atzmon et al., 2004; Barzilai et al., 2003; Barzilai et al., 2001). Over 300 probands (80% female) were already recruited, of which 48% are over the age of 100. Birth certificates or dates of birth as stated on passports defined the participants’ ages.

subjects (55% female) with average age of 70. We used two different control groups. The first control group consisted mainly of age-matched spouses of the offspring to reduce environmental effect, and other age-matched Ashkenazi for a total of 258 subjects.

Percentage in population=e eXnnewwaousBSRSRBS @ Probands @ Offspring Control  m= HINDM MICardiovascular diseaseStroke

Detailed questionnaires, physical examination, and blood tests including assessment of their lipids and lipoprotein subclass levels and particle sizes by proton nuclear magnetic resonance (NMR) were performed. Samples were also genotyped for the amino acid substitution 405 isoleucine to valine (I405V) variation in the cholesteryl ester transfer protein (CETP) gene, which is involved in regulation of lipoprotein and their particle sizes (Atzmon et al., 2002; Atzmon et al., 2004; Barzilai et al., 2003).

Fig. 1. Percentage of CVD among probands, offspring, and control *p < 0.05, **p < 0.01.

eliminate a possible co-founder to the health condition we determined the body mass index (BMI) in offspring as well as probands and control and we demonstrated that although the probands have significant lower BMI (probably this leanness results from their impending end of life) the control groups did not changed significantly compared to the offspring (Atzmon et al., 2004). Because over 30% of our centenarians were overweight or obese, we believe that leanness is not essential part of exceptional longevity.

    2€56 t |2»* 5 .t € 5fo}3aee 232 °2 ZERRS RRR(wu) azis aponaed TqH S (wu) azis apyaed [qTProbands Offspring Control(a)

5. HDL and LDL levels and particle sizes

cause of non-traumatic death in the western world (Jneid and Bhatt, 2003). A possible explanation for the long lives of centenarians is that they may possess ‘‘atherosclerotic protective factors’’. Higher HDL level was described as a main component of those protective factors (Barzilai et al., 2001). In order to focus on candidate genes, we further established the size of lipoproteins. Indeed, while most molecules in our body are similar in size across humans and most species, this is not the case for lipoproteins. In recent years, small LDL particle size has been associated with cardiovascular risks. We measured the lipoprotein size by NMR technology and studied the lipid profile characteristics of centenarians’ offspring ((cid:1)33 years younger) and compared them to a matched control group. Our results indicated that offspring of centenarians have both large HDL and LDL particle size compared to appropriate controls (Fig. 2). We also determined that this profile is highly heritable (0.4–0.7 for heritability) based on gender and the specific lipoproteins. These data suggest that certain lipid profiles may be inherited in families, and probably may play a role in longevity.

Fig. 2. Average HDL and LDL particle sizes among probands, offspring, and control groups. ***p < 0.0001.

7. Polymorphism in the CETP gene and the phenotype of exceptional longevity