plexity emphasizes that changes in the functionality of HDL, some through changes in mass or size, may have pleio- tropic antiaging effects.

study cannot directly answer this ques- tion, we suggest that lipoprotein con- centrations and particle sizes are ex- cellent causal biological candidates. As is the case for HDL levels, HDL and LDL particle sizes are significantly larger in women than in men, and may explain in part why women have lower CVD in- cidence rates and have higher life ex- pectancies than men. Small LDL par- ticlespenetratemorereadilyintoarterial tissue, bind more tightly to arterial pro- teoglycans, are oxidized more rapidly than larger LDL particles, and are as- sociated with endothelial dysfunc- tion, all mechanisms involved in the de- velopment of CVD.15,24 Therefore, large LDL particle size may be important in protecting the vascular bed from age- related atherosclerosis and thus pro- moting exceptional longevity. Simi- larly, small HDL particle size has been demonstrated in patients with CVD,25 and some lipid-lowering drugs may pro- tect from CVD by shifting the HDL par- ticles to larger sizes that are similar to those observed in patients without CVD.26 Increased HDL concentration and particle size are likely to underlie the beneficial effects of exercise on the cardiovascular system and other age- related phenotypes.27 However, causal- ity between HDL particle size and CVD has been debated because of its asso- ciation with small LDL particles and in- creased triglycerides.

In population studies, there is a strong inverse correlation of plasma lev- els of LDL and very LDL to HDL levels and HDL and LDL particle size.12,31 Our study shows that the levels of HDL and LDL, and their respective apolipopro- teins and particle sizes, are correlated with each other. We used ordered lo- gistic regression analysis to untangle these measures. Our analysis indi- cates that LDL and HDL particle sizes remained significant predictors of hav- ing longevity even after taking into ac- count absolute levels of lipids, lipopro- teins, and BMI. This large lipoprotein particle size phenotype is also evident in the offspring of long-lived pro- bands. We interpret these data to indi- cate that lipoprotein particle size is an independent heritable predictor of lon- gevity. Indeed, there is recent compel- ling evidence implicating LDL lipopro- tein particle size as a stronger predictor of CVD than LDL levels.31 Yet it is pos- sible that the lipoprotein levels and not the particle sizes directly may be rel- evant for their protective actions, even if they do decline with aging.

In support of causal relationship between lipoprotein sizes and age- related diseases, offspring have signifi- cantly less hypertension and CVD, and lipoprotein sizes distinguish between those with and without these condi- tions. Insulin resistance and diabetes are associated with significantly lower HDL and LDL particle sizes.32 The fre- quency of insulin resistance, which is the hallmark of the metabolic syn- drome of aging, is significantly lower in the offspring. Furthermore, the in- cidence of insulin resistance in pro- bands is much less than would be ex- pected (approximately 50% after age 70 years).18 The lipoprotein sizes re- ported in probands are significantly larger than these reported in a control group for the insulin resistance and dia- betes study,32 further supporting the clinical significance of relative small changes in their sizes and outcomes.

Until recently, HDL cholesterol was thought to exert its effects through re- verse cholesterol transport. The abil- ity of HDL to clear cholesterol from the endothelium and peripheral tissues may have systemic protective effects from li- potoxicity similar to that obtained in ca- loric-restricted rodents, whose life span is dramatically prolonged.28 In addi- tion to its role in lipid metabolism, other beneficial biological properties of HDL have been described, including anti- inflammatory, antioxidant, antiaggre- gatory, anticoagulant, and profibrino- lytic activities, which are exerted by HDL particles and other components, through their interactions with sev- eral apolipoproteins, enzymes, and even specific phospholipids.29,30 This com-

Although this VV homozygosity ap- pears in less than 20% of the offspring, more than 40% of offspring have very

2038 JAMA, October 15, 2003—Vol 290, No. 15 (Reprinted)

spouses or neighbors of the offspring, neither of which were enriched with longevity genes, and the cases were the offspring group who were children of the probands. Therefore, differences in environment, social, and economic in- fluences are unlikely to arise. The ad- ditional use of the Framingham Off- spring Study as a second control group with similar findings further supports the validity of our findings. A final limi- tation of the case-control design, which does affect this study, is that outcome incidence rates and relative risks can- not be estimated. Although we are aware of the limitations of a case- control study, this approach in fami- lies with exceptional longevity and where genetic markers are tested may be the best possible approach.