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.