Lipoprotein Genotype and Conserved Pathway for Exceptional Longevity in Humans

Abstract

Alteration of single genes involved in nutrient and lipoprotein metabolism increases longevity in several animal models. Because exceptional longevity in humans is familial, it is likely that polymorphisms in genes favorably influence certain phenotypes and increase the likelihood of exceptional longevity. A group of Ashkenazi Jewish centenarians ( n = 213), their offspring ( n = 216), and an age-matched Ashkenazi control group ( n = 258) were genotyped for 66 polymorphisms in 36 candidate genes related to cardiovascular disease (CVD). These genes were tested for association with serum lipoprotein levels and particle sizes, apolipoprotein A1, B, and C-3 levels and with outcomes of hypertension, insulin resistance, and mortality. The prevalence of homozygosity for the −641C allele in the APOC3 promoter (rs2542052) was higher in centenarians (25%) and their offspring (20%) than in controls (10%) ( p = 0.0001 and p = 0.001, respectively). This genotype was associated with significantly lower serum levels of APOC3 and a favorable pattern of lipoprotein levels and sizes. We found a lower prevalence of hypertension and greater insulin sensitivity in the −641C homozygotes, suggesting a protective effect against CVD and the metabolic syndrome. Finally, in a prospectively studied cohort, a significant survival advantage was demonstrated in those with the favorable −641C homozygote ( p < 0.0001). Homozygosity for the APOC3 −641C allele is associated with a favorable lipoprotein profile, cardiovascular health, insulin sensitivity, and longevity. Because modulation of lipoproteins is also seen in genetically altered longevity models, it may be a common pathway influencing lifespan from nematodes to humans.

Lowering apolipoprotein CIII delays onset of type 1 diabetes

“…On the contrary, about 5% of the Lancaster (PA) Amish population are heterozygous carriers of a null mutation (R19X) in the gene encoding apoCIII, and this results in a lifelong 50% reduction of the apoCIII levels and an apparent cardioprotection (13). Furthermore, a group of Ashkenazi Jewish centenarians was found to have a higher prevalence of homozygosity for the-641C allele in the apoCIII promoter, a genotype associated with significantly lower levels of apoCIII, a favorable pattern of lipoproteins, increased insulin sensitivity, lower incidence of hypertension, and longevity (14). Therefore, it could be beneficial from multiple aspects to lower the apoCIII levels in individuals at risk for diabetes and/or cardiovascular disorders.…”

Functionally significant insulin-like growth factor I receptor mutations in centenarians

“…In a case control study, Ashkenazi Jews were recruited as described (13,14,33). This population derived from an undetermined small number (estimated to be several thousands) of founders.…”

“…Health histories were obtained by using a standardized questionnaire. In such visits, the offspring (and participating spouses) underwent similar evaluations as described (13,14,33 Mutation Screening of IGF1 and IGF1R. We screened genomic DNA isolated from blood of centenarians and controls to discover all possible genetic variations in the full coding sequence and intron/exon boundaries of the IGF1 and IGF1R genes by 2D gene scanning (35).…”

“…To overcome this shortcoming, we established a unique cohort of individuals with exceptional longevity and their offspring (approximate age 70 years) and age-and sex-matched controls without a family history of unusual longevity; all of Ashkenazi Jewish descent. This group of offspring of individuals with exceptional longevity and their matched controls is a powerful tool for identifying genetically controlled longevity traits and led to the identification of longevity phenotypes such as lipoprotein sizes and the subsequent discovery of corresponding longevity genotypes (13,14). Here, we report the use of this unique cohort to identify partial loss-of-function mutations in the IGF1 receptor (IGF1R) gene that are overrepresented among centenarians compared with controls, suggesting a role for the IGF signaling pathway in human longevity.…”

Explaining longevity of different animals: is membrane fatty acid composition the missing link?

“…Studies of Danish twins suggests the heritability of longevity is 0.23 for females and 0.26 for males (Herskind et al 1996); hence children of centenarians have been used as a model system for the study of the genetic basis of human aging (e.g. Atzmon et al 2006). The fatty acid profile of erythrocyte membranes has been proposed as a potential biomarker of human longevity.…”