Rare APOB Gene Variant Linked to Exceptional Longevity

Dr. Manuel Serrano PhD Tumour Suppression Group CNIO, Melchor Fernandez Almagro 3, 28029 Madrid, Spain.MedicalResearch.com Interview with:
Dr. Manuel Serrano PhD
Tumour Suppression Group
CNIO, Melchor Fernandez Almagro 3, 28029 Madrid, Spain.


Medical Research: What are the main findings of the study?

Dr. Serrano: We investigated the contribution of rare genetic variation to human exceptional longevity (EL, individuals with ≥100 years of age) by exome-sequencing long-lived siblings in three different families where exceptional longevity clustered. We found only one gene that harbored rare variants that was likely to contribute to human longevity across all three families and this gene was the Apolipoprotein B gene (APOB). We further found that the frequency of these rare APOB variants associated with familial exceptional longevity was greater in a cohort of 206 nonfamilial cases of exceptional longevity compared to the control population, though this association did not reach statistical significance. In addition, we found rare variants in many genes within individual families that are likely to contribute to human longevity given previous studies in animals.

Medical Research: Were any of the findings unexpected?

Dr. Serrano: Though the approach of exome-sequencing was unbiased and designed to obtain novel, unexpected findings, the discovery of a potential association between rare variants in APOB and exceptional longevity is not entirely surprisingly. Strikingly, one of the only genes bearing common genetic variants having an unequivocal association with human longevity is APOE. The APOE and APOB proteins both reside in circulating lipoprotein particles and facilitate uptake of triacylglycerols and cholesterol from the blood to tissues. In addition, two previous reports have described a reciprocal relationship between extended human longevity and the syndrome hypobetalipoproteinemia, a proposed “longevity syndrome”, which results from mutations in the APOB gene.

Medical Research: What should clinicians and patients take away from your report?

Dr. Serrano: This study re-emphasizes the important role of lipid metabolism in human longevity and underscores the importance of following clinicians recommendations for maintaining cardiovascular health through diet and exercise.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Serrano: This work only represents a pilot study which involved the analysis of a small number individuals. Therefore, it is currently difficult to decisively conclude the contribution of rare genetic variation in specific genes to human longevity. To further validate and extend these findings we will have to assess many more individuals exhibiting exceptional longevity for the presence of these variants. Further, we will need to explore the correlation between these variants and physiologic parameters, specifically those associated with age-related diseases (eg, cardiovascular disease, diabetes, Alzheimer’s disease) to determine how these variants contribute to human healthspan and longevity.

Citation:

Exome sequencing of three cases of familial exceptional longevity
Aging Cell
Timothy P. Cash, Guillermo Pita, Orlando Domínguez, Maria R. Alonso, Leticia T. Moreno, Consuelo Borrás, Leocadio Rodríguez-Mañas, Catalina Santiago, Nuria Garatachea, Alejandro Lucia, Juan A. Avellana, Jose Viña, Anna González-Neira and Manuel Serrano