The role of lipid‐related genes, aging‐related processes, and environment in healthspan

Aging Cell

Alexander M. Kulminski¹  Irina Culminskaya¹  Konstantin G. Arbeev¹  Svetlana V. Ukraintseva¹  Eric Stallard¹  Liubov Arbeeva¹ 

[1] Center for Population Health and Aging, Duke University, Durham, NC, USA

关键词: aging;    biology of aging;    disease;    genetics;    healthspan regulation;    trade‐offs;   

DOI  :  10.1111/acel.12046

来源: Wiley

【 摘 要 】

Summary

The inherent complexity of aging-related traits can temper progress in unraveling the genetic origins of healthspan. We focus on two generations in the Framingham Heart Study, the original (FHS) and offspring (FHSO) cohorts, to determine whether aging-related processes in changing environments can substantially impact the role of lipid-related genes discovered in candidate gene (the apolipoprotein E (APOE) e2/3/4 polymorphism) and genome-wide (the APOB rs1042034 (C/T)) studies, in regulation of total cholesterol (TC) and onset of cardiovascular disease (CVD). We demonstrate that the APOE e4 allele and APOB CC genotype can play detrimental, neutral, and protective sex-specific roles in the etiology of CVD at different ages and in different environments. We document antagonistic roles for the e4 allele in the onset of CVD characterized by detrimental effects at younger ages (RR_{≤ 75 years} = 1.49, P = 7.5 × 10⁻⁴) and protective effects at older ages (RR_76+years = 0.77, P = 0.044) for FHS participants. We found that disregarding the role of aging erroneously nullifies the significant effects of the e4 allele in this sample (RR = 0.92, P = 0.387). The leading biogenetic pathways mediating genetic effects on CVD may be more relevant to lipid metabolism for APOB than APOE. Aging-related processes can modulate the strength of genetic associations with TC in the same individuals at different chronological ages. We found substantial differences in the effects of the same APOE and APOB alleles on CVD and TC across generations. The results suggest that aging-related processes in changing environments may play key roles in the genetics of healthspan. Detailed systemic integrative analyses may substantially advance the progress.

【 授权许可】

Unknown   
© 2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland