Abstract
Experimental studies provided numerous evidence that caloric/dietary restriction may improve health and increase the lifespan of laboratory animals, and that the interplay among molecules that sense cellular stress signals and those regulating cell survival can play a crucial role in cell response to nutritional stressors. However, it is unclear whether the interplay among corresponding genes also plays a role in human health and lifespan. Literature about roles of cellular stressors have been reviewed, such as amino acid deprivation, and the integrated stress response (ISR) pathway in health and aging. Single nucleotide polymorphisms (SNPs) in two candidate genes (GCN2/EIF2AK4 and CHOP/DDIT3) that are closely involved in the cellular stress response to amino acid starvation, have been selected using information from experimental studies. Associations of these SNPs and their interactions with human survival in the Health and Retirement Study data have been estimated. The impact of collective associations of multiple interacting SNP pairs on survival has been evaluated, using a recently developed composite index: the SNP-specific Interaction Polygenic Risk Score (SIPRS). Significant interactions have been found between SNPs from GCN2/EIF2AK4 and CHOP/DDI3T genes that were associated with survival 85+ compared to survival between ages 75 and 85 in the total sample (males and females combined) and in females only. This may reflect sex differences in genetic regulation of the human lifespan. Highly statistically significant associations of SIPRS [constructed for the rs16970024 (GCN2/EIF2AK4) and rs697221 (CHOP/DDIT3)] with survival in both sexes also been found in this study. Identifying associations of the genetic interactions with human survival is an important step in translating the knowledge from experimental to human aging research. Significant associations of multiple SNPxSNP interactions in ISR genes with survival to the oldest old age that have been found in this study, can help uncover mechanisms of multifactorial regulation of human lifespan and its heterogeneity.
Highlights
The multifactorial nature of aging, health, and lifespan-related traits is broadly recognized but understudiedIt is generally acknowledged that human lifespan, aging, and age-associated health disorders are multifactorial traits resulting from the complex interplay among numerous genetic and non-genetic factors
Significant interactions have been found between Single nucleotide polymorphisms (SNPs) from GCN2/EIF2AK4 and CHOP/DDI3T genes that were associated with survival 85+ compared to survival between ages 75 and 85 in the total sample and in females only
Significant associations of multiple SNPxSNP interactions in integrated stress response (ISR) genes with survival to the oldest old age that have been found in this study, can help uncover mechanisms of multifactorial regulation of human lifespan and its heterogeneity
Summary
The multifactorial nature of aging, health, and lifespan-related traits is broadly recognized but understudied. It is generally acknowledged that human lifespan, aging, and age-associated health disorders are multifactorial traits resulting from the complex interplay among numerous genetic and non-genetic factors. Observed correlations between biomarkers of biological aging and age-associated diseases indicate a possibility of improving health and increasing lifespan through deceleration of the aging-related processes in the body. A better understanding of the mechanisms of multifactorial regulation of respective traits could substantially facilitate the realization of this idea. Numerous experiments using animal models were performed to improve such understanding. A number of studies revealed that mutations in just one gene in C. elegans could substantially increase the lifespan of laboratory animals (reviewed in[1]). Note that the effects of such mutations on lifespan in other species are much less pronounced
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