Correspondence Address: Prof. Anatoliy I Yashin, Biodemography of Aging Research Unit SSRI, Duke University, 2024 West Main Street, Durhan, NC, 27705 USA. Email: email@example.com; Prof. Svetlana Ukraintseva, Biodemography of Aging Research Unit SSRI, Duke University, 2024 West Main Street, Durhan, NC, 27705 USA. Email: firstname.lastname@example.org
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Aim: Experimental studies provided numerous evidences that caloric/dietary restriction may improve health and increase lifespan of laboratory animals, and that interplay among molecules that sense cellular stress signals and those regulating cell survival can play a crucial role in cell response to nutritional stressors. It is unclear, however, whether the interplay among corresponding genes also plays a role in human health and lifespan.
Methods: We reviewed literature about roles of cellular stressors, such as amino acid deprivation, and the integrated stress response (ISR) pathway in health and aging, and selected SNPs in two candidate genes (GCN2/EIF2AK4 and CHOP/DDI3T) that are closely involved in the cellular stress response to amino acid starvation, based on experimental studies. We estimated associations of these SNPs, and their interactions, with human survival in the Health and Retirement Study (HRS) data. We also evaluated the impact of collective associations of multiple interacting SNP-pairs on survival, using a recently developed in our group composite index: the SNP-specific Interaction Polygenic Risk Score (SI_PRS).
Results: We found significant interactions among SNPs in 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 human lifespan. We also found highly statistically significant associations of SI_PRS (constructed for the rs16970024 (GCN2/EIF2AK4) and rs697221 (CHOP/DDIT3)) with survival in both sexes.
Conclusion: 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, found in this study, can help uncovering mechanisms of multifactorial regulation of human lifespan and its heterogeneity.
Yashin AI, Wu D, Arbeev K, Yashkin AP, Akushevich I, Bagley O, Duan M, Ukraintseva S. Roles of interacting stress related genes in lifespan regulation: insights for translating experimental findings to humans. <em>J Transl Genet Genom</em> 2021;5:[Accept]. http://dx.doi.org/10.20517/jtgg.2021.26