Yashin Anatoliy I, Wu Deqing, Arbeev Konstantin, Yashkin Arseniy P, Akushevich Igor, Bagley Olivia, Duan Matt, Ukraintseva Svetlana
Biodemography of Aging Research Unit, Duke University, Durham, NC 27705, USA.
J Transl Genet Genom. 2021;5(4):357-379. Epub 2021 Oct 19.
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 ( and ) 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 (SIPRS).
Significant interactions have been found between SNPs from and 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.
实验研究提供了大量证据表明热量/饮食限制可能改善健康状况并延长实验动物的寿命，并且感知细胞应激信号的分子与调节细胞存活的分子之间的相互作用在细胞对营养应激源的反应中可能起关键作用。然而，尚不清楚相应基因之间的相互作用是否也对人类健康和寿命产生影响。
回顾了有关细胞应激源作用的文献，例如氨基酸剥夺以及健康与衰老中的综合应激反应（ISR）途径。利用实验研究的信息，选择了两个与氨基酸饥饿的细胞应激反应密切相关的候选基因中的单核苷酸多态性（SNP）。在健康与退休研究数据中估计了这些SNP及其与人类生存的相互作用。使用最近开发的综合指数：（SIPRS）评估了多个相互作用的SNP对的集体关联对生存的影响。
在总样本（男性和女性合并）以及仅女性中，发现与75至85岁之间的生存相比，与85岁以上生存相关的基因和基因中的SNP之间存在显著相互作用。这可能反映了人类寿命遗传调控中的性别差异。在本研究中还发现SIPRS [针对rs16970024（GCN2/EIF2AK4）和rs697221（CHOP/DDIT3）构建]与两性生存之间具有高度统计学意义的关联。
确定遗传相互作用与人类生存的关联是将知识从实验性衰老研究转化为人类衰老研究的重要一步。本研究中发现的ISR基因中多个SNP×SNP相互作用与最长寿老年生存的显著关联，有助于揭示人类寿命多因素调控及其异质性的机制。
