Interactions Between Genes From Aging Pathways May Influence Human Lifespan and Improve Animal to Human Translation.
Interactions Between Genes From Aging Pathways May Influence Human Lifespan and Improve Animal to Human Translation.
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DOI：
10.3389/fcell.2021.692020
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发表时间：
2021
影响因子：
5.5
通讯作者：
Yashin A
中科院分区：
文献类型：
--
作者：
Ukraintseva S;Duan M;Arbeev K;Wu D;Bagley O;Yashkin AP;Gorbunova G;Akushevich I;Kulminski A;Yashin A
衰老研究的一个主要目标是确定可用于减缓或逆转衰老（身体变化和延长人类寿命极限）的遗传目标。然而，除了少数例外，大多数在动物模型中表现出抗衰老和促生存作用的基因并未在人类中复制。缺乏翻译的潜在原因包括遗传对寿命影响的高度条件性特征及其异质性，这意味着更好的生存可能不仅是个体基因活性的结果，还可能是基因-环境和基因-基因相互作用等因素的结果。在本文中，我们探讨了遗传相互作用与人类寿命的关联。我们从众所周知的衰老途径（IGF1/FOXO 生长信号、P53/P16 凋亡/衰老以及 mTOR/SK6 自噬和存活）中选择候选基因，这些基因共同决定细胞对压力和损伤的反应结果，因此可能容易发生相互作用。我们在社区动脉粥样硬化风险研究中估计了这些基因中的 SNP 之间的成对统计上位性与 85 岁以上生存之间的关联，并发现 IGF1R、TGFBR2 和 BCL2 中的 SNP 之间的相互作用对 85 岁以上生存具有显着影响（FDR < 0.05）。我们在心血管健康研究样本中验证了这些发现，P < 0.05，使用 85 岁以上的生存率和第 90 个百分位的生存率作为结果。我们的结果表明，衰老途径基因中的 SNP 之间的相互作用比相同基因中的单个 SNP 之间的相互作用对生存的影响更显着，这可能导致寿命的异质性，并导致衰老研究中缺乏从动物到人类的翻译。
A major goal of aging research is identifying genetic targets that could be used to slow or reverse aging – changes in the body and extend limits of human lifespan. However, majority of genes that showed the anti-aging and pro-survival effects in animal models were not replicated in humans, with few exceptions. Potential reasons for this lack of translation include a highly conditional character of genetic influence on lifespan, and its heterogeneity, meaning that better survival may be result of not only activity of individual genes, but also gene–environment and gene–gene interactions, among other factors. In this paper, we explored associations of genetic interactions with human lifespan. We selected candidate genes from well-known aging pathways (IGF1/FOXO growth signaling, P53/P16 apoptosis/senescence, and mTOR/SK6 autophagy and survival) that jointly decide on outcomes of cell responses to stress and damage, and so could be prone to interactions. We estimated associations of pairwise statistical epistasis between SNPs in these genes with survival to age 85+ in the Atherosclerosis Risk in Communities study, and found significant (FDR < 0.05) effects of interactions between SNPs in IGF1R, TGFBR2, and BCL2 on survival 85+. We validated these findings in the Cardiovascular Health Study sample, with P < 0.05, using survival to age 85+, and to the 90th percentile, as outcomes. Our results show that interactions between SNPs in genes from the aging pathways influence survival more significantly than individual SNPs in the same genes, which may contribute to heterogeneity of lifespan, and to lack of animal to human translation in aging research.
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DOI：
10.4161/15384101.2014.950151
发表时间：
2014
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
de Magalhães JP
通讯作者：
de Magalhães JP
影响因子：
5.4
作者：
Bitto A;Wang AM;Bennett CF;Kaeberlein M
通讯作者：
Kaeberlein M
DOI：
10.1186/s13195-018-0344-4
发表时间：
2018-02-08
期刊：
Alzheimer's research & therapy
影响因子：
--
作者：
Chang CC;Chang YT;Huang CW;Tsai SJ;Hsu SW;Huang SH;Lee CC;Chang WN;Lui CC;Lien CY
通讯作者：
Lien CY
影响因子：
5.8
作者：
Herold, Christine;Steffens, Michael;Becker, Tim
通讯作者：
Becker, Tim
影响因子：
4.2
作者：
Johnson, TE;Henderson, S;Link, C
通讯作者：
Link, C