Interactions Between Genes From Aging Pathways May Influence Human Lifespan and Improve Animal to Human Translation

Abstract

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.

How areAPOE4, changes in body weight, and longevity related? Insights from a causal mediation analysis

“…Previously, we showed that longest-lived individuals reach peak values of weight/BMI and start to decline later in their lives, as compared to people with conventional lifespan (Yashin, et al 2013; Yashin, et al 2016). The ability to grow in size and postpone weight loss till older ages may also correlate with better physical resilience to life stressors, which is essential for survival at the oldest old ages (Ukraintseva et al 2021).…”

Influence of variability in the cyclooxygenase pathway on cardiovascular outcomes of nephrosclerosis patients

“…It is somewhat logical that variants affecting genes participating in a certain pathway relevant for a given outcome may interact to enhance the effect produced by a single SNP. Indeed, it has repeatedly been shown how interactions between SNPs in aging pathways and other routes may influence CV risk more profoundly than individual SNPs in those same genes do 15 – 17 .…”

Sex‐ and APOE‐specific genetic risk factors for late‐onset Alzheimer's disease: Evidence from gene–gene interaction of longevity‐related loci

“…The evaluation of the joint effect of different markers through gene–gene interactions further added insights into the genetic architecture of LOAD. Among the significantly interacting genes, PTPN1 (protein tyrosine phosphatase non‐receptor type 1, IIS pathway), TXNRD1 (thioredoxin reductase 1; stress response), and IGF1R (insulin‐like growth factor 1 receptor; IIS) were already found in combinations affecting survival to old age (Dato et al, 2018 ; Ukraintseva et al, 2021 ). PTPN1 and TXNRD1 were engaged in best risk combinations for longevity, respectively, with IGF1R and TP53 (DNA repair), while IGF1R , interacted with TP53 and TGFBR2 (cell proliferation).…”