Abstract
Across species, lifespan is highly variable among individuals within a population. Even genetically identical Caenorhabditis elegans reared in homogeneous environments are as variable in lifespan as outbred human populations. We hypothesized that persistent inter-individual differences in expression of key regulatory genes drives this lifespan variability. As a test, we examined the relationship between future lifespan and the expression of 22 microRNA promoter::GFP constructs. Surprisingly, expression of nearly half of these reporters, well before death, could effectively predict lifespan. This indicates that prospectively long- vs. short-lived individuals have highly divergent patterns of transgene expression and transcriptional regulation. The gene-regulatory processes reported on by two of the most lifespan-predictive transgenes do not require DAF-16, the FOXO transcription factor that is a principal effector of insulin/insulin-like growth factor (IGF-1) signaling. Last, we demonstrate a hierarchy of redundancy in lifespan-predictive ability among three transgenes expressed in distinct tissues, suggesting that they collectively report on an organism-wide, cell non-autonomous process that acts to set each individual's lifespan.
Highlights
Across the tree of life, lifespan varies greatly, among species and among individuals of the same species (Jones et al, 2014)
We propose that identifying genes whose expression early in life is predictive of future lifespan would provide strong evidence that differences in gene regulation and expression can lead previously identical individuals toward different lifespans
In order to understand the relationship between inter-individual variation in transcriptional / generegulatory states and future lifespan, we used tools previously developed by our lab (Zhang et al, 2016; Pittman et al, 2017) to examine expression of 22 PmiRNA::GFP reporters (Martinez et al, 2008), across hundreds of individuals throughout life
Summary
Across the tree of life, lifespan varies greatly, among species and among individuals of the same species (Jones et al, 2014). Other factors like shared environment explain very little of the remaining variation between individuals (Herskind et al, 1996; Ljungquist et al, 1998; McGue et al, 1993). A reasonable fraction of the variance in human longevity is determined by non-genetic, non-environmental factors, likely of stochastic origin. Understanding what these processes are and how they arise provides insight into why some individuals live longer than others
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