ORCID
https://orcid.org/0000-0001-5681-1388
Date of Award
12-18-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
An outstanding question in the field of aging biology is the origin of variability in lifespans among members of the same species. Traditional wisdom dictates that differences in one individual’s genes or environment, “nature” and “nurture,” could predispose that individual to a long or short life. However, these explanations are radically incomplete. Even in a model system as homogenous as C. elegans, using an isogenic population in a lab-controlled environment, we observe a distribution in lifespans comparable to that seen in outbred human populations. The first part of this dissertation focuses on characterizing this non-genetic, non-environmental variability in the aging process. We hypothesized that differences in lifespan are correlated with persistent differences in the underlying gene-regulatory landscape, potentially originating from stochastic events early in life. To test this, we used biomarkers of aging—physiological measurements which correlate with an individual’s rate of aging relative to the rest of the population and can thus be used to predict future lifespan. We screened several such biomarkers in the form of fluorescent reporters driven by the promoters of several different microRNAs to examine their relationship with future lifespan at the individual level. Surprisingly, despite their expression across a variety of tissues, we found that at least three of these transgenic reporters appeared to correlate with lifespan in a redundant fashion, implying a link to a shared underling state related to organismal health. To better understand the gene expression landscape potentially regulating expression of these reporters, we sorted populations at a timepoint in mid-life by the expression of four different fluorescent biomarkers of aging and performed RNA-sequencing on the resulting long- and short-lived sub-populations. We found that the transcriptomes of long vs. short future lifespan were indeed remarkably similar across all biomarkers tested, supporting the model of a common underlying health state. We hypothesized that these transcriptomes may represent a state of youthful or advanced physiological age—that is, that animals predicted to be long-lived are aging slowly while those predicted to be short-lived are aging rapidly, and that their differences in gene expression would thus appear the same as a difference in apparent chronological age. To test this, we also collected and sequenced RNA from large synchronized populations aged days two through twelve in order to determine the physiological aging trajectory of the average population. By comparison to this average trajectory, we found that biomarker-sorted animals did indeed have transcriptomes which appeared younger or older than their actual chronological age. Unexpectedly, however, we also found that we could control for this signature of physiological age without abolishing the signal of differential gene expression between predicted long-lived and short-lived worms. In other words, we found long- vs. short-lived individuals within a population to be separated not only along the axis of physiological age, but also orthogonally to it. Differentially expressed genes in this second category were strongly enriched for transcripts associated with the germline, raising the exciting possibility that interindividual differences in germline gene expression may play a role in causing variability in lifespan. The latter half of this dissertation focuses on other facets of the aging process, specifically characterizing first the role of Notch signaling in reproductive aging and second the pathway through which the angiotensin-converting enzyme (ACE) inhibitor drug Captopril extends lifespan in C. elegans. The works presented here thus represent enhancements to our understanding of aging at several levels: from wildtype, unperturbed variability to genetic and pharmacological interventions.
Language
English (en)
Chair and Committee
Kerry Kornfeld
Committee Members
Tim Schedl; Michael Brent; Thorold Theunissen; Zachary Pincus
Recommended Citation
Mosley, Matthew, "Aging, Fast and Slow: Gene Expression Signatures of Physiological Age Vs. Future Lifespan in Caenorhabditis elegans" (2024). Arts & Sciences Electronic Theses and Dissertations. 3340.
https://openscholarship.wustl.edu/art_sci_etds/3340