Date of Award

4-17-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Information Science

First Advisor

Robert Shmookler Reis

Abstract

Transcriptional profiling is extensively used to produce a snapshot of gene and pathway activity in a sample at a specific point in time, by utilizing high-throughput sequencing to quantify total gene expression at the transcript level. An isogenic panel of C. elegans longevity mutants, supplemented with a panel of RNAi gene-knockdowns known to convey longevity, both at an assortment of ages, was analyzed in an effort to elucidate transcriptional signatures of both longevity and aging in nematodes. Included in this panel was age-1(mg44) F2, a well-documented mutant characterized by extreme longevity. Genes that were highly differentially expressed between age-1(mg44) F2 and control were used to assemble a list of potential pro-longevity interventions via RNAi gene knockdown. Differential expression analysis was also performed using transcripts from lifespan-extending mutants (including age-1(mg44) F2) vs. controls and RNAi knockdowns vs. controls, seeking correlations with longevity and with aging. The resultant composite profiles were used to query CMap (a transcriptional profile database) to compare against profiles of drug effects on human cells in culture. The top-scoring candidates from these queries were investigated via literature and patent review. Twenty-seven promising candidate drugs were selected for testing from the longevity profile and the inverted-aging profile screens. Of the drugs tested, 24 have been shown to have neuroprotective effects, 19 are known anti-inflammatories, 26 have documented antineoplastic activity, and 18 were reportedly pro-regenerative. Of these 27 compounds, 19 were observed to reduce protein aggregation consistently, 15 were shown to improve resistance to hydrogen peroxide, and 6 were found to increase lifespan in C. elegans. These findings indicate that these strategies of constructing transcriptional profiles are effective and that compounds bearing similar transcriptional profiles do in fact extend lifespan, neutralize aging, and/or confer ancillary benefits.

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