Aging is a biological phenomenon that involves a gradual decline in physiologic homeostasis. As an essential molecular mechanism, transcription is clearly crucial for this homeostasis and yet the specific causal pathways through which transcription influences lifespan are difficult to identify. Disruption of transcription produces diverse pleiotropic effects and compensatory mechanisms, making it hard to isolate the specific pathways of influence involved. To understand the role of basic transcriptional machinery in aging, we developed the Auxin Inducible Degradation (AID) system (Zhang, Liangyu, et al, 2015) as a tool to quantitatively tune the steady-state abundance of essential genes in long-term, time-series experiments. Focusing on
rpb-2, an RNA Polymerase II (B) subunit, we obtained an
rpb-2::AID transgenic line that is viable in the presence of a highly-expressed somatic TIR-1 auxin-dependent E3-ubiquitin ligase. We found that
rpb-2::AID animals exhibit a dose-dependent relationship between auxin and lifespan, with high auxin concentrations replicating the adult lethal phenotype of
rpb-2 RNAi. The dose dependence of lifespan on RPB-2 highlights the quantitative role RNA Polymerase II plays in C.elegans aging. To investigate the pathways through which
rpb-2 influences lifespan, we collected transcriptomic data from populations across an auxin dosage series. Selecting a set of differentially expressed genes for functional validation, we identified profound epistasis in the physiologic response to
rpb-2 knockdown. RNAi of a single gene was sufficient to invert the dose-dependence of RPB-2 degradation on lifespan, causing a paradoxical extension of lifespan. This lifespan extension is similar to the previously characterized increased lifespan of the
ama-1 mutant which is another RNA Polymerase II subunit (Debès, Cedric, et al, 2019). We believe that physiologic dosage series provide a novel, quantitative means for mapping out the pleiotropic action of interventions in aging. Zhang, Liangyu, et al. Development 142.24 (2015): 4374-4384. Debès, Cedric, et al. bioRxiv (2019): 719864.