Pol III Inhibition Extends Longevity in Short-Lived Species

As this paper notes, Pol III is downstream of mTORC1, and like mTORC1, inhibition extends life span in a variety of laboratory species. The network of genes around mTOR relates to the regulation of cellular responses to stress, such as increased autophagy. It is complex and touches upon many aspects of cellular metabolism. Upregulation of these stress response mechanisms, such as via the practice of calorie restriction, improves health and extends life in short lived species. It has similar effects on health in long-lived species such as our own, but the effects on lifespan are much smaller. Calorie restriction extends life by 40% in mice, but does not add more than a few years to human life span.

The transcription of the eukaryotic nuclear genome is performed by three, evolutionarily conserved, multi-subunit RNA polymerases (Pols) that each transcribe a distinct set of genes. A large proportion of the nuclear genome is transcribed by Pol II to generate both coding and non-coding RNAs. In contrast, Pol I only transcribes a single gene, albeit present in multiple copies within the genome, to produce the precursor to most rRNAs. While Pol I and III transcribe fewer genes, they generate some of the most abundant cellular RNAs accounting for much of the cellular transcriptional activity.

Pol III function has also extended beyond the canonical role in transcription of the nuclear genome to now include responses to DNA viruses and homologous recombination-mediated repair of DNA double-strand breaks. Pol III mediated transcription is involved in a wide range of biological processes including cell and organismal growth, cell cycle, stemness and differentiation, development, regeneration, and cellular responses to stress. As a result, Pol III subunits have been implicated in a wide variety of disease states.

More recently, Pol III was identified as an evolutionarily conserved determinant of organismal lifespan acting downstream of mTORC1. Pol III inhibition extends lifespan in yeast, worms and flies, and in worms and flies acts from the intestine and intestinal stem cells respectively to achieve this. Intriguingly, Pol III activation achieved through impairment of its master repressor, Maf1, has also been shown to promote longevity in model organisms, including mice. The evolutionary conservation of Pol III affirms its potential as an exciting, novel therapeutic target for ageing and age-related health.

Link: https://doi.org/10.3389/fgene.2021.705122

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