Fight Aging!

Researchers have established a number of interventions in short-lived species that extend life as a result of degrading the function of a cellular component, usually the mitochondria. Some forms of degraded function induce the cell to increase maintenance activities and otherwise alter its behavior to produce a net benefit to function, resistance to damage, and other line items that combine to reduce the level of age-related dysfunction in tissues and thereby extend life span. Where alterations touch on aspects of the complex processes of gene expression in the cell nucleus, the full effects on cell function are usually unclear. Tinkering with the machineries of gene expression typically has sweeping effects on cellular biochemistry, and it is usually a surprise to find that breaking something in the nucleus yields an increase in life span.

The first step in gene expression is the production of RNA, a step known as transcription. RNA molecules in the cell nucleus are produced by structures that read gene sequences in the genome and assemble the matching RNA piece by piece from the raw materials of nucleotide molecules. An RNA molecule is finalized by giving it a 5` structure at one end and a 3` structure and poly(A) tail of trailing adenine nucleotides at the other. This decoration is managed by a different set of machinery than that responsible for reading and assembling RNA. One of these molecular machines is the Integrator, and in today's open access paper researchers report that degradation of Integrator function results in slowed aging in nematode worms. They believe that this occurs because the chain of cause and consequence spreading out from impaired RNA 3` processing in the cell nucleus leads to mild mitochondrial dysfunction, and thus an improved cell maintenance. Given the breadth of changes, however, this has to be taken as an initial suggestion rather than an answer to the question.

Adulthood depletion of Integrator extends lifespan and healthspan via defective pre-mRNA processing

Identifying strategies to mitigate age-related physiological decline remains a central challenge. During ageing, the transcriptome undergoes extensive remodelling, but how this affects organismal health and lifespan is not well understood. The Integrator complex plays a central role in RNA polymerase II transcription and RNA 3` end processing. Surprisingly, we find that depletion of most Integrator subunits specifically in adults extends lifespan and healthspan in the nematode C. elegans. We show that loss of the catalytic subunit INTS-11 disrupts 3′ end formation of small nuclear and spliced leader RNAs, impairing trans-splicing and promoting outron retention in a subset of transcripts enriched for spliceosomal and nucleocytoplasmic transport genes.

These RNA-processing defects lead to altered levels of endogenous small interfering RNAs (siRNAs), which are required for the longevity and healthspan benefits of INTS-11 depletion. In parallel, outron retention disrupts nuclear-encoded mitochondrial gene expression and protein production, inducing mitochondrial dysfunction and promoting lifespan extension. We also demonstrate that loss of INTS-11 perturbs transcription elongation at genes where Integrator is present at promoters, and that upregulation of enhancer elements within intragenic regions can affect the expression and isoform usage of nearby genes. Together, our findings identify Integrator as a key upstream regulator of non-coding RNA transcription, which in turn impacts protein-coding gene expression and mitochondrial function to shape the ageing process.