A team at UCL’s Institute of Healthy Ageing uses RNAi in Drosophila neurons to knock down the Pol III repressor Maf1. This preserves 5S rRNA transcription and protein synthesis during aging, improving neuromuscular and gut function, and extending female lifespan.
Key points
Neuron-specific RNAi of Maf1 in adult Drosophila boosts Pol III activity and extends female lifespan.
Maf1 knockdown prevents age-related decline in 5S rRNA expression and restores puromycin-labeled translation in aged brains.
Improved neuromuscular function, gut barrier integrity, and partial rescue of C9orf72-repeat toxicity demonstrate broad aging benefits.
Why it matters:
Sustaining neuronal protein synthesis via targeted Maf1 suppression offers a novel route to healthy aging and potential neuroprotective therapies.
Q&A
What is Maf1?
Why target 5S rRNA specifically?
How was the Drosophila model used?
Is this approach relevant to humans?
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Academy
Pol III and 5S rRNA in Longevity Science
Overview: RNA polymerase III (Pol III) is the enzyme responsible for transcribing small, non-coding RNAs, including 5S ribosomal RNA (rRNA) and transfer RNAs (tRNAs). These components are essential for building ribosomes—the cellular machines that synthesize proteins. As organisms age, the capacity to make proteins often declines, contributing to functional deterioration in cells that rely heavily on new protein synthesis, such as neurons.
What Is RNA Polymerase III?
Pol III is one of three RNA polymerases in eukaryotic cells. Unlike Pol I and Pol II, which transcribe ribosomal RNA precursors and messenger RNAs, respectively, Pol III specializes in small RNAs. The major products include:
- 5S rRNA: A core component of the large (~60S) ribosomal subunit.
- tRNAs: Adapter molecules that carry amino acids during protein synthesis.
- U6 snRNA: Involved in pre-mRNA splicing.
Role of Maf1
Maf1 is a conserved negative regulator of Pol III. Under stress, nutrient scarcity, or signaling pathways like TOR, Maf1 is dephosphorylated, migrates to the nucleus, and binds Pol III to repress transcription. This reduces the cell’s capacity to produce ribosomal components and slows down protein synthesis.
5S rRNA and Aging
Studies reveal that aging brains lose Pol III activity and 5S rRNA expression, which diminishes ribosome production and reduces global protein synthesis. This decline can impair neuronal maintenance, synaptic plasticity, and repair processes, accelerating cognitive and motor deficits.
Targeting Maf1 to Boost Healthy Aging
- Neuronal Intervention: By using genetic tools to lower Maf1 in adult neurons, researchers can restore Pol III output.
- Preserving 5S rRNA: Sufficient 5S rRNA ensures continued ribosome assembly, supporting sustained protein synthesis.
- Functional Benefits: Enhanced translation in aging neurons improves locomotion, sleep quality, gut integrity, and resilience to neurotoxic challenges.
Implications for Longevity: Modulating Pol III activity offers a new avenue for interventions aimed at preserving proteostasis in key cell types. By fine-tuning Maf1 function, it may be possible to delay or reverse age-related functional decline and develop therapies against neurodegenerative diseases linked to impaired protein synthesis.
