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Lifespan Linked to Lower Protein Synthesis Gene Expression

NEW YORK – Dampened expression of genes that code for protein translation components in several human organs may correspond with slower aging and stretched-out human lifespans, new research suggests.

"We provide evidence that biogenesis of protein synthesis machinery in specific adult tissues drives human aging," co-senior author Nazif Alic, a genetics, evolution, and environment researcher at University College London, and colleagues wrote in Genome Research on Tuesday.

For their study, the researchers relied on an analytical approach called Mendelian randomization to assess RNA polymerase Pol I and Pol III gene expression and the expression of genes coding for ribosomal proteins in thousands of individuals who had reached at least the 90th percentile for age. The Pol I enzyme contributes to 5S ribosomal RNA and transfer RNAs, they noted, whereas Pol III is known for producing most other rRNAs.

The team's results — which were informed by expression and expression quantitative trait locus data from the Genotype-Tissue Expression project and genotyping data from a prior genome-wide association study involving 11,262 particularly long-lived individuals and nearly 25,500 control individuals — suggested that enhanced lifespan was linked to lower-than-usual expression of the Pol I, Pol III, and ribosomal protein-coding genes.

Those findings line up with those previously described in nonhuman model organisms, the authors noted. But while genes linked to protein production have been implicated in aging and longevity in fruit flies, yeast, and worm models, they explained, alterations in protein translation genes in humans are better known for their role in serious developmental conditions.

"[I]n humans, loss of function in these genes has been seen to cause diseases, such as developmental disorders known as ribosomopathies," Alic said in a statement. "Here, we have found that inhibiting these genes may also increase longevity in people, perhaps because they are most useful early in life before causing problems in late life."

Using available expression data for 11,262 participants, the team turned to Mendelian randomization, identifying previously unappreciated and apparently causal ties between aging and the expression of each of the protein synthesis machinery components considered.

The investigators noted that longevity-associated dips in Pol I-, Pol III-, and ribosomal protein-coding gene expression were particularly pronounced in tissues linked to ribosomopathies in the past, including visceral fat tissue, liver tissue, and skeletal muscle samples.

"Our study shows the utility of leveraging genetic variation in expression to elucidate how essential cellular processes impact human aging," the authors reported. "The findings extend the evolutionary conservation of protein synthesis as a critical process that drives animal aging to include humans."

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