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Longevity‐related molecular pathways are subject to midlife “switch” in humans
There is evidence for important age “switches” in Drosophilia flies which can be modulated to extend lifespan. These new animal studies indicate that molecular aging might not be a constant process, but rather be subject to accelerations during key ages. Whether this occurs in humans, particularly for the non-coding RNA of our genome (AKA transcriptome), is unknown.
A research team from the University of Miami first examined the protein‐coding transcript responses during 30-60y (group 1) and 60-90y of age (group 2). Applying a novel RNA method to quantify coding vs. long non-coding RNA (lncRNA), the team identified around 800 transcripts, related to enhanced longevity in flies, which "switch off" at around 60 years of age in human muscle and brain. In silico analysis demonstrated that this temporary linear “signature” was regulated by drugs, which reduce mortality or extend life span in model organisms, including 24 inhibitors of the IGF‐1/PI3K/mTOR pathway that mimicked, and 5 activators that opposed, the signature.
Another team, Aliper et al., searched for potential anti‐age compounds using an artificial intelligence approach, finding HA‐1004 and Fasudil, both of which regulate the current study's Group 2 age genes. Aliper identified Withaferin A as an mTOR inhibitor, which was also the current study's top‐ranked hit, while another 11 other drugs were common to both projects. This shows that compounds which extend longevity in clinical trials also impact our human age‐related transcriptional signature.
While the key protein regulators of longevity and health-span in short-lived animals have been found for the first time to be crucial to human molecular aging, this new study also determined that many little-studied non-coding genes are involved in human aging. Considered the "dark matter" of the human genome, these non-protein-coding genes are widely present in human cells, but often not found in lower organisms. It now appears they could play an important role in the molecular features of aging.
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