Longevity Papers 2025-11-14

In this episode of Longevity Papers, we critically analyze the five most impactful papers from this week (November 10-14, 2025) selected from longevitypapers.com for biotech researchers and longevity enthusiasts. 1) 'circHERC1-A telomerase activator' (Yumeng Cui et al., Beijing Institute of Biotechnology, November 12, 2025, Science Advances, https://pubmed.ncbi.nlm.nih.gov/41223261/ ) - We explore how the circular RNA circHERC1 activates telomerase expression by recruiting RNA Pol II to the TERT promoter. Notably, circHERC1 declines with age, correlating with reduced telomerase activity. Restoration via AAV or extracellular vesicles enhances telomere elongation and reverses aging phenotypes including improved cognition and physical performance. This addresses telomere attrition as a hallmark of aging, building on decades of telomerase biology since Greider/Blackburn 1985, with a unique endogenous regulatory mechanism distinct from previous failed small-molecule approaches. 2) 'HDAC2 inhibition restores H4K16 Acetylation and Rescues Cellular Senescence in Hutchinson-Gilford progeria syndrome' (Karimpour et al., University of Alberta, November 7, 2025, BioRxiv, https://www.biorxiv.org/content/10.1101/2025.11.07.687234v1 ) - We examine how systematic screening identified HDAC2 (not SIRT1) as the dominant deacetylase responsible for H4K16ac loss in accelerated aging. Pharmacological HDAC2 inhibition restores H4K16 acetylation, rescuing nuclear morphology, proliferative capacity, and reducing senescence in HGPS cells. This represents a specificity win over pan-HDAC inhibitors that failed clinically, with potential transformative implications if HGPS lifespan is extended, proving concept for broader aging populations. 3) 'Targeting Endothelial KDM5A to Attenuate Aging and Ameliorate Age-Associated Metabolic Abnormalities' (Rifeng Gao et al., Zhejiang University, November 14, 2025, Advanced Science, https://pubmed.ncbi.nlm.nih.gov/41236095/ ) - We discuss how endothelial-specific KDM5A deficiency causes shortened lifespan with senescent phenotypes (fat accumulation, reduced thermogenesis, kyphosis), demonstrating causative endothelial aging. The mechanism links epigenetics to metabolism: KDM5A regulates H3K4me3 at FABP4 promoters. Maintaining VEC-specific KDM5A prolongs lifespan, establishing the KDM5A/FABP4 axis as a therapeutic target for vascular aging and systemic metabolic dysfunction. 4) 'Mitochondrial dysfunction drives age-related degeneration of the thoracic aorta' (Arjune S Dhanekula et al., University of Washington, November 14, 2025, GeroScience, https://pubmed.ncbi.nlm.nih.gov/41233677/ ) - We analyze how elamipretide (SS-31), a mitochondria-targeted peptide in clinical trials, restores Complex II respiration to young levels in aged aortas, reducing stiffness, elastin breaks, and inflammatory MMP9 expression. This demonstrates causation via pharmacological rescue of a hallmark aging process, with SS-31 already being tested in Friedreich's ataxia and heart failure—this aging application would expand clinical relevance significantly. 5) 'Defining Microbiota-Derived Metabolite Butyrate as a Senomorphic: Therapeutic Potential in the Age-Related T Cell Senescence' (Nia Paddison Rees et al., University of Birmingham, November 7, 2025, Aging Cell, https://pubmed.ncbi.nlm.nih.gov/41201238/ ) - We examine butyrate as a senomorphic agent preventing senescence accumulation rather than eliminating it. The mechanism: butyrate suppresses IL-6/IL-8 SASP secretion via mTOR/NF-κB inhibition, with reduced DNA damage markers and mitochondrial ROS. Young fecal microbiota reverse aged splenic senescence in vivo, implicating the microbiota-immune axis. Butyrate is dietary, cheap (0/month), and represents a scalable intervention if lifespan studies confirm efficacy. This podcast is AI generated and may contain errors.