This week on Longevity Papers, we dissect five groundbreaking papers from the week of June 16th, 2025, sourced from LongevityPapers.com. We prioritize surprising findings from credible labs that challenge existing models in aging research. 1. The Mediator complex subunit Med19 extends healthy lifespan in Drosophila by preventing cellular and organismal frailty (Payet et al., RESTORE Research Center, June 18, 2025, BioRxiv: https://www.biorxiv.org/content/10.1101/2025.06.18.659864v1) - We start with the most significant paper of the week: a jaw-dropping claim of a nearly 90% median lifespan extension in fruit flies from upregulating a single gene, Med19. This effect size rivals the most potent interventions known. Well discuss how this master regulator of transcription could be a powerful control knob for aging, its potential for rejuvenation, and the healthy dose of skepticism required for a non-peer-reviewed paper with such a large effect. We compare this to other major lifespan-extending mutations in Drosophila, like those in the Indy gene, and discuss the importance of absolute vs. percentage increase given the variability in control lifespans. 2. An insulin-sensitive Drosophila insulin-like receptor mutant remodels methionine metabolism to extend lifespan. (Tatar et al., Brown University, June 16, 2025, PLoS Genetics: https://pubmed.ncbi.nlm.nih.gov/40523036/) - This elegant study tackles a core problem in longevity research: extending lifespan via the insulin/IGF-1 signaling (IIS) pathway often comes with nasty side effects like insulin resistance. The authors identified a specific mutation that uncouples these effects, providing longevity while maintaining health. Well break down how it achieves this by mimicking methionine restriction (MetR), beautifully linking two of the most robust longevity pathways. This work offers a more refined roadmap for developing gerotherapeutics that avoid the pitfalls of blunt pathway inhibition. 3. Lysergic Acid Diethylamide extends lifespan in Caenorhabditis elegans (Carrilho et al., DOr Institute for Research and Education, June 16, 2025, BioRxiv: https://www.biorxiv.org/content/10.1101/2025.06.16.659936v1) - In perhaps the most unexpected finding, researchers show that the classic psychedelic LSD extends lifespan in C. elegans. The key insight is that it appears to act as a caloric restriction (CR) mimetic, activating the key transcription factor PHA-4/FOXA without reducing food intake. This opens a completely new chemical space for geroprotector discovery. We discuss the challenge of human translation and what this implies for other, non-psychedelic serotonergic compounds. We contextualize this by comparing it to known CR mimetics like metformin and rapamycin. 4. Reversible proliferative arrest induced by rapid depletion of RNase MRP. (Liu et al., University of California, Riverside, June 19, 2025, Cell Proliferation: https://pubmed.ncbi.nlm.nih.gov/40533478/) - Achieving suspended animation is a holy grail of medicine. This paper presents a novel and surprisingly simple method to induce a long-term, yet fully reversible, state of quiescence in human cells by targeting ribosome biogenesis. Well discuss how this reinforces the rate of living theory and connects to longevity interventions like rapamycin. This provides a powerful new tool for research and a specific target for manipulating cellular states, with potential applications from organ preservation to extending healthspan. 5. A Nucleic Acid Prodrug That Activates Mitochondrial Respiration, Promotes Stress Resilience, and Prolongs Lifespan. (Anada et al., Kyushu University, June 13, 2025, Journal of the American Chemical Society: https://pubmed.ncbi.nlm.nih.gov/40512174/) - From the high-impact journal JACS, this paper describes a novel small molecule designed to directly combat mitochondrial dysfunction, a hallmark of aging. By increasing the pool of adenine nucleotides (ATP), the prodrug activates AMPK and markedly extends lifespan in C. elegans. Well explore the promise of this direct approach to boosting cellular energy and the critical need to consider long-term safety, as broadly boosting energy could have unintended consequences.