Nick Stroustrup @nstroustrup.bsky.social · 06/09/20262) Many cell types in humans don't live much longer than worms, measured from cell cycle exit until death. So I think about human physiology acting at a wide range of timescales rather than a single long timescale. We do see big cell-type specific differences in mRNA declines in mice. 100
Nick Stroustrup @nstroustrup.bsky.social · 06/09/2026Hi Ian! Two thoughts 1) we looked at worms first, where we could obtain good lifespan data. So we just don't know for mice yet. There is one previous report of increases in pol II immuno-staining in old mouse hepatocytes, but that's not the whole story I think. 100
Nick Stroustrup @nstroustrup.bsky.social · 06/09/2026Fun idea! Point: we worry about confounding mRNA degradation when samples sit out for a few moments in the lab. Counterpoint: doi.org/10.1016/j.ce...doi.orgRedirecting 100
Nick Stroustrup @nstroustrup.bsky.social · 06/09/2026The stoichiometric ratio of mRNA to ribosomes is important! But we know there are several feedback compensatory mechanisms that modulate ribosomes' per-molecule activity, which make the situation harder to predict. 120
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026RNA Pol I and III are the polymerases changing under mTOR inhibition, more than Pol II, no? 010
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026Thank you! Please get in contact with questions or feedback. 470
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026I'd also like to flag a preprint from the Maharana lab, IISc, which implicates nucleotide metabolism and phase-separated condensates in age-associated RNA loss www.biorxiv.org/content/10.6... 22/22biorxiv.orgAging associated RNA loss impairs the dynamics of RNA and protein condensatesAltered biomolecular condensate dynamics are increasingly implicated in age-associated neurodegenerative disorders, yet the molecular principles governing these changes remain incompletely understood.... 1100
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026Our works also suggests a new strategy for interventions in aging: stabilizing youthful disequilibrium states. In particular, we’re now working on approaches to restore mRNA synthesis capacity in aged tissues. Please get in contact with questions or feedback. 21/22 2131
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026The disequilbrium also explains why brief perturbations are "sticky", producing permanent decreases in lifespan. Far from equilibrium there is no homeostatic restoring force pulling Pol II back up, so early losses accumulate rather than recover. 20/22 181
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026There is more in the preprint: we model Pol II dynamics and show individuals enter adulthood in a state of Pol II abundance disequilibrium. The kinetic relaxation of this state drops Pol II abundance, limits RNA synthesis capacity and, it seems, determines lifespan. 19/22 170
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026Across 13 lifespan-altering interventions including changes to diet, body temperature, daf-16 and graded daf-2 depletion, the rate of mRNA decline predicts lifespan with a Pearson correlation of -0.96. Slower decline, longer life. 18/22 193
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026Demographically, acceleration of Pol II degradation looks exactly like aging: it produces a temporal rescaling of the entire survival curve. Rescaled hazard trajectories superimpose, suggesting that Pol II declines can set the rate of aging itself. 17/22 1113
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026Aging rates and mRNA abundance declines are tightly coupled: Across these populations, mRNA abundance tracks the remaining lifespan the population has left. Deplete the pool by a given amount and you can read off the days remaining. 16/22 172
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026This excess is physiologically relevant: it is used to live long. Raising Pol II ubiquitination rates accelerates mRNA declines, shortening lifespan. Even a few hours of extra RPB-2 degradation in youth permanently limits mRNA abundance and shortens healthspan and lifespan. 15/22 181
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026So it seems that individuals enter adulthood with a four-fold excess of Pol II, high above steady state replenishment levels. 14/22 160
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026We can completely abrogate Pol II declines by knocking down the E1 ubiquitin-activating enzyme uba-1 or the 26S proteasome subunits pas-4, pbs-2, rpt-1. (though these treatments ultimately sicken animals due to toxic effects of broad inhibition of the proteosome). 13/22 161
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026We find that Pol II decreases are driven by ubiquitin-mediated proteasomal degradation: during adulthood, Pol II subunits are degraded faster than they are synthesized. 12/22 182
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026We find that nuclear Pol II drops several-fold in abundance with age. This is a somatic phenomenon–the germline seems to maintain Pol II just fine. Somatic declines in Pol II begin at the start of adulthood, a time when individuals still look young and vigorous. 11/22 1229
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026We hypothesized mRNA declines might be a symptom of declines in mRNA synthesis rate. To look at this, we built an RNA Pol II in vivo reporter that lets us measure the abundance of RNA Pol II in the nucleus across adulthood. 10/22 1100
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026Obviously, the abundance of mRNAs is important for cells for many reasons–for example it partially determines much protein a cell can make. Why is absolute mRNA abundance dropping so much during aging? 9/22 1101
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026We went back and also found some previous reports of mRNA decreases: in a super cool paper Davie, Janssens et al.'s single cell atlas that found RNA depletion in the Drosophila brain: pmc.ncbi.nlm.nih.gov/articles/PMC... 8/22pmc.ncbi.nlm.nih.govA Single-Cell Transcriptome Atlas of the Aging Drosophila BrainThe diversity of cell types and regulatory states in the brain, and how these change during aging, remains largely unknown. We present a single-cell transcriptome atlas of the entire adult Drosophila ... 1161
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026We first saw this in our C. elegans data, but then went looking and confirmed that similar decreases exist in mouse single-cell atlases: e.g. we see a >2-fold decrease in aorta, >3-fold in non-myeloid brain by 18-24 months. 7/22 1141
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026But if we perform absolute quantification using short-read RNA-seq with ERCC spike ins, or native long-read sequencing (thanks @evamarianovoa + team for the nanopore data) we see a huge effect. 6/22 1140
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026This phenomenon is invisible to standard computational practice. RNA-seq library-size normalization assumes every sample contains equal amounts of mRNA, and rescales libraries to enforce this assumption. 5/22 1173
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026We confirmed these results in single-cell transcriptomes: RNA depletion is happening in individual cells, across most cell types. On an absolute scale, aged cells seem to be running low on mRNA. 4/22 1150
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026The effect is fairly dramatic in both nematodes and mice. For example: a young adult nematode (equivalent to a teen-ager) contains ~700 million mRNA molecules total. This drops eight-fold by old-age. 3/22 1217
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026The project was spearheaded by @adelcarmenf.bsky.social with contributions from everyone in my group at @crg.eu . You can read the preprint here: www.biorxiv.org/content/10.6... 2/22biorxiv.org 1143
Nick Stroustrup @nstroustrup.bsky.social · 05/09/2026Did you know that the cells of old animals contain much less mRNA than the cells of young ones? Let me share with you some results from an ongoing project in the lab, where we are finding that a progressive depletion of total mRNA abundance is a crucial part of aging 1/22 621185
Reposted by Nick StroustrupBöke Lab @bokelab.bsky.social · 12/08/2026What does an ovary actually look like as it ages—one oocyte at a time? We mapped >85,000 oocytes in >100 intact mouse ovaries, in 3D, across the reproductive lifespan. And the ovary turned out to be much more organized than we expected. 🧵 1/5 www.nature.com/articles/s43...nature.comThree-dimensional mapping of intact ovaries reveals the aging dynamics of the ovarian reserve - Nature AgingThe spatiotemporal dynamics of the depletion of the ovarian reserve remain incompletely understood. Combining whole-ovary imaging, AI and modeling, the authors mapped over 85,000 mouse oocytes and fou... 14816
Reposted by Nick StroustrupMarkus Höpfler @markushopfler.bsky.social · 08/05/2026We're hiring! Join our growing team at the @crg.eu as a postdoc. Curious about how mRNA translation and decay cross-talk? We're looking for a postdoctoral researcher to lead a project in the field of RNA biology and gene regulation. Apply here: recruitment.crg.eu/content/jobs... Please share!recruitment.crg.euPostdoc in the Dynamics of Protein Synthesis and RNA Decay Lab | CRG Online Recruitment Portal 0108
Nick Stroustrup @nstroustrup.bsky.social · 09/06/2026wapo.st/43SQW6qwapo.stPope Leo to bless new tower at Sagrada Família, Gaudí’s unfinished masterpieceThe basilica, designed by Antoni Gaudí, becomes the world's tallest church with the inauguration of its central spire — the 566-foot-high Tower of Jesus Christ. 083
Nick Stroustrup @nstroustrup.bsky.social · 10/04/2026How do wealthy parents help their offspring? By giving them ribosomes! Optimal ribosome provisioning is key to fast development in unpredictable environments. The fastest path to ribosomal wealth in nematodes is a maternal inheritance. Happy we could play a small part in this fascinating work. 031
Nick Stroustrup @nstroustrup.bsky.social · 28/03/2026Do we know the efficacy of the new vaccine candidates? 000
Reposted by Nick StroustrupLukas Röseler @aufdroeseler.bsky.social · 26/03/2026-- New Open Research Game -- I reached the rank of Asst. Prof in #TenureRun! 🎓 I published 98 papers and paid $115.000 in APCs to publishers. My grant money is gone and I am exhausted. 💸 How far can you make it? Play now at forrt.org/TenureRun/ 15720
Nick Stroustrup @nstroustrup.bsky.social · 02/03/2026And of course, I remember his kindness of taking me on as a clueless engineering student and getting me a start in genetics. I only worked with him for a year, more than twenty years ago, but I still think about things he said. David Botstein, 1942 - 2026. www.online-tribute.com/DavidBotsteinonline-tribute.comDavid Botstein | 1942 - 2026 | Online-Tribute.comDavid was a beloved husband, father, brother, scientist, teacher, mentor, musician, friend, who touched the lives of thousands. David’s wide-ranging scientific career spanned decades with a legacy o… 000
Nick Stroustrup @nstroustrup.bsky.social · 02/03/2026So while David is often remembered for his field-defining technological advances, e.g. restriction fragment linkage mapping and microarrays, what I remember most is the way he spoke and thought--integrating complex mechanistic detail with broader ideas about yeast physiology and metabolism. 100
Nick Stroustrup @nstroustrup.bsky.social · 02/03/2026David was super smart and super direct, with a insistence on clear thinking that permeated everything he did. He could speak about "big picture" dynamical properties of cells, but he also had an encyclopedic memory-- ask him about any yeast gene and he'd tell you about it in fascinating detail. 100
Nick Stroustrup @nstroustrup.bsky.social · 02/03/2026hoping to learn what all the excitement was about, at the new genomics institute they'd just built on campus. I cold-emailed David looking for work, and a week later I was sitting in his office, learning about the principles of chemostats. I think I still have the little notebook drawing he made. 100
Nick Stroustrup @nstroustrup.bsky.social · 02/03/2026It's very sad to learn of David Botstein's passing. I worked in David's lab as an undergraduate--one of the most formative periods of my academic life and probably the biggest reason I work in biology today. I vividly remember my first meeting with David. I was a 3rd year engineering student, 120
Reposted by Nick StroustrupJavier Apfeld @javierapfeld.bsky.social · 28/01/2026We found 24 neuron classes that are excited or inhibited by environmental H2O2, spread across the nose, mouth, and inner pharynx. Different neurons trigger at different H2O2 levels (from 1 µM early warning to >1 mM lethal), and many adapt, so responses encode dose + recent history. 7/ 111
Nick Stroustrup @nstroustrup.bsky.social · 25/02/2026I am curious what counterfactual unsettling egg shapes you have in mind! 000
Nick Stroustrup @nstroustrup.bsky.social · 18/02/2026I was today years old when I discovered that "npj Aging" and "Nature Aging" are separate journals, despite being published with identical titles by Springer Nature! 020
Reposted by Nick StroustrupMark Peifer (He, him) @peiferlabunc.bsky.social · 17/02/2026Please consider joining us--the new restrictions on academic freedom are coupled with a move to make all syllabi public and secretly record our classes--UNC's status as a top public university is at stake 0104
Reposted by Nick StroustrupNicole Gerlach @ngerlach.bsky.social · 12/02/2026I knew about the downward part, but not the upward part, and now I'm not okay. 2174
Reposted by Nick StroustrupEMBO @embo.org · 11/02/2026Happy International Day of Women and Girls in Science! 🧪 Don't forget to send in your nominations for the FEBS | EMBO #WomenInScience Award. Deadline: 15 May Read more: www.embo.org/the-embo-communities/f… #award 07038
Nick Stroustrup @nstroustrup.bsky.social · 05/02/2026www.nytimes.com/2026/02/04/o...nytimes.comOpinion | I’m the Prime Minister of Spain. This Is Why the West Needs Migrants. 031
Reposted by Nick StroustrupMonica Bettencourt-Dias @monicabettencourt.bsky.social · 23/01/2026📣 Please spread: we’re hiring a Lab Manager! It is a critical position in our new lab. As our lab moves to Barcelona and joins the @crg.eu, we’re looking for a Lab Manager to help build the lab and set the lab atmosphere. 🔗 Apply here 👉 recruitment.crg.eu/content/jobs... 29194