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SENS Damage Repair (de Grey)

Simple Summary

  • Idea: Aging is caused by a manageable set of damages; periodic, targeted repairs can maintain youthful function and extend lifespan.
  • Not just biomarkers: decisive wins are durable max‑lifespan gains from combined repair stacks with acceptable safety; manage diminishing returns/toxicity.

Conflicts With Other Theories

  • Epigenetic Information (Sinclair)
    • Sinclair: Correcting epigenetic state can restore function without enumerating damage.
    • SENS: Repaired damages are necessary and sufficient for large lifespan gains; biomarker resets may not translate without repairs.
  • Classic Models (Medawar, Williams, Hamilton, Kirkwood)
    • Classics: Repairs should show costs/limits; big gains are unlikely.
    • SENS: Carefully targeted, stacked repairs can push max lifespan beyond best single agents with manageable toxicity, challenging strict budget constraints.
  • Pathogen Control (Lidsky)
    • PC: Under pathogen challenge, extensions should trade off with infection unless paired with anti‑pathogen measures.
    • SENS: Repairs can extend lifespan without infection penalties; clean wins under pathogen challenge weigh against PC.
    • PC argues lifespan varies with population structure (dispersal, eusociality, cohorting), which repair‑first frameworks do not explain by default.
  • Resilience / Criticality (Fedichev)
    • Resilience: Hazard can drop by tuning dynamics without repairs.
    • SENS: Fixing concrete damages shifts the whole hazard curve; resilience‑only wins should be smaller/transient if damage is primary.
  • Bioelectric / Morphogenetic Control (Levin)
    • Levin: Pattern reset may obviate some repairs.
    • SENS: If damage blocks pattern control, repairs are prerequisite; strong repair‑first wins favor SENS primacy.
  • Longevity Bottleneck (Various Proponents)
    • Bottleneck: One/few pathways dominate; relieve the chokepoint.
    • SENS: Multiple damages jointly matter; broad, combined repairs outperform single‑pathway relief.

Questions

What is the status and relevance of LEV Foundation’s Robust Mouse Rejuvenation studies?

  • RMR1 (EV Foundation)
    • What they’re attempting: A “stack vs parts” test in old, normal mice (factorial design). They try each part alone, “all‑but‑one,” and the full stack to see what truly drives benefit. Parts: rapamycin (mTOR dial‑down), targeted senescent‑cell removal (galactose‑conjugated navitoclax), telomerase gene therapy given through the nose once a month (AAV‑mTERT, intranasal), and a blood‑stem‑cell refresh (hematopoietic stem‑cell transplant after mobilization with G‑CSF + AMD3100).
    • End goal: Robust mouse rejuvenation — clear, durable, and safe gains in both average and maximum lifespan, plus better organ function, that hold up under full stats and replication.
    • Status (why few results): The protocol and interim notes are public, but the final statistics (median and maximum lifespan, risk‑of‑death curves/hazards, pathology) are not posted yet. Until those data appear, you can’t judge success or failure — early anecdotes aren’t proof, and “no results yet” can just mean ongoing follow‑up or analysis.
    • Links: https://www.levf.org/projects/robust-mouse-rejuvenation-study-1 and https://www.levf.org/projects/robust-mouse-rejuvenation-study-1/study-updates
  • RMR2
    • What they’re attempting: A different, body‑wide “tune‑up” stack aimed at systemic repair/modulation: cleaner circulating proteins (recombinant serum albumin), repair/support cells (mesenchymal stem cells), dialing down Cdc42 (CASIN), an experimental senolytic targeting lipid metabolism, and oxytocin.
    • End goal: Show that stacked repairs can reliably lift both mean and max lifespan with good safety (a strong test of SENS‑style repair primacy). If effects are small or clash, it argues for re‑tuning the stack or adding other tools.
    • Status (why few results): As with RMR1, treat outcomes as pending until a full statistical report is released. Formal numbers (lifespan, hazards, causes of death, safety) are what will move the needle.
    • Link: https://www.levf.org/projects/robust-mouse-rejuvenation-study-2

If RMR had big wins, wouldn’t we have heard by now? Why the wait?

Short answer: lifespan trials mature slowly, and good groups avoid shouting before the data are locked and reproducible. A long gap raises the probability that results are mixed/modest or operationally noisy, but it’s not proof either way.

Sources

  • Web: https://vxtwitter.com/jpsenescence/status/1962604483357106366
  • Primary: Senolytics (Xu 2018): https://doi.org/10.1038/s41591-018-0092-9; Genetic clearance (Baker 2011): https://doi.org/10.1038/nature10600; Telomerase gene therapy (de Jesus 2012): https://doi.org/10.1002/emmm.201200245