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categories: ["longevity", "genetics"]categories: ["longevity", "genetics"]tags: ["reprogramming", "rejuvenation", "epigenetics", "aging", "gene therapy"]tags: ["reprogramming", "rejuvenation", "epigenetics", "aging", "gene therapy"]summary: "Transient expression of pluripotency factors that resets age-associated epigenetic marks in a cell while stopping short of erasing its differentiated identity."summary: "Transient expression of pluripotency factors that resets age-associated epigenetic marks in a cell while stopping short of erasing its differentiated identity."updated: "2026-07-28"updated: "2026-08-23"humanEvidence: "No human trial has been published as of 2026; the human results are in cultured cells, and every in vivo result is in mice, most of them transgenic lines carrying an inducible factor cassette."humanEvidence: "A phase 1 trial of an OSK therapy in optic neuropathies dosed its first participant in June 2026 and reported no results; published human data are in cultured cells, and every in vivo result is in mice."access: "Not available to patients: no approved product and no published human trial as of 2026, though companies have stated an intention to begin one in an eye indication."access: "Not available to patients: no approved product as of 2026, and the only human exposure is a phase 1 safety trial in optic neuropathies that began dosing in June 2026."reversibility: "context"reversibility: "context"issues: ["The stated company intention to run a first-in-human eye trial is unsourced."]------ ```infobox```infoboxlines 23–29 → 22–284 unchanged lines not shown
{ "label": "Factors used", "value": "OSK, sometimes OSKM", "link": "/wiki/yamanaka-factors" }, { "label": "Factors used", "value": "OSK, sometimes OSKM", "link": "/wiki/yamanaka-factors" }, { "label": "First in vivo result", "value": "2016, progeroid mice" }, { "label": "First in vivo result", "value": "2016, progeroid mice" }, { "label": "Typical readout", "value": "Methylation age, transcriptome" }, { "label": "Typical readout", "value": "Methylation age, transcriptome" }, { "label": "Human data", "value": "None published as of 2026" }, { "label": "Human data", "value": "Phase 1 dosing began 2026; none reported" }, { "label": "Readiness", "value": "TRL 3" } { "label": "Readiness", "value": "TRL 3" } ] ]}}lines 82–87 → 81–9152 unchanged lines not shown
Two failure modes sit inside the tolerated window and are largely invisible to the assays usually run. The first is functional loss without visible dedifferentiation: a hepatocyte can score younger on a clock while metabolising drugs worse, and few studies pair a molecular readout with a tissue-function assay in the same animal. The second is clonal rather than tissue-level. One cell pushed too far can seed a tumour long after the treatment ends, an event that no group-average measurement taken weeks later would detect. Dropping c-Myc lowers this risk without removing it, since Klf4 is also a proto-oncogene and dedifferentiation is itself a step toward malignancy.Two failure modes sit inside the tolerated window and are largely invisible to the assays usually run. The first is functional loss without visible dedifferentiation: a hepatocyte can score younger on a clock while metabolising drugs worse, and few studies pair a molecular readout with a tissue-function assay in the same animal. The second is clonal rather than tissue-level. One cell pushed too far can seed a tumour long after the treatment ends, an event that no group-average measurement taken weeks later would detect. Dropping c-Myc lowers this risk without removing it, since Klf4 is also a proto-oncogene and dedifferentiation is itself a step toward malignancy. > [!caution] The human dose window is still unmeasured> Both bounds above are set by mice. The first human exposure to a partial reprogramming therapy — OSK for optic neuropathies — dosed its first participant in June 2026, in a phase 1 safety study confined to the eye.[^lifebio2026]> A study of that size and design can detect an inflamed retina; it cannot address the failure mode that decides whether the technique is usable at all, a single over-reprogrammed cell seeding a tumour years later.> Nothing shorter than multi-year follow-up in a treated human compartment will move that question. ## Delivery and control## Delivery and control Every result above depends on a control system with no human equivalent. A doxycycline-inducible transgene sits in the germline of the mouse, is present in every cell at a known copy number, and stops when the drug is taken out of the drinking water. None of those properties survives translation: a patient has no transgene, cannot be transduced uniformly, and has no way to have the construct removed if it misbehaves.Every result above depends on a control system with no human equivalent. A doxycycline-inducible transgene sits in the germline of the mouse, is present in every cell at a known copy number, and stops when the drug is taken out of the drinking water. None of those properties survives translation: a patient has no transgene, cannot be transduced uniformly, and has no way to have the construct removed if it misbehaves.lines 92–98 → 96–1024 unchanged lines not shown
## Outlook## Outlook The evidence base is animal, largely mouse, and concentrated in a small number of transgenic lines. A first-in-human trial in an eye indication would supply the safety information the field most lacks, and companies have stated intentions to run one. Until then, the claim that partial reprogramming rejuvenates tissue rests on measures whose relationship to [[biological-age]] is itself unsettled, and any human timeline offered for systemic rejuvenation should be read as advocacy rather than forecast.The evidence base is animal, largely mouse, and concentrated in a small number of transgenic lines. A first-in-human trial in an eye indication, now under way, would supply the safety information the field most lacks. Until it reports, the claim that partial reprogramming rejuvenates tissue rests on measures whose relationship to [[biological-age]] is itself unsettled, and any human timeline offered for systemic rejuvenation should be read as advocacy rather than forecast. ## See also## See also lines 112–116 → 116–12113 unchanged lines not shown
[^browder2022]: `paper` Browder, K.C. et al. "In vivo partial reprogramming alters age-associated molecular changes during physiological aging in mice." *Nature Aging*, 2022.[^browder2022]: `paper` Browder, K.C. et al. "In vivo partial reprogramming alters age-associated molecular changes during physiological aging in mice." *Nature Aging*, 2022.[^chondronasiou2022]: `paper` Chondronasiou, D. et al. "Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming." *Aging Cell*, 2022.[^chondronasiou2022]: `paper` Chondronasiou, D. et al. "Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming." *Aging Cell*, 2022.[^lu2020]: `paper` Lu, Y. et al. "Reprogramming to recover youthful epigenetic information and restore vision." *Nature*, 2020.[^lu2020]: `paper` Lu, Y. et al. "Reprogramming to recover youthful epigenetic information and restore vision." *Nature*, 2020.[^lifebio2026]: `statement` Life Biosciences. "Life Biosciences Announces First Patient Dosed in Phase 1 Trial of ER-100 for Optic Neuropathies." Company announcement, 9 June 2026. {A company announcement of dosing, not a result: it records that a person received an OSK therapy and reports no safety or efficacy outcome. The study is registered as NCT07290244.}[^abad2013]: `paper` Abad, M. et al. "Reprogramming in vivo produces teratomas and iPS cells with totipotency features." *Nature*, 2013. {Sustained whole-body factor expression in mice; it fixes the ceiling on exposure and says nothing about where the tolerated dose sits.}[^abad2013]: `paper` Abad, M. et al. "Reprogramming in vivo produces teratomas and iPS cells with totipotency features." *Nature*, 2013. {Sustained whole-body factor expression in mice; it fixes the ceiling on exposure and says nothing about where the tolerated dose sits.} removed, struck through added, underlinedLine numbers count the serialised markdown of each revision, frontmatter included.
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