OSKM Cyclic Partial Reprogramming
OSKM cyclic partial reprogramming (short cycles of Oct4, Sox2, Klf4 and c-Myc)
Written by Aaron CuhaReviewed Sep 2026
Also known as: OSKM, Four-factor Yamanaka reprogramming, Cyclic partial reprogramming, In vivo reprogramming
The full four-factor Yamanaka set delivered in short bursts. It extended lifespan in a progeroid mouse, not a normal one, and the same manoeuvre in living mice produces teratomas and kidney tumours.
Overview
The 2016 Cell paper from the Izpisua Belmonte laboratory is the foundation of the whole partial reprogramming field, and what it actually reported is narrower than how it is usually quoted. In a progeroid mouse model, a strain engineered to age prematurely, short-term cyclic expression of Oct4, Sox2, Klf4 and c-Myc improved cellular and physiological hallmarks of ageing and prolonged lifespan. In older wild-type mice, the same treatment improved recovery from metabolic disease and from muscle injury. The abstract claims recovery and repair in normal animals. It does not claim lifespan extension in normal animals. Writing that partial reprogramming extends lifespan in mice without the word progeroid attached is the single most common error in coverage of this literature.
No human has received OSKM. There is no registered human trial of four-factor reprogramming anywhere. The one registered human reprogramming study in the world uses OSK, the three-factor set with c-Myc removed, injected into one eye.
The reason c-Myc was dropped is on the record. In 2013, transitory four-factor induction in reprogrammable mice produced teratomas emerging from stomach, intestine, pancreas and kidney, along with circulating induced pluripotent stem cells in the blood. In 2014, transient expression of the reprogramming factors followed by withdrawal produced tumours in various mouse tissues, including kidney tumours sharing characteristics with Wilms tumour, a paediatric cancer. Those tumours were epigenetically rather than genetically driven, which was demonstrated by deriving stem cells from them that then gave rise to normal kidney cells. Starting and then stopping reprogramming in a living animal is itself oncogenic in mice, and that is the exact manoeuvre partial reprogramming depends on.
Mechanism of action
Established in mice only. Short pulses of Oct4, Sox2, Klf4 and c-Myc push cells part-way along the dedifferentiation trajectory, resetting epigenetic marks associated with age while, if the pulse is short enough, stopping before the cell loses its identity and becomes pluripotent. Continuous induction is lethal in mice through teratoma formation and tissue dysfunction, which is why every protocol is cyclic. The therapeutic window is defined by duration and dose and has been mapped only in mice. Nothing about this mechanism has been characterised in a human being.
Human evidence
None. No human has received OSKM reprogramming, and no trial of four-factor reprogramming is registered on ClinicalTrials.gov. The entire evidence base is mouse work plus cell culture.
What this does not tell you: Because no human has been dosed, nothing is known about whether four-factor reprogramming does anything in a person, and nothing is known about whether the teratoma and Wilms-tumour-like cancers seen in mice would occur in people. The mouse safety findings are the reason the only product to reach a human trial uses three factors rather than four and is confined to one eye.
Reading the research record
Two things get collapsed in coverage of this paper, and both matter. The first is the progeroid distinction. The 2016 lifespan result is in a mouse engineered to age prematurely from a specific lesion; delaying that lesion extends that animal's life without showing anything about normal ageing. In the older wild-type mice in the same paper, what improved was recovery from metabolic disease and muscle injury, not lifespan. The second is that this literature's own safety papers are as strong as its efficacy papers, and they point the other way: Nature 2013 and Cell 2014 both show that inducing and then stopping reprogramming in a living mouse causes cancer.
Commercially, the field has moved past OSKM for exactly this reason. c-Myc is an oncogene, the four-factor set is the one with the teratoma literature attached, and every clinical-stage programme uses the three-factor OSK set instead. This page exists because OSKM is the foundational experiment that the whole field cites, not because anyone is planning to give it to a human.
The evidence, charted
Fig. 1 · evidence composition
0of 6 citations (0%) are in people
Every citation cited here is Animal work; no other study type is cited on this page. This count is of our own citation list and understates any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 5 distinct years, 2013 to 2024, counted from the citation list on this page.
Fig. 3 · legal status at a glance
US
Not approved
UK
Approved
AU
Approved
CA
Not approved
Approved in 2 of 4, prescription route in 0, not approved in 2. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Fig. 4 · dose response
No human dose response curve exists
We draw this figure where the data supports it. For this compound in humans it does not, so the panel stays empty rather than borrowing an animal curve and implying it transfers.
Key studies & citations
- Animal2016
In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming
Mouse. In a PROGEROID model of premature ageing, short-term cyclic expression of Oct4, Sox2, Klf4 and c-Myc ameliorated cellular and physiological hallmarks of ageing and prolonged lifespan. In older WILD-TYPE mice the same treatment improved recovery from metabolic disease and muscle injury, with no lifespan claim made for those animals.
Cell - Animal2013
Reprogramming in vivo produces teratomas and iPS cells with totipotency features
Mouse. Transitory induction of the four factors produced teratomas emerging from multiple organs, dedifferentiated NANOG-expressing cells in stomach, intestine, pancreas and kidney, and circulating induced pluripotent stem cells in the blood. Those in vivo cells were transcriptionally closer to embryonic stem cells than standard cultured iPS cells and generated embryo-like structures when injected intraperitoneally.
Nature - Animal2014
Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation
Mouse, from the Yamada and Yamanaka laboratories. Transient expression of reprogramming factors followed by doxycycline withdrawal produced tumours in various tissues, consisting of undifferentiated dysplastic cells with global DNA methylation changes. Kidney tumours shared characteristics with Wilms tumour. Stem cells derived from those tumour cells gave rise to non-neoplastic kidney cells, proving the tumours were epigenetically rather than genetically driven.
Cell - Animal2024
In vivo cyclic overexpression of Yamanaka factors restricted to neurons reverses age-associated phenotypes and enhances memory performance
Mouse. Cyclic four-factor expression restricted to neurons reversed age-associated phenotypes and improved memory performance. Restricting expression to one cell type is one of the strategies being used to narrow the safety window.
Communications Biology - Animal2024
Expansion of the neocortex and protection from neurodegeneration by in vivo transient reprogramming
Mouse. Transient in vivo reprogramming expanded the neocortex and protected against neurodegeneration.
Cell Stem Cell - Animal2022
In vivo partial reprogramming alters age-associated molecular changes during physiological aging in mice
Mouse. The authors open by naming the gap directly: partial reprogramming extends the lifespan of a premature ageing mouse model, but the effects of longer-term partial reprogramming in physiologically ageing wild-type mice were unknown. Their result is molecular and tissue-level rejuvenation plus protocol safety, not lifespan.
Nature Aging
Frequently asked questions
Did partial reprogramming extend lifespan in mice?
In a progeroid mouse, yes. The 2016 Cell paper reported prolonged lifespan with short cyclic four-factor expression in a strain engineered to age prematurely. In older normal mice in the same paper, what improved was recovery from metabolic disease and muscle injury, and no lifespan claim was made. The distinction is the single most common error in coverage of this field.
Is OSKM dangerous?
In mice, yes, and the evidence is direct. Transitory four-factor induction produced teratomas from stomach, intestine, pancreas and kidney and put pluripotent cells into the bloodstream. Starting and then stopping reprogramming produced tumours resembling Wilms tumour, a paediatric kidney cancer, driven epigenetically rather than by mutation. Continuous induction is lethal in mice.
Why do companies use OSK instead of OSKM?
Because c-Myc is an oncogene and the four-factor set carries the teratoma literature. Dropping it gives the three-factor OSK set, which is what the only registered human trial uses, injected into one eye with a switch that can be turned off.
Can I get this?
No. No human has received OSKM by any route, no four-factor trial is registered anywhere, and nothing in this area is sold. Anyone offering reprogramming as a treatment is not offering something that exists in the clinical record.