How can cells escape local cell state minima and regain youthful, healthy optima? Our model proposes that the potency β determines the regions of the Cell State Landscape accessible to a cell. We define this as the cell’s ‘Möglichkeitsraum’: the portion of the hyperdimensional manifold accessible by a given cell at a given time. This space is small for cells at low potency as only minima within the same cell type valley are easily accessible. In contrast, at high potency, qualitative transformation is possible with access to entirely different cell type valleys. In this view the generation of induced pluripotent stem cells (iPSCs) is an expansion of the Möglichkeitsraum through increase of Cell Potency to a level that ultimately allows access to all cell types and states.14

Multiple studies have shown that time-restricted expression of four transcription factors (4F) can reverse age-associated phenotypes both in vitro and in vivo, and extend lifespan as initially demonstrated in a mouse progeroid model.15 This partial reprogramming and derivative protocols have been shown to be effective across cell lineages, tissues, and organs.16,17,18

Strikingly, cellular rejuvenation has also been achieved using 4F-independent approaches including through manipulation of ECM- or systemic signalling, employing chemical cocktails that alter the epigenome and changes to the metabolome.19,20,21,22,23,24,25,26 Despite their diversity, these interventions converge on overlapping, similar outcomes, suggesting that there could be a broader underlying principle that transcends the specific molecular pathways involved. These interventions appear to not simply overwrite cell identity; rather, they seem to alter cells such that their systems can self-correct. In our model this can be explained by a process we term Cell Annealing.

In materials science annealing restores old, brittle metals by heating them to above the recrystallization point followed by a slow cooldown.27 This relieves internal stresses and restores structural order, recovering macroscopic properties like malleability and toughness. Thermodynamically, annealing briefly increases entropy, allowing the system to explore new configurations and settle into optimal states, guided by the free energy landscape governing crystal formation.

We propose that aged, unhealthy cells can anneal in a similar manner: a moderate, transient increase, a mild shock, to Potency β allows the cell to escape local minima, briefly extend their Möglichkeitsraum and rapidly re-anneal to the optimal state at this elevated potency. Upon subsequent reduction of β, the cell remains in or close to its optimal Cell State position (Fig. 1c). We propose that this process does not necessitate dedifferentiation.

Reprogramming effectiveness is age-dependent and, in our model, shaped by a cell’s initial state and the dynamics of potency modulation. It can fail if cells are trapped too deeply in troughs and conversely, sustained, strong β-elevation can lead to identity loss or even iPSC formation.28 In contrast, mild and transient β elevation could, in principle, drive controlled annealing to optimal states without loss of cell identity. This may explain both the broad capacity for partial reprogramming across cell types and the observed cell-by-cell heterogeneity, which likely reflect different cell states before treatment. Our model may also explain transcription factor-independent rejuvenation protocols: as long as an intervention rapidly elevates Cell Potency to the right level and for the right duration, the cell’s intrinsic capability to reconfigure to a youthful state is unlocked. This can happen without explicit instructions for an embryonic or other natural gene expression program and does not require external information transfer towards a healthy target state. In Cell Annealing, instead of postulating an error-free back-up copy of youthful information, that information is stored in a distributed fashion across modalities.29