Partial Cellular Reprogramming: Epigenetic Age Reversal

OSKM Reprogramming Pulse

Factor dose 60%

Pulse duration 6 days

Baseline aging rate 1.0×

No pulse active

Population State

Mean epigenetic age

55.0 yr

Mean identity

100%

Past point of no return

0.0% of cells

Simulated time

day 0

How it works

Each cell carries two state variables: an epigenetic age A (a Horvath-clock-style proxy, in years) and an identity/differentiation index I ∈ [0,1], where I = 1 is a fully differentiated, terminally specialised cell and I → 0 is a dedifferentiated, pluripotent-like state.

Baseline (no pulse):     dA/dt = +agingRate
During an OSKM pulse:    dA/dt = +agingRate − k_A·dose
                          dI/dt = −k_I·dose·sensitivity_i
After pulse ends:        dI/dt = +k_R·(1 − I)   (only if I never fell below I_crit)

This mirrors the real partial-reprogramming finding (Ocampo et al. 2016; Lu et al. 2020, vision restoration in mice): a short, controlled pulse of Yamanaka factors (Oct4, Sox2, Klf4, Myc) resets the epigenetic clock faster than it erases cell identity, so the cell re-differentiates back to I = 1 once the pulse stops — net effect: younger cell, same job. But identity erosion accumulates with dose × duration. Past a critical threshold I_crit = 0.45, the cell is permanently locked out of re-differentiation — it stays "young" by the clock but loses its specialised identity, which is exactly the dedifferentiation/teratoma-risk regime real reprogramming protocols are tuned to avoid.

Dose — how strongly OSKM factors are expressed during a pulse; scales both age erasure and identity erosion.
Duration — how many simulated days the pulse stays on; the longer it runs, the more identity erodes even at a fixed dose.
Baseline aging rate — how fast untreated cells accumulate epigenetic age between pulses.
Cells vary in reprogramming sensitivity (±20%), so a single dose/duration setting pushes some cells past the point of no return before others — exactly the heterogeneity real cell populations show.

Young / low epigenetic age Old epigenetic age Past point of no return

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