# Research timeline and gaps: Partial Reprogramming and Human Aging

Selected publication milestones, not an exhaustive history or discovery priority claim.

**2011 — Full pluripotent reprogramming resets aged-human-cell traits but entails identity loss and redifferentiation.** [Original PMID22056670](https://pubmed.ncbi.nlm.nih.gov/22056670/).

**2013 — In vivo factor induction demonstrates pluripotency and multi-organ teratoma hazards.** [Original PMID24025773](https://pubmed.ncbi.nlm.nih.gov/24025773/).

**2016 — Senescence and IL6 create a permissive mouse tissue state for reprogramming.** [Original PMID27884981](https://pubmed.ncbi.nlm.nih.gov/27884981/).

**2016 — Cyclic partial factors improve progeroid survival and selected old-wild-type recovery outcomes.** [Original PMID27984723](https://pubmed.ncbi.nlm.nih.gov/27984723/).

**2018 — AAV delivery achieves full reprogramming and teratomas even without c-Myc in a specific setting.** [Original PMID29985406](https://pubmed.ncbi.nlm.nih.gov/29985406/).

**2018 — PhenoAge develops clinical-risk prediction, which is distinct from intervention surrogate validation.** [Original PMID29676998](https://pubmed.ncbi.nlm.nih.gov/29676998/).

**2020 — Transient human-cell mRNAs improve cellular measures and graft function in mouse recipients.** [Original PMID32210226](https://pubmed.ncbi.nlm.nih.gov/32210226/).

**2020 — Retinal OSK provides actual mouse vision benefit and TET/TDG dependence with demethylation alone insufficient.** [Original PMID33268865](https://pubmed.ncbi.nlm.nih.gov/33268865/).

**2021 — A short diet/lifestyle pilot shifts a clock without establishing partial reprogramming or clinical years regained.** [Original PMID33844651](https://pubmed.ncbi.nlm.nih.gov/33844651/).

**2022 — A single OSKM cycle resets mouse multiomics, retaining the marker-versus-function boundary.** [Original PMID35235716](https://pubmed.ncbi.nlm.nih.gov/35235716/).

**2022 — Human fibroblasts regain identity after temporary suppression; migration varies independently of clock changes.** [Original PMID35390271](https://pubmed.ncbi.nlm.nih.gov/35390271/).

**2022 — Factor-subset screens separate youthful expression from partly separable somatic-identity suppression.** [Original PMID35690067](https://pubmed.ncbi.nlm.nih.gov/35690067/).

**2022 — Fly cyclic-versus-continuous expression maps survival benefit and regimen-dependent harms.** [Original PMID36287172](https://pubmed.ncbi.nlm.nih.gov/36287172/).

**2022 — Technical clock-replicate noise motivates more reliable measurement without supplying clinical surrogacy.** [Original PMID36277076](https://pubmed.ncbi.nlm.nih.gov/36277076/).

**2023 — Induced epigenomic-change models give mechanistic aging leads, with an attached erratum and forced-injury limits.** [Original PMID36638792](https://pubmed.ncbi.nlm.nih.gov/36638792/).

**2023 — Chemical cell cocktails reset selected transcript/compartment measures, providing cellular rather than human clinical evidence.** [Original PMID37437248](https://pubmed.ncbi.nlm.nih.gov/37437248/).

**2023 — Continuous systemic induction causes organ dysfunction; organ exclusions attenuate mouse toxicity.** [Original PMID38012287](https://pubmed.ncbi.nlm.nih.gov/38012287/).

**2023 — Retinal follow-up shows duration and withdrawal-dependent vision benefits within the same therapeutic platform.** [Original PMID38060815](https://pubmed.ncbi.nlm.nih.gov/38060815/).

**2024 — Very-old male mouse remaining-life and frailty positives require buffer-control and survivor-selection interpretation.** [Original PMID38381405](https://pubmed.ncbi.nlm.nih.gov/38381405/).

**2024 — Immune composition is explicitly separated from cell-intrinsic clock change.** [Original PMID39095531](https://pubmed.ncbi.nlm.nih.gov/39095531/).

**2024 — Aged-cell-directed OSK expands mouse functional/survival and observed-tumor feasibility evidence.** [Original PMID39259812](https://pubmed.ncbi.nlm.nih.gov/39259812/).

**2024 — Human cultured-MSC rejuvenation coexists with a viral-residue adverse assay.** [Original PMID39684245](https://pubmed.ncbi.nlm.nih.gov/39684245/).

**2025 — Old female rat cognition improves in a short neural gene-therapy context, with limited safety follow-up.** [Original PMID39037528](https://pubmed.ncbi.nlm.nih.gov/39037528/).

**2025 — Chemical reprogramming combines human-cell hallmarks with worm lifespan, preserving species separation.** [Original PMID40588563](https://pubmed.ncbi.nlm.nih.gov/40588563/).

**2026 — Engram-targeted OSK expands selected mouse cognitive contexts rather than human efficacy.** [Original PMID41672073](https://pubmed.ncbi.nlm.nih.gov/41672073/).

**2026 — Original public-dataset reanalysis identifies conserved CpGs without adding five new functional trials.** [Original PMID42647204](https://pubmed.ncbi.nlm.nih.gov/42647204/).

## Research gaps

Controlled durable adult-human clinical function rather than cell or animal transfer.

Independent clock-to-function intervention-surrogate validation and separate safety prediction.

Quantified exact-factor delivery/duration safety windows across relevant tissues and baseline diseases.

Mechanism-specific rescue distinguishing epigenetic repair from selection, dedifferentiation, altered metabolism and injury-specific regeneration.

Late-life versus developmental, sex, species and tissue generalization; remaining lifespan distinguished from total life.

Complete supplements, source-overlap reconstruction and long-term safety beyond the selected body passages.

## Boundary experiment

A prospective exact-delivery adult-human trial measures independently masked objective clinical function and disease trajectory against a justified concurrent comparator, with prespecified exposure duration and full-recipient estimands. Analyze clock change independently of training/selection and test whether it predicts function beyond baseline factors. Use monitored dose/duration windows and long-term identity, inflammatory, delivery and tumor surveillance; no outcome-defined recipient exclusions.