Partial reprogramming can change molecular age measures and selected functional outcomes in models. Whether these effects establish epigenetic information loss as the necessary cause of normal aging is distinct from showing rejuvenation-associated changes, and toxicity depends strongly on protocol and tissue.
This dated addendum adds selected evidence and tests that could resolve the remaining questions. It does not regrade the archived review.
Each question identifies a limit in the checked evidence. A missing search result alone does not establish a gap in the entire field.
Competing explanation: Repair stress, cell-state change or other damage may produce similar age markers.
Discriminating test: Selective epigenetic perturbations and rescue with measured genome damage and cell composition; test naturally aged animals independently of induced injury.
Competing explanation: Clocks may directly respond to reprogramming without measuring durable tissue performance.
Discriminating test: Prespecified multi-tissue functions, frailty and survival alongside orthogonal clocks; examine discordant molecular and functional responders.
Competing explanation: Regeneration, clonal selection or altered cell mixture may mimic restoration of a retained youthful programme.
Discriminating test: Lineage tracing, single-cell multi-omics and pathway-specific blockade/rescue with identity and functional measures.
Competing explanation: Dedifferentiation, tissue failure or proliferative risk may offset short-term molecular improvement.
Discriminating test: Independent dose/tissue/duration comparisons with long follow-up, tumour surveillance, functional endpoints and matched vector/vehicle controls.
Electronic publication dates are used where recorded, with issue years shown separately. This is a selected chronology, not a claim of scientific priority or independent replication for every entry.
Reprogramming perturbation produced dysplastic tumours with altered epigenetic regulation.
What it cannot establish: Epigenetic plasticity can cause harm; marker resetting is not intrinsically beneficial.
Age-associated measures improved and survival increased in a premature-aging model.
What it cannot establish: Progeroid survival and injury recovery do not establish general human aging reversal.
Axon/vision recovery and youthful molecular patterns required TET1/TET2.
What it cannot establish: A tissue-specific dependency does not demonstrate organism-wide aging mediation.
Several tissue molecular and serum measures shifted toward younger profiles.
What it cannot establish: Molecular reversal is not automatically a durable functional or survival benefit.
Molecular age measures and selected fibroblast functions improved.
What it cannot establish: Cultured cells are not whole-person healthspan.
DNA-break repair perturbation produced aging-related phenotypes reversible by OSK.
What it cannot establish: An induced repair system does not isolate the necessary initiating cause of natural aging.
Hepatic and intestinal dysfunction contributed to early mortality.
What it cannot establish: Tissue distribution and induction duration determine harms and apparent benefit.
Late-life treatment improved frailty and reported remaining survival.
What it cannot establish: Remaining-life effects, sample/model scope and vector controls require replication.
Higher-dose treatment caused lipid accumulation, stress and severe toxicity.
What it cannot establish: Chemical-cocktail toxicity cannot be generalized to every genetic reprogramming protocol.
Case-specific Consensus records assisted gap discovery, chronology and targeted paper questions. Shared template wording about an amyloid-specific Deep follow-up is not evidence of a Deep run for this topic; the dated source records establish the actual use and access limits. Primary identifiers, selected abstract passages, correction notices and available primary-body passages were cross-checked. Generated absence cells, duplicate milestones and unsupported access claims were rejected.
Primary abstract/metadata checked. Additional Consensus full-text details remain provider-reported because a separately readable body was unavailable in this update.
This focused addendum does not establish 50–70 complete primary Methods/Results examinations per review. Baseline reading receipts and scores retain their original scope.
Selected full-text checks: 0; abstract checks: 9; metadata-only anchors: 0. Complete-paper examinations credited in this update: 0.
New enrichment: HSEF v5.3 causal distinctions. Archived scorecard schema: 5.4; retained as recorded.
PMID 24529372 · DOI 10.1016/j.cell.2014.01.005
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 27984723 · DOI 10.1016/j.cell.2016.11.052
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 33268865 · DOI 10.1038/s41586-020-2975-4
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 35235716 · DOI 10.1111/acel.13578
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 35390271 · DOI 10.7554/eLife.71624
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 36638792 · DOI 10.1016/j.cell.2022.12.027
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
Linked notices: Correction 38428398
Linked notice presence was checked in the primary record; its scientific impact was not verified in this update.
PMID 38012287 · DOI 10.1038/s43587-023-00528-5
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 38381405 · DOI 10.1089/cell.2023.0072
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
PMID 41589348 · DOI 10.1111/acel.70390
Selected abstract passages checked. Primary record and selected abstract passages checked; no complete-paper appraisal credited.
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