Senescence Geometry Persists Beyond Canonical Markers and Converges Across Morphology and Transcriptomics Evidence for a marker-robust, cross-modal state geometry in independent human fibroblast datasets
Year: 2026
Type: preprint
Abstract: Cellular senescence is commonly identified using canonical markers, yet individual markers vary across cell types, induction paradigms, and temporal states. Here we tested a different hypothesis: whether a senescence-associated state geometry remains detectable after canonical senescence markers are deliberately removed, and whether independently measured cell morphology and transcriptomics converge on a similar progression geometry. We performed a secondary analysis of two public human fibroblast resources: the SenSCOUT single-cell morphology/biomarker dataset (Dryad DOI: 10.5061/dryad.rbnzs7hp8) and the GSE63577 replicative-senescence RNA-seq series. In SenSCOUT untreated controls, a morphology-only state coordinate constructed without donor-age labels or molecular biomarkers separated young and old donor populations (old-like fraction 18.3% versus 33.5%; enrichment 1.83; AUC 0.601) and was independently associated with higher SA-beta-gal fluorescence, p16, and p21. The continuous morphology coordinate also revealed a broad intermediate region with partial molecular senescence burden. In GSE63577, we then removed a broad panel of canonical senescence, cell-cycle, DNA-damage, and SASP genes before constructing a blind transcriptomic coordinate from 9,704 remaining genes. Despite this marker depletion, the coordinate remained strongly associated with normalized population-doubling progression (Spearman rho=0.800, P=6.8x10^-5; stratified permutation P=0.0006). Random removal of 50% of the remaining genes preserved a positive progression association in 100/100 resamples (median rho=0.800; empirical 95% interval 0.790-0.834), whereas several individual canonical markers were not directionally consistent across HFF and MRC-5. Finally, independently derived morphology and transcriptomic trajectories showed quantitative three-dimensional concordance: trajectory-shape rho=0.848, endpoint cosine=0.950, and Procrustes disparity=0.0506. The geometry correlation was significant against an exact 48-transformation axis null (P=0.0417), although an exact three-stage order test was intrinsically underpowered and non-significant. The distinctive result is therefore not merely senescence heterogeneity or continuum behavior, but the persistence of distributed senescence-associated organization after canonical-marker depletion together with quantitative convergence across independent morphology and transcriptomic modalities. We term this testable hypothesis marker-robust cross-modal senescence geometry. Paired single-cell multimodal and multi-donor validation will be required to determine whether this convergence reflects a shared biological manifold. NOVELTY STATEMENT. Rather than proposing another senescence marker or classifier, this study asks whether the higher-order state structure of senescence survives removal of canonical markers and reappears in an independent measurement modality. The principal novelty hypothesis is the joint observation of canonical-marker-depleted transcriptomic progression and quantitative 3D convergence with an independently derived morphology trajectory. Keywords: cellular senescence; morphology; transcriptomics; latent state; fibroblast; heterogeneity; manifold; biomarker; replicative senescence
Author: Doijiri, Osuke
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7204571342
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