⚠️ Auto-extracted by Claude on 2026-06-13 — preprint; not peer-reviewed. Content sourced exclusively from the verbatim abstract (biorxiv doi:10.1101/2025.11.30.691415). No primary-data results, gene lists, quantitative figures, or section content have been inferred beyond the abstract. Do NOT rely on any quantitative specifics from this page until a full-text verification pass is completed. gap/preprint-not-peer-reviewed gap/no-fulltext-access

Freizus et al. 2025 — Cell surface ATP6V1B2 marks a persistent apoptosis-resistant senescent subset

Preprint (bioRxiv), posted 2025-12-01 (biorxiv submission 2025-11-30). doi:10.1101/2025.11.30.691415. Authors: Freizus N, Majewska JM, Ovadya Y, Kopitman E, Porat Z, Mayo A, Meir-Salame T, Dassa B, Stelzer G, Alon U, Krizhanovsky V — Weizmann Institute of Science, Israel (Krizhanovsky lab). Not a SenNet consortium paper.

Access: Preprint; bioRxiv open access. Not yet peer-reviewed or journal-published as of seeding date.

What this paper is

A primary data preprint from the Krizhanovsky laboratory at the Weizmann Institute identifying a functionally distinct subset of senescent cells marked by cell-surface expression of ATP6V1B2 (V-type proton ATPase subunit B2; csV1B2). This subset is characterized by resistance to apoptosis and persistence in vivo in aging and fibrotic lung tissue.

This is a companion preprint to cherqui-2025-senescence-burden-organs from the same lab and addresses a specific functional heterogeneity dimension within the senescent cell population — the existence of a subset that is more difficult to clear. Both preprints collectively provide empirical support for the tissue-specific, functionally heterogeneous senotype framework proposed in suryadevara-2026-senotypes.

Model systems

Per the abstract:

Human senescent cells — in vitro (senescence induced by DNA damage)
Mouse senescent cells — in vitro
Aging lungs — in vivo tissue context (mouse and/or human; specific details require full-text)
Fibrotic lungs — in vivo tissue context; establishes disease-relevance of the csV1B2+ subset
ABT-737 in vitro apoptosis assay — functional senolytic-resistance readout

Key protein: ATP6V1B2 (csV1B2)

atp6v1b2 (V-type proton ATPase subunit B, brain isoform; UniProt P21281; NCBI Gene 526) is a subunit of the vacuolar-type H+-ATPase (v-ATPase), a proton pump primarily known for its role in lysosomal acidification and endosomal trafficking. This paper reports a novel finding: in response to DNA-damage-induced senescence, a subset of senescent cells relocates or upregulates ATP6V1B2 to the cell surface (designated csV1B2). This cell-surface localization is the defining feature of the reported subset.

Central findings (abstract only)

Per the verbatim abstract:

csV1B2 upregulation in a senescent subset: In response to DNA damage, a subset of senescent cells upregulates ATP6V1B2 on the cell surface. The mechanism of this relocalization is not specified in the abstract.
Associated cellular changes: csV1B2 upregulation is associated with (a) altered lysosomal activity and (b) changes in intracellular pH. These are consistent with altered v-ATPase function but mechanistic causality is not established from the abstract.
In vivo presence: csV1B2 heterogeneity is present in naturally occurring senescent cells in both aging lungs and fibrotic lungs, establishing that this is not solely an in-vitro artifact.
Transcriptional signature: Senescent cells expressing csV1B2 show “an age-independent transcriptional signature associated with DNA repair and resistance to apoptosis.” The age-independence is notable — this subset arises based on cellular state, not chronological age per se.
Functional apoptosis resistance: csV1B2 expression correlates with resistance to ABT-737-induced apoptosis in culture. ABT-737 is a BCL-2 / BCL-xL / BCL-w BH3-mimetic (tool compound; the in-vitro analog of the navitoclax/ABT-263 senolytic class). This is the functional consequence with direct therapeutic relevance: csV1B2-positive cells are harder to kill with BH3-mimetic senolytics.

Critical caveat: Quantitative effect sizes, cell counts, correlation coefficients, and mechanistic details underlying these findings are NOT available from the abstract. They require full-text verification before being cited numerically on any atomic wiki page.

Significance for the senotype and senolytic frameworks

Senotype framework: This paper identifies a molecularly defined senescent subset (csV1B2+) with a distinct functional property (apoptosis resistance). This is exactly the type of within-tissue senescent heterogeneity that the senotype concept predicts — senescent cells within a single tissue (lung) are not uniformly susceptible to the same death signal. The csV1B2+ subset represents a functional senotype defined not by cell identity but by a dynamically acquired molecular feature.

Senolytic resistance: The correlation between csV1B2 expression and ABT-737 resistance is the most therapeutically significant finding in this abstract. The navitoclax/ABT-263 senolytic class (BCL-2/BCL-xL/BCL-w pan-inhibitor) and ABT-737 (its in-vitro analog) are among the most potent characterized senolytics. A subset of cells resistant to this class — identifiable by csV1B2 cell-surface expression — represents a candidate biomarker for senolytic treatment failure and a mechanistic explanation for incomplete senescent-cell clearance in vivo. See senolytics for the full ABT-737/navitoclax class context. gap/needs-replication

Lysosomal and pH changes: The associated lysosomal activity alteration and intracellular pH change are consistent with known roles of v-ATPase in lysosomal acidification and with reports that SA-β-galactosidase (the canonical senescence biomarker; detectable at pH 6.0 per Dimri 1995) reflects lysosomal expansion. Whether csV1B2 is causal for the pH change, or whether both are co-regulated downstream of DNA damage, is not resolvable from the abstract. gap/no-mechanism

Extrapolation table

Dimension	Status
Mechanism (v-ATPase/csV1B2 → apoptosis resistance) conserved in humans?	unknown (abstract cites human + mouse cells; mechanistic causality not established)
csV1B2 subset found in human tissue in vivo?	partial (aging + fibrotic lungs cited; extent of human vs mouse unclear from abstract)
ABT-737 resistance replicated independently?	no — single study, preprint gap/preprint-not-peer-reviewed gap/needs-replication

Limitations

Preprint status — not yet peer-reviewed; results should be weighted accordingly. gap/preprint-not-peer-reviewed
Abstract-only extraction — quantitative specifics, exact lung tissue composition, mechanistic pathway from csV1B2 → apoptosis resistance, and cell-line identities are not available for this seeding pass. gap/no-fulltext-access
ABT-737 is a tool compound; direct extrapolation to navitoclax (clinical) or ABT-263 requires the full-text methods and dose-response data.
Causal relationship between csV1B2 surface expression and apoptosis resistance is not established from the abstract (correlation stated).

Cross-references

atp6v1b2 — protein stub for the marker gene product
cellular-senescence — primary hallmark home; see § Senescent-cell heterogeneity and the senotype concept
senolytics — csV1B2 as candidate marker of BH3-mimetic senolytic resistance; see resistance/heterogeneity note
cherqui-2025-senescence-burden-organs — companion Krizhanovsky-lab preprint on multi-organ senescence dynamics
suryadevara-2026-senotypes — SenNet Perspective framing the senotype concept this study empirically informs
sasp — lysosomal activity changes and pH shifts may relate to SASP regulation; not established

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Cell surface ATP6V1B2 marks a subset of persistent senescent cells with increased resistance to apoptosis