bims-cesemi 2026-01-04 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2026–01–04
eight papers selected by
Julio Cesar Cardenas, Universidad Mayor

Senolytic-Resistant Senescent Cells Have a Distinct SASP Profile and Functional Impact: The Path to Developing Senosensitizers.
TGF-β1-induced downregulation of the mitochondrial Ca2+ uniporter facilitates the migration of hepatic stellate cells.
Targeting Sestrin2 impairs survival of senescent cancer cells following DNA-damaging therapies.
Rejuvenating the aging gut by targeting senescence.
Chemotherapy-induced adipo-lineage cell senescence drives bone loss.
Integrative multi-omics analysis proposes a metabolic classification of gliomas: distinct metabolic states, immune infiltration, and prognosis.
A Histone Code Functionally Linked to Replicative Senescence.
Senescent cells secrete chromatin components via senescence-associated extracellular particles.

Aging Cell. 2026 Jan;25(1): e70358

Senolytic-Resistant Senescent Cells Have a Distinct SASP Profile and Functional Impact: The Path to Developing Senosensitizers.

Utkarsh Tripathi, Masayoshi Suda, Vagisha Kulshreshtha, Bryan T Piatkowski, Allyson K Palmer, Nino Giorgadze, Christina Inman, Nathan Gasek, Ming Xu, Kurt O Johnson, Tamar Pirtskhalava, Selim Chaib, Larissa P G Langhi Prata, Yi Zhu, Renuka Kandhaya-Pillai, Stefan G Tullius, Saranya P Wyles, Rambabu Majji, Hari Krishna Yalamanchili, David B Allison, Tamar Tchkonia, James L Kirkland.

  The senescent cell (SC) fate is linked to aging, multiple disorders and diseases, and physical dysfunction. Senolytics, agents that selectively eliminate 30%-70% of SCs, act by transiently disabling the senescent cell antiapoptotic pathways (SCAPs), which defend those SCs that are proapoptotic and pro-inflammatory from their own senescence-associated secretory phenotype (SASP). Consistent with this, a JAK/STAT inhibitor, Ruxolitinib, which attenuates the pro-inflammatory SASP of senescent human preadipocytes, caused them to become "senolytic-resistant". Administering senolytics to obese mice selectively decreased the abundance of the subset of SCs that is pro-inflammatory. In cell cultures, the 30%-70% of human senescent preadipocytes or human umbilical vein endothelial cells (HUVECs) that are senolytic-resistant (to Dasatinib or Quercetin, respectively) had increased p16INK4a, p21CIP1, senescence-associated β-galactosidase (SAβgal), γH2AX, and proliferative arrest similarly to the total SC population (comprising senolytic-sensitive plus-resistant SCs). However, the SASP of senolytic-resistant SCs entailed less pro-inflammatory/apoptotic factor production, induced less inflammation in non-senescent cells, and was equivalent or richer in growth/fibrotic factors. Senolytic-resistant SCs released less mitochondrial DNA (mtDNA) and more highly expressed the anti-inflammatory immune evasion signal, glycoprotein non-melanoma-B (GPNMB). Transplanting senolytic-resistant SCs intraperitoneally into younger mice caused less physical dysfunction than transplanting the total SC population. Because Ruxolitinib attenuates SC release of proapoptotic SASP factors, while pathogen-associated molecular pattern factors (PAMPs) can amplify the release of these factors rapidly (acting as "senosensitizers"), senolytic-resistant and senolytic-sensitive SCs appear to be interconvertible.

Keywords:  cellular senescence; senescent cell subtypes; senolytics; senosensitizers

DOI:  https://doi.org/10.1111/acel.70358
Biochem Biophys Res Commun. 2025 Dec 23. pii: S0006-291X(25)01900-X. [Epub ahead of print]797 153184

TGF-β1-induced downregulation of the mitochondrial Ca2+ uniporter facilitates the migration of hepatic stellate cells.

Naoki Kawata, Rubii Kondo, Yoshiaki Suzuki, Hisao Yamamura.

  Transforming growth factor-β1 (TGF-β1) is a key profibrogenic cytokine that activates hepatic stellate cells (HSCs) and promotes their migration; however, its influence on mitochondrial Ca2+ regulation remains unclear. The mitochondrial Ca2+ uniporter (MCU) is essential for mitochondrial Ca2+ uptake and intracellular Ca2+ homeostasis, but its involvement in HSC activation has not been fully elucidated. Here, we investigated whether TGF-β1 modulates MCU expression and Ca2+ dynamics in HSCs. In LX-2 cells, TGF-β1 markedly reduced MCU mRNA and protein levels, and this repression was completely prevented by the ALK5 inhibitor SB431542. Both TGF-β1 treatment and MCU knockdown diminished mitochondrial Ca2+ uptake while increasing cytosolic Ca2+ responses to angiotensin II, and each intervention significantly enhanced HSC migration. These stimuli also increased CREB phosphorylation. Moreover, the CaMKII inhibitor KN-93, but not its inactive analog KN-92, suppressed HSC migration. Together, these findings indicate that TGF-β1-induced downregulation of MCU reshapes Ca2+ dynamics and promotes HSC migration, consistent with the involvement of CaMK-dependent signaling. This study demonstrates that TGF-β1 suppresses MCU expression, revealing a previously unrecognized link between a profibrogenic cytokine and mitochondrial Ca2+ regulation. Furthermore, our results show that MCU loss enhances migration in non-malignant HSCs, extending observations that were previously limited to cancer cells.

Keywords:  Calcium signaling; Hepatic stellate cell; Migration; Mitochondrial calcium uniporter; TGF-β1

DOI:  https://doi.org/10.1016/j.bbrc.2025.153184
Biochem Biophys Res Commun. 2025 Dec 23. pii: S0006-291X(25)01883-2. [Epub ahead of print]797 153167

Targeting Sestrin2 impairs survival of senescent cancer cells following DNA-damaging therapies.

Sangyeon Won, Minjoong Kim, Seungyeon Yang, Jiyoon Seo, Minbeom Ko, Eun Kyung Lee, Seung Min Jeong.

  Cellular senescence is a stable growth arrest commonly triggered in cancer cells by chemotherapy or radiotherapy. Although therapy-induced senescence (TIS) initially suppresses tumor proliferation, the persistence of senescent cells can promote relapse and therapeutic resistance. Here, we identify Sestrin2 as a critical regulator of senescent cancer cell survival following DNA-damaging therapies. Sestrin2 expression is robustly induced in TIS cancer cells in a p53-dependent manner. Genetic depletion of Sestrin2 selectively impairs the viability of senescent, but not proliferating, cancer cells. Mechanistically, Sestrin2 knockdown amplifies SASP gene expression and NF-κB activation, leading to endoplasmic reticulum (ER) stress and apoptotic cell death. Importantly, Sestrin2 depletion consistently enhances the elimination of senescent cancer cells across diverse genotoxic therapies. These findings reveal a pivotal pro-survival role for Sestrin2 in TIS cancer cells and highlight its potential as a therapeutic target to improve the efficacy of DNA-damaging cancer therapies.

Keywords:  DNA damage; Endoplasmic reticulum stress; Sestrin2; Therapy-induced senescence

DOI:  https://doi.org/10.1016/j.bbrc.2025.153167
Nat Aging. 2026 Jan 02.

Rejuvenating the aging gut by targeting senescence.

Marina Kolesnichenko.

DOI: https://doi.org/10.1038/s43587-025-01045-3
Nat Commun. 2025 Dec 30.

Chemotherapy-induced adipo-lineage cell senescence drives bone loss.

Ganesh Kumar Raut, Taylor Malachowski, Anupama Melam, Renata Ramalho-Oliveira, Taylor Holt, Xianmin Luo, Zhangting Yao, Douglas V Faget, Qihao Ren, David G DeNardo, Sheila A Stewart.

Chemotherapy-induced bone loss is a debilitating and common side effect of cancer treatment, though its underlying mechanisms remain poorly understood. Here, we show that, despite the systemic administration of chemotherapy, cellular senescence is restricted to bone marrow adipo-lineage cells specifically Cxcl12-abundant reticular (CAR) cells and bone marrow adipocytes (BMAds). Induction of senescence within these populations promotes RANK ligand (RANKL)-mediated osteoclastogenesis, leading to significant bone loss. Notably, we find that inhibition of the p38MAPK-MK2 pathway suppresses the senescence-associated secretory phenotype (SASP), including RANKL production abrogating bone loss. Furthermore, treatment with the senolytic combination dasatinib and quercetin (D + Q) selectively eliminates senescent CAR cells and BMAds, effectively preventing chemotherapy-induced bone loss. Given that nearly all chemotherapy treated patients experience bone loss and associated fracture risk, our findings offer a promising therapeutic avenue to preserve bone integrity and improve quality of life for cancer patients.

DOI: https://doi.org/10.1038/s41467-025-67793-3
J Transl Med. 2025 Dec 30.

Integrative multi-omics analysis proposes a metabolic classification of gliomas: distinct metabolic states, immune infiltration, and prognosis.

Qiang Zhu, Wanxiang Niu, Maolin Mu, Chengkun Ye, Chaoshi Niu.



Keywords:  Gliomas; Immunity metabolism; Metabolic heterogeneity; Metabolic reprogramming; Unsupervised classification

DOI:  https://doi.org/10.1186/s12967-025-07602-z
Aging Cell. 2026 Jan;25(1): e70343

A Histone Code Functionally Linked to Replicative Senescence.

Thomas Suter, Meyer J Friedman, Cagdas Tazearslan, Amir Gamliel, Daria Merkurjev, Kenneth Ohgi, Zhongjun Zhou, Michael G Rosenfeld, Yousin Suh.

  Cell states and biological processes are defined by their epigenetic profiles, distinctive composites of DNA- and histone-based chromatin components. However, the specific histone posttranslational modifications that distinguish cellular senescence and the impact of their distribution on transcription, especially with regard to gene length, have not been fully elucidated. Here, we show that promoter loss of symmetric dimethylated H4R3 (H4R3me(2s)) and spreading of trimethylated H3K79 (H3K79me3) across gene bodies are functional features of replicative senescence associated with gene upregulation. We report that highly upregulated genes in replicative senescence exhibit enrichment of H3K79me3 and, in contrast to the characteristic trend of aging cells and tissues, are substantially longer than those that are significantly downregulated. Furthermore, by assessing all expressed genes, we demonstrate that gene body accumulation of H3K79me3 during the transition to replicative senescence constitutes a broader phenomenon that is positively correlated with gene length and expression level genome-wide. Consistently, pharmacological inhibition of H3K79me3 deposition attenuates gene upregulation in replicative senescence. We also document a striking increase in the levels of H3K79me3 as well as a robust H4R3me(2s) to asymmetric dimethylated H4R3 (H4R3me(2as)) epigenetic switch that manifest globally in late-passage cells, suggesting that these histone modifications might represent novel molecular biomarkers of replicative senescence. Finally, we implicate the associated epigenetic regulators, including DOT1L, PRMT1, PRMT5, and JMJD6, as modifiers of cellular lifespan, potentially disclosing unappreciated therapeutic targets for interventions in normal and pathological aging. Collectively, our findings provide novel insights into the histone code that mediates altered transcriptional regulation in replicative senescence.

Keywords:  H3K79me3; H4R3me(2as); H4R3me(2s); aging; gene length; histone code; replicative senescence; transcription

DOI:  https://doi.org/10.1111/acel.70343
bioRxiv. 2025 Dec 16. pii: 2025.12.12.694055. [Epub ahead of print]

Senescent cells secrete chromatin components via senescence-associated extracellular particles.

Sviatlana Zaretski, Jose L Nieto Torres, Xue Lei, John P Nolan, Malene Hansen, Peter D Adams.

Senescent cells influence their surroundings through the senescence-associated secretory phenotype (SASP), an assortment of secreted molecules and macromolecular complexes. Among SASP's intracellular drivers are cytoplasmic chromatin fragments (CCFs), nuclear-derived DNA that activates the pro-inflammatory cGAS/STING pathway. While autophagy contributes to CCFs degradation, the full repertoire of CCF fates and signaling functions remains unclear. Here, we show that senescent cells release CCF components, ɣH2AX and double-stranded DNA (dsDNA), into the extracellular space via an ESCRT-independent multivesicular body pathway. Secreted CCF components localize to extracellular particles exhibiting an unusual "popcorn"-like morphology, distinct from canonical small extracellular vesicles. Notably, inhibition of autophagy enhances secretion of CCF components and particles, suggesting an inverse relationship between intracellular clearance and extracellular release. A fraction of CCF-containing extracellular particles activates cGAS-STING signaling in non-senescent proliferating cells and is enriched in the circulation of aged mice, pointing to a previously unrecognized mode of extracellular signaling by senescent cells.

DOI: https://doi.org/10.64898/2025.12.12.694055