bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2026–07–12
fifteen papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. SenFlag gene signature identifies senescent cells in mouse and human tissues through a conserved core transcriptional program.
  2. Mitochondria produce lactate to vent redox pressure.
  3. An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA.
  4. Targeting cellular senescence in dermatology: senolytic and senomorphic strategies.
  5. Senescent cells accumulate lipid droplets.
  6. Mitonuclear discordance modulates mitochondrial ageing dynamics in natural Drosophila populations.
  7. Long-lived mammals contain more phosphorylation sites in the SIRT6 C-terminus that enhance PARP1 interaction and resistance to oxidative stress.
  8. Mitochondrial transplantation reverses the senescence phenotype of SH-SY5Y cells.
  9. Inhibition of peroxisomal protein PRX-11 promotes longevity in Caenorhabditis elegans via enhancements to mitochondria.
  10. A metabolite-bridged complex between SerRS and SIRT2 couples NAD⁺ metabolism to translation control.
  11. ER-mitochondria contacts and mitochondrial fusion correlate with increased mitochondrial activity during vertebrate embryogenesis.
  12. Calorie restriction modulates beta cell IP3R activity to regulate Ca2+ homeostasis and cell network connectivity.
  13. A note to my younger self.
  14. FGF21 connects ER stress to sulfide signaling to enhance cellular resilience.
  15. Epigenetic Reprogramming with DNMT Inhibitors: A Multi-Mechanistic Approach to Enhance Immunotherapy in Glioblastoma.
  1. EMBO J. 2026 Jul 06.
    SenFlag gene signature identifies senescent cells in mouse and human tissues through a conserved core transcriptional program.
    Abdullah Altulea, Sebastian Mackedenski, Jamil Nehme, Marco Demaria.
      Identifying senescent cells via single-cell transcriptome profiling data remains challenging due to cellular heterogeneity and overlap with other cellular states. Here, we present SenFlag, a streamlined gene signature for enhanced identification of senescent cells based on integration of core gene expression features. SenFlag was derived through systematic assessment of bulk and single-cell RNA-sequencing datasets across multiple senescence models. It captures a conserved transcriptional program characterized by reduced expression of proliferation-associated genes and chromatin-associated genes (HMGB1/2, HMGN2), combined with upregulation of cell-cycle inhibitors (CDKN1A/CDKN2A) and of CCND1. Additionally, SenFlag incorporates lysosomal features, including increased expression of V-ATPase subunits and cathepsins. SenFlag identifies a rare but progressively accumulating population of senescent cells across tissues in both mice and humans in vivo, with enrichment in epithelial and endothelial compartments. SenFlag-positive cells increase with age and following tissue injury, and are reduced in datasets involving senescence-targeting interventions, supporting its specificity in vivo. Together, SenFlag provides a robust and interpretable signature for identifying senescent cells in single-cell datasets and facilitates the study of senescence across physiological and pathological contexts.
    DOI:  https://doi.org/10.1038/s44318-026-00845-6
  2. Trends Endocrinol Metab. 2026 Jul 04. pii: S1043-2760(26)00149-9. [Epub ahead of print]
    Mitochondria produce lactate to vent redox pressure.
    Serwah A Danquah, Lucas B Sullivan.
      Conventionally viewed as a waste product or a cytosolic pyruvate source, recent findings suggest that lactate may also directly contribute to mitochondrial oxidative metabolism. Using an intramitochondrial lactate biosensor, Rauseo et al. instead find that energized mitochondria are producers of lactate, which buffers mitochondrial redox to mitigate reactive oxygen species production.
    DOI:  https://doi.org/10.1016/j.tem.2026.06.005
  3. Dev Cell. 2026 Jul 08. pii: S1534-5807(26)00151-6. [Epub ahead of print]61(7): 1589
    An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA.
    Marco Demaria, Naoko Ohtani, Sameh A Youssef, Francis Rodier, Wendy Toussaint, James R Mitchell, Remi-Martin Laberge, Jan Vijg, Harry Van Steeg, Martijn E T Dollé, Jan H J Hoeijmakers, Alain de Bruin, Eiji Hara, Judith Campisi.
      
    DOI:  https://doi.org/10.1016/j.devcel.2026.04.004
  4. Geroscience. 2026 Jul 08.
    Targeting cellular senescence in dermatology: senolytic and senomorphic strategies.
    Diala Haykal, Frederic Flament, Lilit Garibyan, Kachiu Lee, Julie Escot, Audrey Gueniche, James Kirkland.
      Cellular senescence has emerged as a central mechanism driving cutaneous aging, impaired regeneration, and numerous dermatologic pathologies. Initially evolved as a protective mechanism to prevent malignant transformation and facilitate wound repair, senescence becomes maladaptive when senescent cells persist. Senescent keratinocytes, fibroblasts, and melanocytes can secrete pro-inflammatory mediators and other factors, collectively termed the senescence-associated secretory phenotype (SASP), which may degrade extracellular matrix components, disrupt pigmentary balance, and impair barrier function. Senescent cells are resistant to conditions that cause death of non-senescent cells and are generally removed by the immune system. Persisting senescent cells can become increasingly pro-inflammatory and fibrotic, perhaps due to accumulating DNA damage within these cells. Two primary geroscience-based therapeutic paradigms (gerotherapeutics) have been proposed: senolytics, which selectively eliminate senescent cells, and senomorphics, which modulate or suppress SASP activity without inducing senescent cell death. In dermatology, these approaches are particularly relevant given skin's accessibility, visible aging markers, and ability to serve as a translational platform for systemic gerotherapeutic interventions. Interfering with the development of senescent cells, for example by interfering with such regulators of senescent cell formation as p16, retinoblastoma protein (pRB), p53, or p21, can be detrimental due to the protective roles of transient senescence in wound healing and cancer suppression. However, senolytics, which do not prevent senescent cells from developing but rather act by clearing already formed persisting and tissue-damaging senescent cells, offer the potential to delay, prevent, alleviate, or treat aged or fibrotic skin. Because of the days to weeks for senescent cells to form fully and their inability to divide, senolytics can be administered intermittently, for example for brief intervals every 2 weeks or once a month. Senomorphics, conversely, can modulate the detrimental effects of the SASP and generally need to be administered continuously or more frequently than senolytics. Some agents are both senolytic and senomorphic. This review considers the mechanistic underpinnings of senescence in skin, the evidence for both therapeutic approaches, and the future directions for integrating senotherapeutics into regenerative and aesthetic dermatology. Advances in cutaneous biomarkers, topical delivery systems, and AI-assisted patient stratification are expected to accelerate translation into clinical practice.
    Keywords:  Cellular senescence; Cutaneous aging; Gerotherapeutics; SASP; Senolytics; Senomorphics; Skin regeneration
    DOI:  https://doi.org/10.1007/s11357-026-02379-5
  5. Aging (Albany NY). 2026 Jul 01. 18(1): 768-786
    Senescent cells accumulate lipid droplets.
    Noa Rachmian-Cooper, Riva Shmulevich, Hagay Akiva, Sarka Pokorna, Bareket Dassa, Ulysse Cherqui, Sergey Malitsky, Maxim Itkin, Binyamin Amichai Kliger, Inna Goliand, Tomer Meir Salame, Valery Krizhanovsky.
      Senescent cells (SnCs) are growth-arrested yet remain metabolically active and undergo extensive reprogramming to support their survival and the Senescence-Associated Secretory Phenotype (SASP). SnCs undergo key metabolic changes, including increased glycolysis, altered mitochondrial function and dysregulated lipid metabolism. While these metabolic changes are increasingly recognized, a comprehensive understanding of how they contribute to the pathophysiological effects of SnCs is still lacking. Here, through metabolic profiling, we identified elevated levels of glycolytic metabolites in SnCs, which coincided with an increased presence of lipid metabolites, specifically triacylglycerol derivatives, the precursors of lipid droplets (LDs). We show that SnCs accumulate LDs in a classical primary human fibroblast model, and that senescent microglia upregulate LDs markers in a mouse model of Alzheimer's disease (AD), where they play a pathological role. Single-nucleus analysis of brains from AD patients further revealed an elevated levels of LDs markers in senescent brain cells, including microglia. Previous studies implicated both lipid droplet-containing microglia and senescent microglia in AD pathology. Our findings provide evidence that these may represent the same cell population, in which the co-occurrence of LDs accumulation and the senescent state jointly contribute to their disease-promoting properties.
    Keywords:  Alzheimer’s disease; aging; lipid droplets; metabolism; senescence
    DOI:  https://doi.org/10.18632/aging.206390
  6. Proc Natl Acad Sci U S A. 2026 Jul 14. 123(28): e2529208123
    Mitonuclear discordance modulates mitochondrial ageing dynamics in natural Drosophila populations.
    Stefano Bettinazzi, Avishikta Chakraborty, Finley Grover-Thomas, Damian K Dowling, M Florencia Camus.
      Mitochondrial decline is a hallmark of ageing, yet the role of intergenomic compatibility in shaping ageing trajectories remains poorly understood, particularly in an ecologically relevant framework. Hormetic interventions have been proposed as strategies to modulate metabolism and lifespan, but it is unknown how this operates in the context of mitonuclear discordance. Here, we demonstrate that mitonuclear mismatch accelerates age-related mitochondrial decline, elevates reactive oxygen species production, and shortens lifespan. Strikingly, early-life mitochondrial stress induced by dietary modulation counteracts these effects, promoting mitochondrial homeostasis and longevity. Our findings reveal mitonuclear interactions shaping ageing trajectories in natural populations and provide unique evidence that targeted interventions can act as a buffer against the detrimental impact of genetic discordance.
    Keywords:  Drosophila; ageing; mitochondrial metabolism; mitohormesis; mitonuclear discordance
    DOI:  https://doi.org/10.1073/pnas.2529208123
  7. Geroscience. 2026 Jul 08.
    Long-lived mammals contain more phosphorylation sites in the SIRT6 C-terminus that enhance PARP1 interaction and resistance to oxidative stress.
    Jonathan Gigas, Michael E Meadow, Jing Guo, Catherine Lan, Eric Hillpot, John C Martinez, Gregory Tombline, Philip Bellomio, Valeria Rivera-Almodóvar, Kevin A Welle, Kyle Swovick, Jennifer R Hryhorenko, Julia Ablaeva, Sina Ghaemmaghami, Andrei Seluanov, Vera Gorbunova.
      Sirtuin 6 (SIRT6) is a protein deacetylase and ribosyltransferase that is a vital hub for maintaining epigenetic homeostasis, regulating the transcriptome, and repairing DNA double stranded breaks (DSBs). Comprehensive proteomic profiling of the SIRT6 posttranslational landscape, however, remains elusive. The SIRT6 C-terminal domain contains multiple phosphorylation sites. We find that the presence and the use of these sites are strongly correlated with maximum lifespan across mammals. Subsequent biochemical and in silico analyses revealed that SIRT6 hyperphosphorylation enhances its interaction with PARP1. Mutating the T294 phosphorylation site in human fibroblasts led to decreased survival after oxidative stress in the phospho-null T294A and improved oxidative stress resistance in the phospho-mimetic T294E. Together, these results suggest SIRT6 C-terminal phosphorylation increases stress resistance and interaction with PARP1 and that this phosphorylation is more abundant in long-lived mammalian species.
    Keywords:  Comparative biology; Longevity; Phosphorylation; SIRT6; Stress resistance
    DOI:  https://doi.org/10.1007/s11357-026-02389-3
  8. Mol Ther Adv. 2026 Sep 10. 34(3): 201788
    Mitochondrial transplantation reverses the senescence phenotype of SH-SY5Y cells.
    Liqun Xu, Yilang Wu, Wanfei Wu, Xiao Li, Ronghao Deng, Haibao Zhu, Aihua Mao, Pingnan Sun, Xin Zhang, Wencan Xu, Chi-Ju Wei.
      Fusogenic plasma membrane vesicles (PMVs) were engineered as carriers for mitochondrial delivery into senescent SH-SY5Y cells, a human neuroblastoma cell line widely used as an in vitro model for neurodegenerative diseases. Mitochondrial transfer was achieved via cell fusion mediated by the fusogenic vesicular stomatitis virus glycoprotein G. After mitochondrial transplantation, senescent SH-SY5Y cells exhibited marked phenotypic reversal, accompanied by restoration of glucose metabolism, ATP production, lactate levels, and mitochondrial respiratory activity to near-normal levels. In addition, mitochondrial transplantation regulated the senescence-associated secretory phenotype and associated inflammatory signaling pathways, while significantly enhancing antiapoptotic activity. Single-nucleotide polymorphism tracing of mitochondrial DNA confirmed the stable persistence of transplanted mitochondria within recipient cells, which was associated with recovery of normal mitochondrial morphology, function, and biogenesis. Notably, autophagic activity decreased after mitochondrial transplantation. Finally, alpha-synuclein expression was reduced, whereas dopamine production and the activities of enzymes involved in dopamine synthesis were increased after mitochondrial transplantation. The results demonstrated that mitochondrial transplantation can effectively reverse the senescence phenotype of SH-SY5Y cells, suggesting that mitochondrial transplantation may represent a promising therapeutic strategy for neurodegenerative disorders such as Parkinson disease.
    Keywords:  PMVs; Parkinson disease; SH-SY5Y cells; SNP analysis; autophagy; cellular senescence; mitochondria transplantation; plasma membrane vesicles; single-nucleotide polymorphism analysis
    DOI:  https://doi.org/10.1016/j.omta.2026.201788
  9. Aging (Albany NY). 2026 Jul 06. 18(1): 787-812
    Inhibition of peroxisomal protein PRX-11 promotes longevity in Caenorhabditis elegans via enhancements to mitochondria.
    Yash Flora, Dhriti Shastri, Kathryn R DeLeo, K Adam Bohnert.
      Peroxisomes execute essential functions in cells, including detoxification and lipid oxidation. Despite their centrality to cell biology, the relevance of peroxisomes to aging remains understudied. We recently reported that peroxisomes are degraded en masse via pexophagy during early aging in the nematode Caenorhabditis elegans, and we found that downregulating the peroxisome-fission protein PRX-11/PEX11 prevents this age-dependent pexophagy and extends lifespan. Here, we further investigated how prx-11 inhibition promotes longevity. Remarkably, we found that reducing peroxisome degradation with age led to concurrent improvements in another organelle: the mitochondrion. Animals lacking prx-11 function showed tubular, youthful mitochondria in older ages, and these enhancements required multiple factors involved in mitochondrial tubulation and biogenesis, including FZO-1/Mitofusin, UNC-43 protein kinase, and DAF-16/FOXO. Importantly, mutation of each of these factors negated lifespan extension in prx-11-defective animals, indicating that pexophagy inhibition promotes longevity only if mitochondrial health is co-maintained. We also found that experimental perturbation of mitochondria precipitated faster pexophagy with aging, implying bidirectionality in signaling between these two organelles. Our data support a model in which peroxisomes and mitochondria track together with age and interdependently influence animal lifespan.
    Keywords:  cellular aging; inter-organelle crosstalk; lifespan; mitochondrial tubulation; pexophagy
    DOI:  https://doi.org/10.18632/aging.206395
  10. Nat Commun. 2026 Jul 08.
    A metabolite-bridged complex between SerRS and SIRT2 couples NAD⁺ metabolism to translation control.
    Qian Zhang, Huimin Zhang, Marscha Hirschi, Sheng Li, Gabriel C Lander, Jie Yang, Xiang-Lei Yang.
      Cellular homeostasis requires tight coordination between metabolic and translational networks. Here we identify a direct molecular link between these processes through a cryo-EM structure of human cytosolic seryl-tRNA synthetase (SerRS) in complex with the NAD⁺-dependent deacetylase SIRT2. This interaction is promoted by the NAD⁺ metabolite ADP-ribose (ADPR), which acts as a molecular bridge between the two enzymes. Within the SIRT2 active site, ADPR engages SerRS residue K414 located in a flexible catalytic-domain loop. Acetylation of K414 is dispensable for binding. Functionally, complex formation inhibits SIRT2 deacetylase activity by blocking substrate access, while SIRT2 association suppresses SerRS aminoacylation activity by preventing tRNA binding. Thus, SerRS and SIRT2 mutually regulate each other, with ADPR enhancing while tRNA attenuating their interaction. Oxidative stress promotes this interaction via a PARP1-dependent pathway, revealing an ADPR-responsive regulatory module that couples metabolic state to translational output. This regulatory module is likely conserved across vertebrates.
    DOI:  https://doi.org/10.1038/s41467-026-75266-4
  11. Cell Rep. 2026 Jul 09. pii: S2211-1247(26)00693-5. [Epub ahead of print]45(7): 117615
    ER-mitochondria contacts and mitochondrial fusion correlate with increased mitochondrial activity during vertebrate embryogenesis.
    Anastasia Chugunova, Isabelle Schütz, Hannah Keresztes, Roksolana Kobylinska, Maria Novatchkova, Thomas Lendl, Marcus Strobl, Jörg Fallmann, David Márquez Oller, Michael Schutzbier, Gerhard Dürnberger, Richard Imre, Elisabeth Roitinger, Phylicia Kidd, Pawel Pasierbek, Alberto Moreno Cencerrado, Marlene Brandstetter, Thomas Köcher, Benedikt Agerer, Jakob-Wendelin Genger, Andreas Bergthaler, Andrea Pauli.
      Increased mitochondrial activity is essential for embryo development. Although conserved across organisms, the molecular basis of this increase is unknown, as detailed biochemical analysis in vertebrates is hampered by the limited availability of material. Using zebrafish as a model for vertebrate development, we comprehensively profile mitochondrial activity, morphology, metabolome, proteome, and phospho-proteome, as well as respiratory chain activity. Our data show that the mitochondrial proteome undergoes major changes during embryogenesis. While respiratory chain complex levels remain largely constant, we identify a marked increase in mitochondrial-ER association during early embryogenesis. Moreover, time-lapse imaging of mitochondrial dynamics reveals a transition from fragmented to elongated mitochondria starting during somitogenesis. Overall, our systematic profiling of the molecular and morphological changes of mitochondria during embryogenesis provides a valuable resource for further investigation of mitochondrial function. Our study reveals that increased mitochondrial-ER interaction and changes in mitochondrial morphology may contribute to its regulation during vertebrate development.
    Keywords:  CP: cell biology; CP: developmental biology; ER-mitochondrial interaction; metabolism; mitochondria; mitochondrial activation; proteomics; vertebrate embryogenesis; zebrafish
    DOI:  https://doi.org/10.1016/j.celrep.2026.117615
  12. Cell Calcium. 2026 Jun 18. pii: S0143-4160(26)00054-0. [Epub ahead of print]136 103161
    Calorie restriction modulates beta cell IP3R activity to regulate Ca2+ homeostasis and cell network connectivity.
    Johannes Pfabe, Amanda Cambraia, Prasanna K Dadi, Melanie Cutler, Cristiane Dos Santos, Christopher Acree, Aliyah Habashy, Guy Perkins, Mark H Ellisman, David A Jacobson, Marjan Slak Rupnik, Rafael Arrojo E Drigo.
      Calorie restriction (CR) promotes beta cell longevity by regulating cell identity, organelle and protein homeostasis, and metabolism pathways. CR beta cells have higher cAMP levels and mitochondria with an elevated potential to generate ATP. However, CR beta cells have reduced insulin secretion due to increased peripheral insulin sensitivity. How CR impacts beta cell Ca²⁺ homeostasis to regulate beta cell insulin release remains unknown. We investigated this question using acute pancreatic tissue slices prepared from ad-libitum (AL) or CR mice loaded with a low affinity Ca²⁺ indicator and recorded cytosolic Ca²⁺ gradients with fast confocal imaging. We exposed these slices to increasing glucose concentrations and applied our semi-automatic analysis pipeline to detect thousands of individual beta cells followed by identification of individual Ca²⁺ spiking events. We observed that elevated cAMP in CR beta cells causes fast short-amplitude Ca²⁺ oscillations that potentiate insulin release despite a largely disconnected beta cell network landscape. Using acetylcholine stimulation, we found that faster IP3R-driven Ca²⁺ oscillations linked to higher cytosolic cAMP levels protect beta cells against acute depletion of ER Ca²⁺. Therefore, this study demonstrates that CR promotes beta cell cAMP and ER Ca²⁺ homeostasis to enhance beta cell secretory function.
    Keywords:  Beta cell calcium; Calorie restriction; Endoplasmic reticulum (er)
    DOI:  https://doi.org/10.1016/j.ceca.2026.103161
  13. Science. 2026 Jul 09. 393(6807): 218
    A note to my younger self.
    Becca Neumann.
      
    DOI:  https://doi.org/10.1126/science.aek3445
  14. Cell Metab. 2026 Jul 07. pii: S1550-4131(26)00235-4. [Epub ahead of print]38(7): 1255-1257
    FGF21 connects ER stress to sulfide signaling to enhance cellular resilience.
    Sarah Hatem, András K Ponti, Christopher Hine.
      Fibroblast growth factor 21 (FGF21) is a stress-induced endocrine hormone that regulates metabolism. Grandl et al. show that FGF21, through its receptor β-klotho (KLB), enhances sulfide signaling and hydrogen sulfide production, strengthening the unfolded protein response and integrated stress response to promote stress resilience, metabolic adaptation, and potentially healthy aging.
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.009
  15. J Cancer Immunol (Wilmington). 2025 ;7(1): 39-44
    Epigenetic Reprogramming with DNMT Inhibitors: A Multi-Mechanistic Approach to Enhance Immunotherapy in Glioblastoma.
    Thomas J Lai, Robert M Prins, Richard G Everson.
      
    DOI:  https://doi.org/10.33696/cancerimmunol.7.103
This page is being maintained by Thomas Krichel. It was last updated on 2026‒07‒12 at 20:55.