bims-cesemi 2025-10-19 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2025–10–19
eleven papers selected by
Julio Cesar Cardenas, Universidad Mayor

Longevity clinics: between promise and peril.
Analyzing Endolysosome-Mitochondria Membrane Contact Sites by Thin Section TEM of Human Fibroblasts.
Regulation of endoplasmic reticulum-mitochondria transfer and its importance in GBM.
Preservation of Autophagy May Be a Mechanism Behind Healthy Aging.
The role of mitochondria-endoplasmic reticulum crosstalk in colorectal cancer.
Enhancing Mitochondrial Matrix Antioxidant SOD2 in Astrocytes Mitigates Cellular Senescence and Cognitive Impairment in Aging.
NAD+ precursor supplementation in human ageing: clinical evidence and challenges.
Aged mice exhibit widespread metabolic changes but preserved major fluxes.
Men's brains shrink faster than women's: what that means for Alzheimer's.
The Role of Chaf1b in Maintaining Glioma Stem Cells Stemness and Regulating Microglial Polarization.
CRISPR screen reveals SOX2 as a critical regulator of CD133 and cellular stress response in glioblastoma.

Aging (Albany NY). 2025 Oct 13. 17

Longevity clinics: between promise and peril.

Marco Demaria.



Keywords:  aging; biomarkers; frailty; longevity clinics; senescence

DOI:  https://doi.org/10.18632/aging.206330
Methods Mol Biol. 2026 ;2976 119-134

Analyzing Endolysosome-Mitochondria Membrane Contact Sites by Thin Section TEM of Human Fibroblasts.

Claudia Parra-Ruiz, Carlos Enrich, Silvana Zanlungo.

  Membrane contact sites (MCS) are dynamic nanoregions of close apposition between two different organelles, functioning as discrete lipid or ion transfer sites. This new concept in cell biology involves unique proteins at both membrane sites, named tethers, and emerges in early observations by transmission electron microscopy (TEM). Currently, this technique still constitutes a valuable tool for MCS visualization and quantification. In the last decade, Lysosomal Storage Diseases (LSD) have been instrumental in studying the MCS between lysosomes (Ly), or endolysosomes (EL), and other organelles in close proximity such as mitochondria or the endoplasmic reticulum (ER). At present, the analysis of composition, functioning, and alterations/rewiring of MCS in health and disease represents an innovative area of research for designing therapeutic strategies in a variety of pathologies. Here, we describe procedures for chemical fixation using the Flat Embedding technique to characterize and quantify the MCS between LE/Lys and mitochondria in human fibroblasts by thin-section TEM.

Keywords:  Flat embedding; Image analysis; Lysosomal storage diseases; Lysosomes; Membrane contact sites; Mitochondria; Transmission electron microscopy-chemical fixation

DOI:  https://doi.org/10.1007/978-1-0716-4844-5_10
Int J Cancer. 2025 Oct 17.

Regulation of endoplasmic reticulum-mitochondria transfer and its importance in GBM.

Jinyi Zhao, Tian Li, Yue Jing, Haoran Yang, Xuemei Ma, Mengyu Liu.

  The traditional view of organelles as isolated functional entities is increasingly being replaced by a perspective that emphasizes dynamic connections. In particular, the membrane contact site between mitochondria and endoplasmic reticulum, mitochondrial associated endoplasmic reticulum membrane (MAM), has been extensively studied. MAM, as a key intracellular signaling hub, regulates various key activities including lipid metabolism, mitochondrial function, calcium ion homeostasis, and cell survival and apoptosis. Given its central role in maintaining cellular homeostasis, increasing evidence suggests that dysfunction of the endoplasmic reticulum mitochondrial axis may be associated with tumorigenesis, particularly in glioblastoma. This review aims to summarize the current understanding of the role and underlying mechanisms of MAM.

Keywords:  ER; GBM; MAM; carcinogenesis; mitochondria

DOI:  https://doi.org/10.1002/ijc.70173
Aging Cell. 2025 Oct 13. e70246

Preservation of Autophagy May Be a Mechanism Behind Healthy Aging.

Arsun Bektas, Shepherd H Schurman, Julián Candia, Olaya Santiago-Fernández, Susmita Kaushik, Ana Maria Cuervo, Luigi Ferrucci.

  Autophagy is intricately linked with protective cellular processes, including mitochondrial function, proteostasis, and cellular senescence. Animal studies have indicated that autophagy becomes dysfunctional with aging and may contribute to T cell immunosenescence. In humans, it remains unclear whether autophagy is impaired in CD4+ T cells as people age. To answer this question, we examined basal and inducible autophagic activity in a series of experiments comparing CD4+ T cells from younger (23-35 years old) and older (67-93 years old) healthy donors. We used immunofluorescence to detect LC3 (a marker of autophagosomes and autolysosomes) and LAMP2 (a marker of endolysosomes) in conjunction with bafilomycin A1 (which inhibits the acidification of lysosomes) and CCCP (a mitochondrial uncoupler) to manipulate autophagic flux. We found a significantly higher autophagy flux in CD4+ T cells from older compared to younger donors and a higher number of LC3+ compartments among older donors. Since the overall amount of autophagosomes degraded was comparable between the two groups, we concluded that autophagosome biogenesis was reduced in the older group. Rather than a decline, our findings in healthy older donors point toward a compensatory enhancement of human CD4+ T cell autophagy with age, which may be a mechanism behind healthy aging.

Keywords:  CD4+ T cells; autophagy; healthy aging

DOI:  https://doi.org/10.1111/acel.70246
Genes Dis. 2026 Jan;13(1): 101766

The role of mitochondria-endoplasmic reticulum crosstalk in colorectal cancer.

Lanshu Xiao, Yao Wei, Yiping Qin, Bianqin Guo.

  Colorectal cancer (CRC) is a significant health burden globally, with the third highest incidence and the second highest mortality among all types of cancer. Understanding the mechanisms underlying CRC progression is crucial for advancing therapeutic strategies. Organelles are essential components of cells and play a critical role in the initiation and progression of cancer. Over the past decades, numerous studies have demonstrated that mitochondria and the endoplasmic reticulum (ER) can communicate through signaling pathways, thereby regulating cellular homeostasis and function in both normal and cancer cells. This interaction primarily occurs through mitochondria-associated endoplasmic reticulum membranes (MAMs). MAMs, as key nodes in cancer initiation and progression, are also potential vulnerabilities of cancer cells, offering promising opportunities for cancer treatment. Recent research further emphasizes the close association between MAMs and CRC in terms of proliferation, apoptosis, and invasion. To deepen our understanding of the interactions and mechanisms between mitochondria and the ER in CRC, this review, for the first time, synthesizes the research advancements concerning the crosstalk between these organelles in CRC. It innovatively identifies potential targets associated with MAMs, aiming to uncover novel therapeutic strategies for CRC.

Keywords:  CRC; ER; MAMs; Mitochondria; Therapeutic strategy

DOI:  https://doi.org/10.1016/j.gendis.2025.101766
Aging Dis. 2025 Oct 09.

Enhancing Mitochondrial Matrix Antioxidant SOD2 in Astrocytes Mitigates Cellular Senescence and Cognitive Impairment in Aging.

Matthew P Baier, Sophia I Sharum, Jenna L Wilson, Sanjit Narasimhan, Chinnu Salim, Sreemathi Logan.

Accumulating evidence implicates hallmarks of brain aging, namely oxidative stress, reactive gliosis, and cellular senescence, as key contributors to hippocampal dysfunction and associated age-related cognitive deficits. Astrocytes robustly express antioxidants such as superoxide dismutases to detoxify reactive oxygen species (ROS) generated as a result of the high metabolic activity in the brain. However, aging is associated with transcriptional downregulation of antioxidant genes concomitant with polarization towards reactive, proinflammatory phenotypes in astrocytes. Given prior findings that astrocyte-specific ablation of SOD2 induces phenotypes of cognitive aging, we hypothesized that enhancing astrocyte antioxidant capacity via SOD2 overexpression (aSOD2OE) would ameliorate molecular hallmarks of aging and preserve cognitive function. To test this, we overexpressed SOD2 in astrocytes of aged (22 mo) male C57Bl/6N mice using an AAV(PHP.eB)-GFAP-hSOD2 viral vector and assessed hippocampal-dependent spatial working memory using a high-resolution, automated home-cage behavioral testing platform. We found that aSOD2OE significantly improved spatial working memory performance compared to aged GFP controls. Using molecular and histological approaches, aSOD2OE was associated with reductions in markers of cellular senescence and reactive astrogliosis within the hippocampus. These findings suggest that enhancement of astrocyte mitochondrial antioxidant activity is sufficient to alleviate maladaptive cellular programs associated with cognitive decline. Together, these data identify astrocyte redox biology as a potential therapeutic target in preserving hippocampal function in aging.

DOI: https://doi.org/10.14336/AD.2025.0760
Nat Metab. 2025 Oct 13.

NAD+ precursor supplementation in human ageing: clinical evidence and challenges.

Kasper T Vinten, Maria M Trętowicz, Evrim Coskun, Michel van Weeghel, Carles Cantó, Rubén Zapata-Pérez, Georges E Janssens, Riekelt H Houtkooper.

Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in cellular metabolism, and its decline has been implicated in ageing and age-related disorders. However, evidence for an age-related decline in NAD+ levels in humans has been consistently observed only in a limited number of studies. Similarly, although preclinical studies support the idea that supplementation with NAD+ precursors is a promising therapeutic strategy to promote healthy ageing, human clinical trials have shown limited efficacy. Therefore, an increasing understanding of how NAD+ metabolism is affected in different tissues during disease and following NAD+ precursor supplementation is crucial to defining the therapeutic value of NAD+-targeted therapies. In this Review, we evaluate the clinical evidence supporting the notion that NAD+ levels decline with age, as well as the tissue-specific effects of NAD+ precursor supplementation. Viewed in perspective, the published body of data on NAD+ dynamics in human tissues remains sparse, and the extrapolation of rodent-based data is not straightforward, underscoring the need for more clinical studies to gain deeper insights into systemic and tissue-specific NAD+ metabolism.

DOI: https://doi.org/10.1038/s42255-025-01387-7
Cell Metab. 2025 Oct 16. pii: S1550-4131(25)00394-8. [Epub ahead of print]

Aged mice exhibit widespread metabolic changes but preserved major fluxes.

Connor S R Jankowski, Laith Z Samarah, Michael R MacArthur, Sarah J Mitchell, Daniel R Weilandt, Craig J Hunter, Xianfeng Zeng, Melanie R McReynolds, Joshua D Rabinowitz.

  Metabolic dysregulation is a hallmark of aging. Here, we investigate in mice age-induced metabolic alterations using metabolomics and stable isotope tracing. Circulating metabolite fluxes and serum and tissue concentrations were measured in young and old (20-30 months) C57BL/6J mice, with young obese (ob/ob) mice as a comparator. For major circulating metabolites, concentrations changed more with age than fluxes, and fluxes changed more with obesity than with aging. Specifically, glucose, lactate, 3-hydroxybutryate, and many amino acids (but notably not taurine) change significantly in concentration with age. Only glutamine circulatory flux does so. The fluxes of major circulating metabolites remain stable despite underlying metabolic changes. For example, lysine catabolism shifts from the saccharopine toward the pipecolic acid pathway, and both pipecolic acid concentration and flux increase with aging. Other less-abundant metabolites also show coherent, age-induced concentration and flux changes. Thus, while aging leads to widespread metabolic changes, major metabolic fluxes are largely preserved.

Keywords:  aging; fluxomics; glutamine; metabolic flux; metabolism; metabolomics; obesity; stable isotope tracing; systemic metabolism

DOI:  https://doi.org/10.1016/j.cmet.2025.09.009
Nature. 2025 Oct 13.

Men's brains shrink faster than women's: what that means for Alzheimer's.

Rachel Fieldhouse.



Keywords:  Ageing; Brain; Neurodegeneration

DOI:  https://doi.org/10.1038/d41586-025-03353-5
J Neurosci. 2025 Oct 16. pii: e1372252025. [Epub ahead of print]

The Role of Chaf1b in Maintaining Glioma Stem Cells Stemness and Regulating Microglial Polarization.

Yong-Lin He, Liang Niu, Chen Wang, Zhi-Peng Liao, Kai Liu, Shuo Gao, Ai-Chao Du, Wei-Guo Liu, Juan Jia, Yu-Bo Zhang, Hang Yin, Guo-Qiang Yuan, Ya-Wen Pan.

Glioblastoma (GBM), the most aggressive tumor in the adult central nervous system, remains a major therapeutic challenge due to its high recurrence and resistance to conventional therapies. Recent evidence underscores the pivotal role of glioma stem cells (GSCs) in driving these malignant features. In this study, using intracranial xenograft models established in four-week-old male BALB/c nude mice and patient-derived primary glioma stem cells, we uncover a critical function of the chromatin assembly factor subunit Chaf1b in sustaining the stemness of GSCs and modulating the tumor immune microenvironment. We show that Chaf1b is markedly overexpressed in high-grade gliomas and GSC populations. Genetic silencing of Chaf1b led to a significant reduction in GSC self-renewal capacity and tumorigenicity, both in vitro and in intracranial xenograft models. Mechanistically, Chaf1b was found to upregulate IL-33 secretion, thereby promoting microglial M2 polarization and activating the PI3K/AKT signaling pathway-effects that were reversible upon IL-33 neutralization. These findings position Chaf1b as a key mediator of GBM aggressiveness and suggest it as a promising target for disrupting the stem-immune axis in glioblastoma.Significance Statement This study reveals the critical role of the chromatin assembly factor Chaf1b in glioma stem cells (GSCs). We found that Chaf1b is significantly upregulated in subventricular zone-positive (SVZ⁺) glioblastoma (GBM) patients and in their derived GSCs. Functional experiments demonstrated that Chaf1b knockdown markedly inhibits GSC proliferation, self-renewal, and tumorigenicity in vivo. Mechanistically, Chaf1b induces IL-33 secretion from GSCs, promotes microglial polarization toward the immunosuppressive M2 phenotype, and activates the PI3K/AKT signaling pathway. These processes collectively reshape the immune microenvironment, enhance GSC stemness, and drive GBM progression. This study systematically elucidates the pivotal role of Chaf1b in stemness maintenance and immune modulation of GSCs, highlighting its potential as a therapeutic target for GBM.

DOI: https://doi.org/10.1523/JNEUROSCI.1372-25.2025
Sci Rep. 2025 Oct 16. 15(1): 36228

CRISPR screen reveals SOX2 as a critical regulator of CD133 and cellular stress response in glioblastoma.

Neil Savage, Etienne Danis, Chirayu R Chokshi, Stefan Custers, Muhammad Vaseem Shaikh, Petar Miletic, Chitra Venugopal, Kevin R Brown, Rajeev Vibhakar, Jason Moffat, Sheila K Singh.

Glioblastoma (GBM) remains a formidable challenge in clinical settings due to limited treatments available. The surface protein CD133 marks glioblastoma stem cells (GSCs), cells capable of overcoming therapeutic pressures and correlate with more aggressiveness tumor phenotypes. In this study, we employed a CRISPR-Cas9 functional screen to deconvolute CD133 dynamics in tumors. This led us to establish that SOX2 is a key player in controlling the PROM1 gene, which in turn influences how cells react to stress factors, including those induced by chemoradiation treatment. The discoveries in this study shed light on the complex web of mechanisms that control the survival and resistance of GSCs, offering promising new avenues for targeting and potentially overcoming therapy resistance.

DOI: https://doi.org/10.1038/s41598-025-20183-7