bims-cesemi 2024-07-21 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2024‒07‒21
fourteen papers selected by
Julio Cesar Cardenas, Universidad Mayor

Developmental disruption of the mitochondrial fission gene drp-1 extends the longevity of daf-2 insulin/IGF-1 receptor mutant.
Modelling the spatiotemporal dynamics of senescent cells in wound healing, chronic wounds, and fibrosis.
Counteracting tissue aging through TERT activation.
Striking senescence with sodium transporter inhibition.
Inhibition of PERK mediated UPR acts as a switch for reversal of residual senescence and as senolytic therapy in glioblastoma.
PRC2-AgeIndex as a universal biomarker of aging and rejuvenation.
The SASP factor IL-6 sustains cell-autonomous senescent cells via a cGAS-STING-NFκB intracrine senescent noncanonical pathway.
Nup358 restricts ER-mitochondria connectivity by modulating mTORC2/Akt/GSK3β signalling.
Immune surveillance of senescence: potential application to age-related diseases.
Revolutionizing Senescence Detection: Advancements from Traditional Methods to Cutting-Edge Techniques.
Regulation of and challenges in targeting NAD+ metabolism.
Ketomimetic Medium Promotes Metastatic Disposition and Chemoresistance in Breast Cancer Cells through Hypersialylation and Lipid Synthesis.
Inositol 1,4,5-Trisphosphate Receptors Regulate Vascular Smooth Muscle Cell Proliferation and Neointima Formation in Mice.
NFκB dynamics-dependent epigenetic changes modulate inflammatory gene expression and induce cellular senescence.

Geroscience. 2024 Jul 19.

Developmental disruption of the mitochondrial fission gene drp-1 extends the longevity of daf-2 insulin/IGF-1 receptor mutant.

Annika Traa, Aura A Tamez González, Jeremy M Van Raamsdonk.

  The dynamic nature of the mitochondrial network is regulated by mitochondrial fission and fusion, allowing for re-organization of mitochondria to adapt to the cell's ever-changing needs. As organisms age, mitochondrial fission and fusion become dysregulated and mitochondrial networks become increasingly fragmented. Modulation of mitochondrial dynamics has been shown to affect longevity in fungi, yeast, Drosophila and C. elegans. Disruption of the mitochondrial fission gene drp-1 drastically increases the already long lifespan of daf-2 insulin/IGF-1 signaling (IIS) mutants. In this work, we determined the conditions required for drp-1 disruption to extend daf-2 longevity and explored the molecular mechanisms involved. We found that knockdown of drp-1 during development is sufficient to extend daf-2 lifespan, while tissue-specific knockdown of drp-1 in neurons, intestine or muscle failed to increase daf-2 longevity. Disruption of other genes involved in mitochondrial fission also increased daf-2 lifespan as did treatment with RNA interference clones that decrease mitochondrial fragmentation. In exploring potential mechanisms involved, we found that deletion of drp-1 increases resistance to chronic stresses. In addition, we found that disruption of drp-1 increased mitochondrial and peroxisomal connectedness in daf-2 worms, increased oxidative phosphorylation and ATP levels, and increased mitophagy in daf-2 worms, but did not affect their ROS levels, food consumption or mitochondrial membrane potential. Disruption of mitophagy through RNA interference targeting pink-1 decreased the lifespan of daf-2;drp-1 worms suggesting that increased mitophagy contributes to their extended lifespan. Overall, this work defined the conditions under which drp-1 disruption increases daf-2 lifespan and has identified multiple changes in daf-2;drp-1 mutants that may contribute to their lifespan extension.

Keywords:   C. elegans ; Aging; Biological resilience; DRP1; Insulin/IGF-1 signaling; Mitochondrial fission

DOI:  https://doi.org/10.1007/s11357-024-01276-z
bioRxiv. 2024 Jul 08. pii: 2024.07.04.602041. [Epub ahead of print]

Modelling the spatiotemporal dynamics of senescent cells in wound healing, chronic wounds, and fibrosis.

Sharmilla Chandrasegaran, James P Sluka, Daryl Shanley.

Cellular senescence is known to drive age-related pathology through the senescence-associated secretory phenotype (SASP). However, it also plays important physiological roles such as cancer suppression, embryogenesis and wound healing. Wound healing is a tightly regulated process which when disrupted results in conditions such as fibrosis and chronic wounds. Senescent cells appear during the proliferation phase of the healing process where the SASP is involved in maintaining tissue homeostasis after damage. Interestingly, SASP composition and functionality was recently found to be temporally regulated, with distinct SASP profiles involved: a fibrogenic, followed by a fibrolytic SASP, which could have important implications for the role of senescent cells in wound healing. Given the number of factors at play a full understanding requires addressing the multiple levels of complexity, pertaining to the various cell behaviours, individually followed by investigating the interactions and influence each of these elements have on each other and the system as a whole. Here, a systems biology approach was adopted whereby a multi-scale model of wound healing that includes the dynamics of senescent cell behaviour and corresponding SASP composition within the wound microenvironment was developed. The model was built using the software CompuCell3D, which is based on a Cellular Potts modelling framework. We used an existing body of data on healthy wound healing to calibrate the model and validation was done on known disease conditions. The model provides understanding of the spatiotemporal dynamics of different senescent cell phenotypes and the roles they play within the wound healing process. The model also shows how an overall disruption of tissue-level coordination due to age-related changes results in different disease states including fibrosis and chronic wounds. Further specific data to increase model confidence could be used to explore senolytic treatments in wound disorders.

DOI: https://doi.org/10.1101/2024.07.04.602041
Nat Biotechnol. 2024 Jul;42(7): 1027

Counteracting tissue aging through TERT activation.

Iris Marchal.

DOI: https://doi.org/10.1038/s41587-024-02327-8
Trends Mol Med. 2024 Jul 13. pii: S1471-4914(24)00188-6. [Epub ahead of print]

Striking senescence with sodium transporter inhibition.

Bettina Schock, Steven O'Reilly.

  Senescence is associated with multiple morbidities and therapeutic targeting of these cells is a key aim. In a recent study, Katsuumi et al. found that targeting sodium-glucose co-transporter 2 (SGLT2) promoted immune clearance of senescent cells via programmed cell death-1 ligand (PD-L1) suppression, thus promoting immunosurveillance. This could have profound implications for many age-related diseases, including cancer and frailty.

Keywords:  AMPK; age-related diseases; immunosurveillance; senescence; senolysis

DOI:  https://doi.org/10.1016/j.molmed.2024.07.002
Neuro Oncol. 2024 Jul 18. pii: noae134. [Epub ahead of print]

Inhibition of PERK mediated UPR acts as a switch for reversal of residual senescence and as senolytic therapy in glioblastoma.

Madhura Ketkar, Sanket Desai, Pranav Rana, Rahul Thorat, Sridhar Epari, Amit Dutt, Shilpee Dutt.

  BACKGROUND: Glioblastoma due to recurrence is clinically challenging with 10-15months overall survival. Previously we showed therapy induced senescence (TIS) in glioblastoma reverses causing recurrence. Here, we aim to delineate TIS reversal mechanism for potential therapeutic intervention to prevent GBM recurrence.METHODS: Residual senescent (RS) and End of Residual Senescence (ERS) cells were captured from GBM patient-derived primary-cultures and cell lines mimicking clinical scenario. RNA-sequencing, transcript/protein validations, knock-down/inhibitor studies, ChIP RT-PCR, biochemical assays and IHCs were performed for mechanistics of TIS reversal. In vivo validations were conducted in GBM orthotopic mouse model.
RESULTS: Transcriptome analysis showed co-expression of ER stress-UPR and senescence associated secretory phenotype (SASP) with TIS induction and reversal. Robust SASP production and secretion by RS cells could induce senescence, ROS, DNA damage and ER stress in paracrine fashion independent of radiation. Neutralization of most significantly enriched cytokine from RS-secretome IL1β, suppressed SASP and delayed senescence reversal. Mechanistically, with SASP and massive protein accumulation in Endoplasmic reticulum, RS cells displayed stressed ER morphology, upregulated ER stress markers and PERK pathway activation via peIF2α-ATF4-CHOP which was spontaneously resolved in ERS. ChIP RT-PCR showed CHOP occupancy at CXCL8/IL8, CDKN1A/p21 and BCL2L1/BCLXL aiding survival. PERK knockdown/inhibition with GSK2606414 in combination with radiation led to sustained ER stress and senescence without SASP. PERKi in RS functioned as senolytic via apoptosis and prevented recurrence in vitro and in vivo ameliorating overall survival.
CONCLUSION: We demonstrate that PERK mediated UPR regulates senescence reversal and its inhibition can be exploited as potential seno-therapeutic option in glioblastoma.

Keywords:  ER stress; Glioblastoma; PERK; TIS reversal; Unfolded protein response

DOI:  https://doi.org/10.1093/neuonc/noae134
Nat Commun. 2024 Jul 16. 15(1): 5956

PRC2-AgeIndex as a universal biomarker of aging and rejuvenation.

Mahdi Moqri, Andrea Cipriano, Daniel J Simpson, Sajede Rasouli, Tara Murty, Tineke Anna de Jong, Daniel Nachun, Guilherme de Sena Brandine, Kejun Ying, Andrei Tarkhov, Karolina A Aberg, Edwin van den Oord, Wanding Zhou, Andrew Smith, Crystal Mackall, Vadim N Gladyshev, Steve Horvath, Michael P Snyder, Vittorio Sebastiano.

DNA methylation (DNAm) is one of the most reliable biomarkers of aging across mammalian tissues. While the age-dependent global loss of DNAm has been well characterized, DNAm gain is less characterized. Studies have demonstrated that CpGs which gain methylation with age are enriched in Polycomb Repressive Complex 2 (PRC2) targets. However, whole-genome examination of all PRC2 targets as well as determination of the pan-tissue or tissue-specific nature of these associations is lacking. Here, we show that low-methylated regions (LMRs) which are highly bound by PRC2 in embryonic stem cells (PRC2 LMRs) gain methylation with age in all examined somatic mitotic cells. We estimated that this epigenetic change represents around 90% of the age-dependent DNAm gain genome-wide. Therefore, we propose the "PRC2-AgeIndex," defined as the average DNAm in PRC2 LMRs, as a universal biomarker of cellular aging in somatic cells which can distinguish the effect of different anti-aging interventions.

DOI: https://doi.org/10.1038/s41467-024-50098-2
Aging Cell. 2024 Jul 16. e14258

The SASP factor IL-6 sustains cell-autonomous senescent cells via a cGAS-STING-NFκB intracrine senescent noncanonical pathway.

Florencia Herbstein, Melanie Sapochnik, Alejandra Attorresi, Cora Pollak, Sergio Senin, David Gonilski-Pacin, Nicolas Ciancio Del Giudice, Manuel Fiz, Belén Elguero, Mariana Fuertes, Lara Müller, Marily Theodoropoulou, Lucas B Pontel, Eduardo Arzt.

  Senescent cells produce a Senescence-Associated Secretory Phenotype (SASP) that involves factors with diverse and sometimes contradictory activities. One key SASP factor, interleukin-6 (IL-6), has the potential to amplify cellular senescence in the SASP-producing cells in an autocrine action, while simultaneously inducing proliferation in the neighboring cells. The underlying mechanisms for the contrasting actions remain unclear. We found that the senescence action does not involve IL-6 secretion nor the interaction with the receptor expressed in the membrane but is amplified through an intracrine mechanism. IL-6 sustains intracrine senescence interacting with the intracellular IL-6 receptor located in anterograde traffic specialized structures, with cytosolic DNA, cGAS-STING, and NFκB activation. This pathway triggered by intracellular IL-6 significantly contributes to cell-autonomous induction of senescence and impacts in tumor growth control. Inactivation of IL-6 in somatotrophic senescent cells transforms them into strongly tumorigenic in NOD/SCID mice, while re-expression of IL-6 restores senescence control of tumor growth. The intracrine senescent IL-6 pathway is further evidenced in three human cellular models of therapy-induced senescence. The compartmentalization of the intracellular signaling, in contrast to the paracrine tumorigenic action, provides a pathway for IL-6 to sustain cell-autonomous senescent cells, driving the SASP, and opens new avenues for clinical consideration to senescence-based therapies.

Keywords:  interleukin‐6; intracellular; pituitary; senescence; signaling; therapy‐induced senescence; tumors

DOI:  https://doi.org/10.1111/acel.14258
EMBO Rep. 2024 Jul 18.

Nup358 restricts ER-mitochondria connectivity by modulating mTORC2/Akt/GSK3β signalling.

Misha Kalarikkal, Rimpi Saikia, Lizanne Oliveira, Yashashree Bhorkar, Akshay Lonare, Pallavi Varshney, Prathamesh Dhamale, Amitabha Majumdar, Jomon Joseph.

  ER-mitochondria contact sites (ERMCSs) regulate processes, including calcium homoeostasis, energy metabolism and autophagy. Previously, it was shown that during growth factor signalling, mTORC2/Akt gets recruited to and stabilizes ERMCSs. Independent studies showed that GSK3β, a well-known Akt substrate, reduces ER-mitochondria connectivity by disrupting the VAPB-PTPIP51 tethering complex. However, the mechanisms that regulate ERMCSs are incompletely understood. Here we find that annulate lamellae (AL), relatively unexplored subdomains of ER enriched with a subset of nucleoporins, are present at ERMCSs. Depletion of Nup358, an AL-resident nucleoporin, results in enhanced mTORC2/Akt activation, GSK3β inhibition and increased ERMCSs. Depletion of Rictor, a mTORC2-specific subunit, or exogenous expression of GSK3β, was sufficient to reverse the ERMCS-phenotype in Nup358-deficient cells. We show that growth factor-mediated activation of mTORC2 requires the VAPB-PTPIP51 complex, whereas, Nup358's association with this tether restricts mTORC2/Akt signalling and ER-mitochondria connectivity. Expression of a Nup358 fragment that is sufficient for interaction with the VAPB-PTPIP51 complex suppresses mTORC2/Akt activation and disrupts ERMCSs. Collectively, our study uncovers a novel role for Nup358 in controlling ERMCSs by modulating the mTORC2/Akt/GSK3β axis.

Keywords:  Annulate Lamellae; ER-mitochondria Contact Sites; GSK3β; Nucleoporins; mTORC2

DOI:  https://doi.org/10.1038/s44319-024-00204-8
Trends Cell Biol. 2024 Jul 17. pii: S0962-8924(24)00121-1. [Epub ahead of print]

Immune surveillance of senescence: potential application to age-related diseases.

Teh-Wei Wang, Makoto Nakanishi.

  Several lines of evidence suggest that the age-dependent accumulation of senescent cells leads to chronic tissue microinflammation, which in turn contributes to age-related pathologies. In general, senescent cells can be eliminated by the host's innate and adaptive immune surveillance system, including macrophages, NK cells, and T cells. Impaired immune surveillance leads to the accumulation of senescent cells and accelerates the aging process. Recently, senescent cells, like cancer cells, have been shown to express certain types of immune checkpoint proteins as well as non-classical immune-tolerant MHC variants, leading to immune escape from surveillance systems. Thus, immune checkpoint blockade (ICB) may be a promising strategy to enhance immune surveillance of senescence, leading to the amelioration of some age-related diseases and tissue dysfunction.

Keywords:  immune checkpoint blockade; immune clearance; senescence

DOI:  https://doi.org/10.1016/j.tcb.2024.06.007
Aging Dis. 2024 Jul 08.

Revolutionizing Senescence Detection: Advancements from Traditional Methods to Cutting-Edge Techniques.

Ruopeng Xiao, Sinan Hu, Xiaohui Du, Yiwen Wang, Ke Fang, Yibin Zhu, Nanbin Lou, Chunhui Yuan, Jing Yang.

The accumulation of senescent cells is an important factor in the complex progression of aging, with significant implications for the development of numerous diseases. Thus, understanding the fundamental mechanisms of senescence is paramount for advancing preventive and therapeutic approaches to age-related conditions. Important to this pursuit is the precise identification and examination of senescent cells, contingent upon the recognition of specific biomarkers. Historically, detection methods relied on assessing molecular protein and mRNA levels and various staining techniques. While these conventional approaches have contributed substantially to the field, they possess limitations in capturing the dynamic evolution of cellular aging in real time. The emergence of novel technologies has led to a paradigm shift in senescence research. Gene-edited mouse models and the application of advanced probes have revolutionized our ability to detect senescent cells. These cutting-edge methodologies provide a more detailed and accurate means of dynamically monitoring, characterizing and potentially eliminating senescent cells, thus enhancing our understanding of the complex mechanisms of aging. This review comprehensively explores both traditional and innovative senescent cell detection methods, elucidating their advantages, limitations and implications for future investigations and could serve as a comprehensive guide and catalyst for further advancements in the understanding of aging and associated pathologies.

DOI: https://doi.org/10.14336/AD.202.0565
Nat Rev Mol Cell Biol. 2024 Jul 18.

Regulation of and challenges in targeting NAD+ metabolism.

Marie E Migaud, Mathias Ziegler, Joseph A Baur.

Nicotinamide adenine dinucleotide, in its oxidized (NAD+) and reduced (NADH) forms, is a reduction-oxidation (redox) co-factor and substrate for signalling enzymes that have essential roles in metabolism. The recognition that NAD+ levels fall in response to stress and can be readily replenished through supplementation has fostered great interest in the potential benefits of increasing or restoring NAD+ levels in humans to prevent or delay diseases and degenerative processes. However, much about the biology of NAD+ and related molecules remains poorly understood. In this Review, we discuss the current knowledge of NAD+ metabolism, including limitations of, assumptions about and unappreciated factors that might influence the success or contribute to risks of NAD+ supplementation. We highlight several ongoing controversies in the field, and discuss the role of the microbiome in modulating the availability of NAD+ precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), the presence of multiple cellular compartments that have distinct pools of NAD+ and NADH, and non-canonical NAD+ and NADH degradation pathways. We conclude that a substantial investment in understanding the fundamental biology of NAD+, its detection and its metabolites in specific cells and cellular compartments is needed to support current translational efforts to safely boost NAD+ levels in humans.

DOI: https://doi.org/10.1038/s41580-024-00752-w
bioRxiv. 2024 Jul 05. pii: 2024.07.03.601966. [Epub ahead of print]

Ketomimetic Medium Promotes Metastatic Disposition and Chemoresistance in Breast Cancer Cells through Hypersialylation and Lipid Synthesis.

Mohini Kamra, Yuan-I Chen, Paula C Delgado, Erin Seeley, Stephanie K Seidlits, Hsin-Chin Yeh, Amy Brock, Sapun H Parekh.

Although metastasis accounts for the vast majority of cancer-related fatalities, the triggers for the metastatic transformation of breast cancer (BC) cells remain unknown. Recent evidence suggests that a common feature of invasive and resistant cells could be their metabolic state. However, attempts to control metabolic state via nutrient intake, e.g., ketogenic or low carbohydrate diets, have shown inconsistent results with respect to improving chemotherapy efficacy and curbing metastasis. Aiming to decode the molecular mechanisms that alter cell phenotype upon nutrient alteration, we study how a ketomimetic (ketone body-rich, low glucose) medium affects Doxorubicin (DOX) susceptibility and invasive disposition of BC cells. We quantified glycocalyx sialylation and found an inverse correlation with DOX-induced cytotoxicity and DOX internalization. These measurements were coupled with single-cell metabolic imaging, bulk migration studies, and transcriptomic and metabolomic analyses to map the mechanisms involved in ketone body-driven BC cell metabolic maneuvering. Our findings revealed that a ketomimetic medium enhances chemoresistance and invasive disposition of BC cells via two main oncogenic pathways: hypersialylation and lipid accumulation. We propose that the crosstalk between these pathways leads to synthesis of the glycan precursor UDP-GlcNAc, which leads to advancement of a metastatic phenotype in BC cells under ketomimetic conditions.

DOI: https://doi.org/10.1101/2024.07.03.601966
J Am Heart Assoc. 2024 Jul 18. e034203

Inositol 1,4,5-Trisphosphate Receptors Regulate Vascular Smooth Muscle Cell Proliferation and Neointima Formation in Mice.

Fang Huang, Fei Zhang, Lei Huang, Xiangbin Zhu, Can Huang, Na Li, Qingen Da, Yu Huang, Huihua Yang, Hong Wang, Lingyun Zhao, Qingsong Lin, Zee Chen, Junjie Xu, Jie Liu, Mingming Ren, Yan Wang, Zhen Han, Kunfu Ouyang.

  BACKGROUND: Vascular smooth muscle cell (VSMC) proliferation is involved in many types of arterial diseases, including neointima hyperplasia, in which Ca2+ has been recognized as a key player. However, the physiological role of Ca2+ release via inositol 1,4,5-trisphosphate receptors (IP3Rs) from endoplasmic reticulum in regulating VSMC proliferation has not been well determined.METHODS AND RESULTS: Both in vitro cell culture models and in vivo mouse models were generated to investigate the role of IP3Rs in regulating VSMC proliferation. Expression of all 3 IP3R subtypes was increased in cultured VSMCs upon platelet-derived growth factor-BB and FBS stimulation as well as in the left carotid artery undergoing intimal thickening after vascular occlusion. Genetic ablation of all 3 IP3R subtypes abolished endoplasmic reticulum Ca2+ release in cultured VSMCs, significantly reduced cell proliferation induced by platelet-derived growth factor-BB and FBS stimulation, and also decreased cell migration of VSMCs. Furthermore, smooth muscle-specific deletion of all IP3R subtypes in adult mice dramatically attenuated neointima formation induced by left carotid artery ligation, accompanied by significant decreases in cell proliferation and matrix metalloproteinase-9 expression in injured vessels. Mechanistically, IP3R-mediated Ca2+ release may activate cAMP response element-binding protein, a key player in controlling VSMC proliferation, via Ca2+/calmodulin-dependent protein kinase II and Akt. Loss of IP3Rs suppressed cAMP response element-binding protein phosphorylation at Ser133 in both cultured VSMCs and injured vessels, whereas application of Ca2+ permeable ionophore, ionomycin, can reverse cAMP response element-binding protein phosphorylation in IP3R triple knockout VSMCs.
CONCLUSIONS: Our results demonstrated an essential role of IP3R-mediated Ca2+ release from endoplasmic reticulum in regulating cAMP response element-binding protein activation, VSMC proliferation, and neointima formation in mouse arteries.

Keywords:  Ca2+ signaling; IP3 receptor; cell proliferation; neointima formation; vascular remodeling; vascular smooth muscle cell

DOI:  https://doi.org/10.1161/JAHA.124.034203
FEBS J. 2024 Jul 16.

NFκB dynamics-dependent epigenetic changes modulate inflammatory gene expression and induce cellular senescence.

Sho Tabata, Keita Matsuda, Shou Soeda, Kenshiro Nagai, Yoshihiro Izumi, Masatomo Takahashi, Yasutaka Motomura, Ayaka Ichikawa Nagasato, Kazuyo Moro, Takeshi Bamba, Mariko Okada.

  Upregulation of nuclear factor κB (NFκB) signaling is a hallmark of aging and a major cause of age-related chronic inflammation. However, its effect on cellular senescence remains unclear. Here, we show that alteration of NFκB nuclear dynamics from oscillatory to sustained by depleting a negative feedback regulator of NFκB pathway, NFκB inhibitor alpha (IκBα), in the presence of tumor necrosis factor α (TNFα) promotes cellular senescence. Sustained NFκB activity enhanced inflammatory gene expression through increased NFκB-DNA binding and slowed the cell cycle. IκBα protein was decreased under replicative or oxidative stress in vitro. Furthermore, a decrease in IκBα protein and an increase in DNA-NFκB binding at the transcription start sites of age-associated genes in aged mouse hearts suggested that nuclear NFκB dynamics may play a critical role in the progression of aging. Our study suggests that nuclear NFκB dynamics-dependent epigenetic changes regulated over time in a living system, possibly through a decrease in IκBα, enhance the expression of inflammatory genes to advance the cells to a senescent state.

Keywords:  NFκB; SASP; cellular senescence; inflammatory aging; nuclear dynamics

DOI:  https://doi.org/10.1111/febs.17227