bims-cesemi 2024-04-07 papers

Issue of 2024–04–07
eight papers selected by
Julio Cesar Cardenas, Universidad Mayor

Cancer Discov. 2024 Apr 04. 14(4): 635-638

Targeting Senescence for Next-Generation Cancer Treatments.

Eric Gilson, Pierre Soubeyran, Eric Solary.

SUMMARY: Cellular senescence has paradoxical effects on cancer emergence, progression, and therapeutic response. We herein identify four lessons that emerged from studying senescence interaction with cancer and emphasize four bottlenecks in the therapeutic manipulation of cellular senescence to prevent or cure cancer.

DOI: https://doi.org/10.1158/2159-8290.CD-24-0089

Mech Ageing Dev. 2024 Mar 30. pii: S0047-6374(24)00029-0. [Epub ahead of print]219 111929

In the land of not-unhappiness: On the state-of-the-art of targeting aging and age-related diseases by biomedical research.

Eirini Klinaki, Mikolaj Ogrodnik.

The concept of the Land of Not-Unhappiness refers to the potential achievement of eliminating the pathologies of the aging process. To inform of how close we are to settling in the land, we summarize and review the achievements of research on anti-aging interventions over the last hundred years with a specific focus on strategies that slow down metabolism, compensate for aging-related losses, and target a broad range of age-related diseases. We critically evaluate the existing interventions labeled as "anti-aging," such as calorie restriction, exercise, stem cell administration, and senolytics, to provide a down-to-earth evaluation of their current applicability in counteracting aging. Throughout the text, we have maintained a light tone to make it accessible to non-experts in biogerontology, and provide a broad overview for those considering conducting studies, research, or seeking to understand the scientific basis of anti-aging medicine.

Keywords: Age-related diseases; Aging; Anti-aging interventions; Biogerontology; Healthspan; Senescence

DOI: https://doi.org/10.1016/j.mad.2024.111929

J Gerontol A Biol Sci Med Sci. 2024 Apr 02. pii: glae088. [Epub ahead of print]

Inhibition of DAPK3 suppresses radiation-induced cellular senescence by activation of a PGC1α-dependent metabolism pathway in brain endothelial cells.

Ji-Eun Park, Jeong Woo Park, Myong-Kyu Sim, So Ra Kim, Kwang Seok Kim.

In the brain, environmental changes, such as neuroinflammation, can induce senescence, characterized by the decreased proliferation of neurons and dendrites and synaptic and vascular damage, resulting in cognitive decline. Senescence promotes neuroinflammatory disorders by senescence-associated secretory phenotypes and ROS. In human brain microvascular endothelial cells (HBMVECs), we demonstrate that chronological aging and irradiation increase death-associated protein kinase 3 (DAPK3) expression. To confirm the role of DAPK3 in HBMVEC senescence, we disrupted DAPK3 activity using small interfering RNA (siRNA) or a dominant-negative mutant (DAPK3-P216S), which reduced cellular senescence phenotypes, as assessed by changes in tube formation, senescence-associated beta-galactosidase activity, and cell proliferation. In endothelial cells, DAPK3 promotes cellular senescence by regulating the phosphorylation and inactivation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) via the protein kinase B pathway, resulting in the decreased expression of mitochondrial metabolism-associated genes, such as ATP5G1, BDNF, and COX5A. Our studies show that DAPK3 is involved in cellular senescence and PGC1α regulation, suggesting that DAPK3 regulation may be important for treating aging-related brain diseases or the response to radiation therapy.

Keywords: DAPK3; brain aging; cellular senescence; endothelial cell; metabolic decline

DOI: https://doi.org/10.1093/gerona/glae088

Acta Biomater. 2024 Mar 30. pii: S1742-7061(24)00164-8. [Epub ahead of print]

Cellular senescence imaging and senolysis monitoring in cancer therapy based on a β-galactosidase-activated aggregation-induced emission luminogen.

Peili Cen, Chunyi Cui, Jiani Huang, Hetian Chen, Fei Wu, Jiaqi Niu, Yan Zhong, Chentao Jin, Wei-Hong Zhu, Hong Zhang, Mei Tian.

Cellular senescence is a permanent state of cell cycle arrest characterized by increased activity of senescence associated β-galactosidase (SA-β-gal). Notably, cancer cells have been also observed to exhibit the senescence response and are being considered for sequential treatment with pro-senescence therapy followed by senolytic therapy. However, there is currently no effective agent targeting β-galactosidase (β-Gal) for imaging cellular senescence and monitoring senolysis in cancer therapy. Aggregation-induced emission luminogen (AIEgen) demonstrates strong fluorescence, good photostability, and biocompatibility, making it a potential candidate for imaging cellular senescence and monitoring senolysis in cancer therapy when endowed with β-Gal-responsive capabilities. In this study, we introduced a β-Gal-activated AIEgen named QM-β-gal for cellular senescence imaging and senolysis monitoring in cancer therapy. QM-β-gal exhibited good amphiphilic properties and formed aggregates that emitted a fluorescence signal upon β-Gal activation. It showed high specificity towards the activity of β-Gal in lysosomes and successfully visualized DOX-induced senescent cancer cells with intense fluorescence both in vitro and in vivo. Encouragingly, QM-β-gal could image senescent cancer cells in vivo for over 14 days with excellent biocompatibility. Moreover, it allowed for the monitoring of senescent cancer cell clearance during senolytic therapy with ABT263. This investigation indicated the potential of the β-Gal-activated AIEgen, QM-β-gal, as an in vivo approach for imaging cellular senescence and monitoring senolysis in cancer therapy via highly specific and long-term fluorescence imaging. STATEMENT OF SIGNIFICANCE: This work reported a β-galactosidase-activated AIEgen called QM-β-gal, which effectively imaged DOX-induced senescent cancer cells both in vitro and in vivo. QM-β-gal specifically targeted the increased expression and activity of β-galactosidase in senescent cancer cells, localized within lysosomes. It was cleared rapidly before activation but maintained stability after activation in the DOX-induced senescent tumor. The AIEgen exhibited a remarkable long-term imaging capability for senescent cancer cells, lasting over 14 days and enabled monitoring of senescent cancer cell clearance through ABT263-induced apoptosis. This approach held promise for researchers seeking to achieve prolonged imaging of senescent cells in vivo.

Keywords: AIE; Cancer; Cellular senescence; Fluorescence imaging; Senolysis; β-galactosidase

DOI: https://doi.org/10.1016/j.actbio.2024.03.027

JCI Insight. 2024 Apr 02. pii: e169213. [Epub ahead of print]

Role of the mitochondrial protein cyclophilin D in skin wound healing and collagen.

Ritu Bansal, Monica Torres, Matthew Hunt, Nuoqi Wang, Margarita Chatzopoulou, Mansi Manchanda, Evan P Taddeo, Cynthia Shu, Orian S Shirihai, Etty Bachar-Wikstrom, Jakob D Wikstrom.

Central for wound healing is the formation of granulation tissue, which largely consists of collagen and whose importance stretches past wound healing, including being implicated in both fibrosis and skin aging. Cyclophilin D (CyD) is a mitochondrial protein that regulates the permeability transition pore, known for its role in apoptosis and ischemia-reperfusion. To date, the role of CyD in human wound healing and collagen generation ihas been largely unexplored. Here, we show that CyD was upregulated in normal wounds and venous ulcers, likely adaptive as CyD inhibition impaired re-epithelialization, granulation tissue formation, and wound closure in both human and pig models. Overexpression of CyD increased keratinocyte migration and fibroblast proliferation, whilst its inhibition reduced migration. Independent of wound healing, CyD inhibition in fibroblasts reduced collagen secretion and caused endoplasmic reticulum collagen accumulation, while its overexpression increased collagen secretion. This was confirmed in a Ppif knockout mouse model, which showed a reduction in skin collagen. Overall, this study revealed previously unreported roles of CyD in skin, with implications for wound healing and beyond.

Keywords: Collagens; Dermatology; Mitochondria; Skin

DOI: https://doi.org/10.1172/jci.insight.169213

Mech Ageing Dev. 2024 Mar 28. pii: S0047-6374(24)00031-9. [Epub ahead of print] 111931

Mitochondria-targeted esculetin and metformin delay endothelial senescence by promoting fatty acid β-oxidation: Relevance in age-associated atherosclerosis.

Sriravali Pulipaka, Hridya Chempon, Gajalakshmi Singuru, Shashikanta Sahoo, Altab Shaikh, Sunita Kumari, Rajamannar Thennati, Srigiridhar Kotamraju.

Impaired mitochondrial fatty acid β-oxidation (FAO) plays a role in the onset of several age-associated diseases, including atherosclerosis. In the current work, we investigated the efficacies of mitochondria-targeted esculetin (Mito-Esc) and metformin in enhancing FAO in human aortic endothelial cells (HAECs), and its relevance in the delay of cellular senescence and age-associated atherosclerotic plaque formation in Apoe-/- mice. Chronic culturing of HAECs with either Mito-Esc or metformin increased oxygen consumption rates (OCR), and caused delay in senescence features. Conversely, etomoxir (CPT1 inhibitor) reversed Mito-Esc- and metformin-induced OCR, and caused premature endothelial senescence. Interestingly, Mito-Esc, unlike metformin, in the presence of etomoxir failed to preserve OCR. Thereby, underscoring Mito-Esc's exclusive reliance on FAO as an energy source. Mechanistically, chronic culturing of HAECs with either Mito-Esc or metformin led to AMPK activation, increased CPT1 activity, and acetyl-CoA levels along with a concomitant reduction in malonyl-CoA levels, and lipid accumulation. Similar results were observed in Apoe-/- mice aorta and liver tissue with a parallel reduction in age-associated atherosclerotic plaque formation and degeneration of liver with either Mito-Esc or metformin administration. Together, Mito-Esc and metformin by potentiating FAO, may have a role in the delay of cellular senescence by modulating mitochondrial function.

Keywords: Ageing; Atherosclerosis; Endothelial senescence; Metformin; Mito-Esc; fatty acid β-oxidation

DOI: https://doi.org/10.1016/j.mad.2024.111931

Biochim Biophys Acta Mol Cell Res. 2024 Mar 29. pii: S0167-4889(24)00057-0. [Epub ahead of print] 119714

MICU1's calcium sensing beyond mitochondrial calcium uptake.

Sarah D Kaye, Shanikumar Goyani, Dhanendra Tomar.

The discovery of MICU1 as gatekeeper of mitochondrial calcium (mCa2+) entry has transformed our understanding of mCa2+ flux. Recent studies revealed an additional role of MICU1 as a Ca2+ sensor at MICOS (mitochondrial contact site and cristae organizing system). MICU1's presence at MICOS suggests its involvement in coordinating Ca2+ signaling and mitochondrial ultrastructure. Besides its role in Ca2+ regulation, MICU1 influences cellular signaling pathways including transcription, epigenetic regulation, metabolism, and cell death signaling pathways, thereby affecting human health. Here, we summarize recent findings on MICU1's canonical and noncanonical functions, and its relevance to human health and diseases.

Keywords: Calcium; MCU; MICOS; MICU1; Mitochondria

DOI: https://doi.org/10.1016/j.bbamcr.2024.119714

Trends Endocrinol Metab. 2024 Feb;pii: S1043-2760(23)00214-X. [Epub ahead of print]35(2): 125-141

Common and divergent molecular mechanisms of fasting and ketogenic diets.

Antonio Paoli, Grant M Tinsley, Mark P Mattson, Immaculata De Vivo, Ravi Dhawan, Tatiana Moro.

Intermittent short-term fasting (ISTF) and ketogenic diets (KDs) exert overlapping but not identical effects on cell metabolism, function, and resilience. Whereas health benefits of KD are largely mediated by the ketone bodies (KBs), ISTF engages additional adaptive physiological responses. KDs act mainly through inhibition of histone deacetylases (HDACs), reduction of oxidative stress, improvement of mitochondria efficiency, and control of inflammation. Mechanisms of action of ISTF include stimulation of autophagy, increased insulin and leptin sensitivity, activation of AMP-activated protein kinase (AMPK), inhibition of the mechanistic target of rapamycin (mTOR) pathway, bolstering mitochondrial resilience, and suppression of oxidative stress and inflammation. Frequent switching between ketogenic and nonketogenic states may optimize health by increasing stress resistance, while also enhancing cell plasticity and functionality.

Keywords: brain; fasting; ketogenic diet; ketone bodies; mitochondria; time-restricted eating

DOI: https://doi.org/10.1016/j.tem.2023.10.001