bims-cesemi Biomed News
on Cellular senescence and mitochondria
Issue of 2024–03–31
twelve papers selected by
Julio Cesar Cardenas, Universidad Mayor
  1. Accelerated Aging in Cancer Survivors: Cellular Senescence, Frailty, and Possible Opportunities for Interventions.
  2. Senescence Promotes the Recovery of Stemness among Cancer Cells via Reprograming.
  3. CLCA2: A Potential Guardian against Premature Senescence and Skin Aging.
  4. Senolytic CAR T cells reverse aging-associated defects in intestinal regeneration and fitness.
  5. The Molecular Mechanisms in Senescent Cells Induced by Natural Aging and Ionizing Radiation.
  6. High Glucose Promotes and Aggravates the Senescence and Dysfunction of Vascular Endothelial Cells in Women with Hyperglycemia in Pregnancy.
  7. Cellular and molecular mechanisms of skin wound healing.
  8. Tricarboxylic Acid Cycle Intermediates and Individual Ageing.
  9. The Mitochondrial Connection: The Nek Kinases' New Functional Axis in Mitochondrial Homeostasis.
  10. Exercise-Regulated Mitochondrial and Nuclear Signalling Networks in Skeletal Muscle.
  11. Subcellular structure, heterogeneity, and plasticity of senescent cells.
  12. Stress-induced microautophagy is coordinated with lysosome biogenesis and regulated by PIKfyve.
  1. Int J Mol Sci. 2024 Mar 14. pii: 3319. [Epub ahead of print]25(6):
    Accelerated Aging in Cancer Survivors: Cellular Senescence, Frailty, and Possible Opportunities for Interventions.
    Shuo Wang, Najla El Jurdi, Bharat Thyagarajan, Anna Prizment, Anne H Blaes.
      The population of cancer survivors has markedly increased due to the rapid improvements in cancer treatment. However, cancer survivors experience accelerated aging, which leads to chronic diseases and other age-related conditions, such as frailty. Those conditions may persist years after cancer diagnosis and treatment. Cellular senescence, a hallmark of aging, is one of the mechanisms that contribute to accelerated aging in cancer survivors. Several aging measures, including measures based on clinical markers and biomarkers, have been proposed to estimate the aging process, and some of them have shown associations with mortality and frailty in cancer survivors. Several anti-aging interventions, including lifestyle changes and anti-aging drugs, have been proposed. Future research, particularly in large-scale studies, is needed to determine the efficiency of these aging measures and anti-aging interventions before considering their application in clinics. This review focuses on the mechanisms of cellular senescence and accelerated aging in cancer survivors, assessment of the aging process using clinical markers and biomarkers, and the high prevalence of frailty in that population, as well as possible opportunities for anti-aging interventions. A deeper understanding of aging measures and anti-aging interventions in cancer survivors will contribute to the development of effective strategies to mitigate accelerated aging in cancer survivors and improve their quality of life.
    Keywords:  accelerated aging; anti-aging interventions; cancer survivors; cellular senescence; frailty
    DOI:  https://doi.org/10.3390/ijms25063319
  2. Biomolecules. 2024 Feb 28. pii: 288. [Epub ahead of print]14(3):
    Senescence Promotes the Recovery of Stemness among Cancer Cells via Reprograming.
    Di Wang, Lingbo Liu.
      Both the senescence of cancer cells and the maintenance of cancer stem cells seem to be mutually exclusive because senescence is considered a physiological mechanism that effectively suppresses tumor growth. Recent studies have revealed common signaling pathways between cellular senescence and the maintenance of stemness in cancer cells, thus challenging the conventional understanding of this process. Although the links between these processes have not yet been fully elucidated, emerging evidence indicates that senescent cancer cells can undergo reprograming to recover stemness. Herein, we provide a comprehensive overview of the close correlation between senescence and stemness reprograming in cancer cells, with a particular focus on the mechanisms by which senescent cancer cells recover their stemness in various tumor systems.
    Keywords:  cancer stem cells (CSCs); leukemia stem cells (LSCs); oncogene-induced senescence (OIS); senescence; senescence-associated secretory phenotype (SASP); senescence-associated stemness (SAS); stemness reprograming; therapy-induced senescence (TIS)
    DOI:  https://doi.org/10.3390/biom14030288
  3. Biomedicines. 2024 Mar 06. pii: 592. [Epub ahead of print]12(3):
    CLCA2: A Potential Guardian against Premature Senescence and Skin Aging.
    Lena Guerrero-Navarro, Ines Martic, Christian Ploner, Pidder Jansen-Dürr, Maria Cavinato.
      Cellular senescence, a state of irreversible growth arrest, is implicated in various age-related pathologies, including skin aging. In this study, we investigated the role of CLCA2, a calcium-activated chloride channel accessory protein, in cellular senescence and its implications for skin aging. Utilizing UVB and Nutlin3a-induced senescence models, we observed the upregulation of CLCA2 at both transcriptomic and proteomic levels, suggesting its involvement in senescence pathways. Further analysis revealed that the depletion of CLCA2 led to accelerated senescence onset, characterized by classic senescence markers and a unique secretome profile. In 3D skin equivalent models, SEs constructed with CLCA2 knockdown fibroblasts exhibited features reminiscent of aged skin, underscoring the importance of CLCA2 in maintaining skin homeostasis. Our findings highlight CLCA2 as a novel regulator of cellular senescence and its potential implications for skin aging mechanisms.
    Keywords:  CLCA2; Nutlin3a; UVB; senescence; skin aging; tBHP
    DOI:  https://doi.org/10.3390/biomedicines12030592
  4. bioRxiv. 2024 Mar 22. pii: 2024.03.19.585779. [Epub ahead of print]
    Senolytic CAR T cells reverse aging-associated defects in intestinal regeneration and fitness.
    Onur Eskiocak, Saria Chowdhury, Vyom Shah, Emmanuella Nnuji-John, Charlie Chung, Jacob A Boyer, Alexander S Harris, Jill Habel, Michel Sadelain, Semir Beyaz, Corina Amor.
      Intestinal stem cells (ISCs) drive the rapid regeneration of the gut epithelium to maintain organismal homeostasis. Aging, however, significantly reduces intestinal regenerative capacity. While cellular senescence is a key feature of the aging process, little is known about the in vivo effects of senescent cells on intestinal fitness. Here, we identify the accumulation of senescent cells in the aging gut and, by harnessing senolytic CAR T cells to eliminate them, we uncover their detrimental impact on epithelial integrity and overall intestinal homeostasis in natural aging, injury and colitis. Ablation of intestinal senescent cells with senolytic CAR T cells in vivo or in vitro is sufficient to promote the regenerative potential of aged ISCs. This intervention improves epithelial integrity and mucosal immune function. Overall, these results highlight the ability of senolytic CAR T cells to rejuvenate the intestinal niche and demonstrate the potential of targeted cell therapies to promote tissue regeneration in aging organisms.
    DOI:  https://doi.org/10.1101/2024.03.19.585779
  5. Cells. 2024 Mar 21. pii: 550. [Epub ahead of print]13(6):
    The Molecular Mechanisms in Senescent Cells Induced by Natural Aging and Ionizing Radiation.
    Milana Ibragimova, Assiya Kussainova, Akmaral Aripova, Rakhmetkazhi Bersimbaev, Olga Bulgakova.
      This review discusses the relationship between cellular senescence and radiation exposure. Given the wide range of ionizing radiation sources encountered by people in professional and medical spheres, as well as the influence of natural background radiation, the question of the effect of radiation on biological processes, particularly on aging processes, remains highly relevant. The parallel relationship between natural and radiation-induced cellular senescence reveals the common aspects underlying these processes. Based on recent scientific data, the key points of the effects of ionizing radiation on cellular processes associated with aging, such as genome instability, mitochondrial dysfunction, altered expression of miRNAs, epigenetic profile, and manifestation of the senescence-associated secretory phenotype (SASP), are discussed. Unraveling the molecular mechanisms of cellular senescence can make a valuable contribution to the understanding of the molecular genetic basis of age-associated diseases in the context of environmental exposure.
    Keywords:  DNA damage; SASP; cellular senescence; ionizing radiation; miRNAs; mitochondrial dysfunction; natural aging
    DOI:  https://doi.org/10.3390/cells13060550
  6. Biomolecules. 2024 Mar 10. pii: 329. [Epub ahead of print]14(3):
    High Glucose Promotes and Aggravates the Senescence and Dysfunction of Vascular Endothelial Cells in Women with Hyperglycemia in Pregnancy.
    Lin Zheng, Mingqing Li, Huaping Li.
      Hyperglycemia in pregnancy (HIP) is linked to fetoplacental endothelial dysfunction, which might be a result of hyperglycemia. Hyperglycemia is associated with cell senescence; however, the role and mechanism of high glucose and cell senescence in HIP endothelial cell failure are largely unknown. Our study discovered that human umbilical vein endothelial cells (HUVECs) obtained from HIP pregnant women exhibit excessive senescence, with significantly elevated expression of senescence markers senescence-associated beta-galactosidase (SA-β-gal), p16, p21, and p53. Subsequently, we found that exposing primary HUVECs and cell lines to high glucose resulted in an increase in the synthesis of these senescence indicators, similar to what had been observed in pregnant women with HIP. A replicate senescence model and stress-induced premature senescence (SIPS) model showed higher amounts of vascular damage indicators, including von Willebrand factor (vWF), chemotactic C-C motif chemokine ligand 2 (CCL2), intercellular adhesion molecule 1 (ICAM-1), along with the anti-apoptotic protein BCL2. However, lower expressions of the pro-apoptotic component BAX, in addition to defective proliferation and tubulogenesis, were seen. Further studies indicated that hyperglycemia can not only induce these alterations in HUVECs but also exacerbate the aforementioned changes in both aging HUVECs. The experiments outlined above have also been validated in pregnant women with HIP. Collectively, these data suggest that exposure to high glucose accelerates cell senescence-mediated vein endothelial cell dysfunction, including excessive inflammation, cell adhesion, impaired angiogenesis, and cell proliferation possibly contributing to pregnancy complications and adverse pregnancy outcomes.
    Keywords:  cellular senescence; hyperglycemia; pregnancy; umbilical vein endothelial cells
    DOI:  https://doi.org/10.3390/biom14030329
  7. Nat Rev Mol Cell Biol. 2024 Mar 25.
    Cellular and molecular mechanisms of skin wound healing.
    Oscar A Peña, Paul Martin.
      Wound healing is a complex process that involves the coordinated actions of many different tissues and cell lineages. It requires tight orchestration of cell migration, proliferation, matrix deposition and remodelling, alongside inflammation and angiogenesis. Whereas small skin wounds heal in days, larger injuries resulting from trauma, acute illness or major surgery can take several weeks to heal, generally leaving behind a fibrotic scar that can impact tissue function. Development of therapeutics to prevent scarring and successfully repair chronic wounds requires a fuller knowledge of the cellular and molecular mechanisms driving wound healing. In this Review, we discuss the current understanding of the different phases of wound healing, from clot formation through re-epithelialization, angiogenesis and subsequent scar deposition. We highlight the contribution of different cell types to skin repair, with emphasis on how both innate and adaptive immune cells in the wound inflammatory response influence classically studied wound cell lineages, including keratinocytes, fibroblasts and endothelial cells, but also some of the less-studied cell lineages such as adipocytes, melanocytes and cutaneous nerves. Finally, we discuss newer approaches and research directions that have the potential to further our understanding of the mechanisms underpinning tissue repair.
    DOI:  https://doi.org/10.1038/s41580-024-00715-1
  8. Biomolecules. 2024 Feb 22. pii: 260. [Epub ahead of print]14(3):
    Tricarboxylic Acid Cycle Intermediates and Individual Ageing.
    Natalia Kurhaluk.
      Anti-ageing biology and medicine programmes are a focus of genetics, molecular biology, immunology, endocrinology, nutrition, and therapy. This paper discusses metabolic therapies aimed at prolonging longevity and/or health. Individual components of these effects are postulated to be related to the energy supply by tricarboxylic acid (TCA) cycle intermediates and free radical production processes. This article presents several theories of ageing and clinical descriptions of the top markers of ageing, which define ageing in different categories; additionally, their interactions with age-related changes and diseases related to α-ketoglutarate (AKG) and succinate SC formation and metabolism in pathological states are explained. This review describes convincingly the differences in the mitochondrial characteristics of energy metabolism in animals, with different levels (high and low) of physiological reactivity of functional systems related to the state of different regulatory systems providing oxygen-dependent processes. Much attention is given to the crucial role of AKG and SC in the energy metabolism in cells related to amino acid synthesis, epigenetic regulation, cell stemness, and differentiation, as well as metabolism associated with the development of pathological conditions and, in particular, cancer cells. Another goal was to address the issue of ageing in terms of individual characteristics related to physiological reactivity. This review also demonstrated the role of the Krebs cycle as a key component of cellular energy and ageing, which is closely associated with the development of various age-related pathologies, such as cancer, type 2 diabetes, and cardiovascular or neurodegenerative diseases where the mTOR pathway plays a key role. This article provides postulates of postischaemic phenomena in an ageing organism and demonstrates the dependence of accelerated ageing and age-related pathology on the levels of AKG and SC in studies on different species (roundworm Caenorhabditis elegans, Drosophila, mice, and humans used as models). The findings suggest that this approach may also be useful to show that Krebs cycle metabolites may be involved in age-related abnormalities of the mitochondrial metabolism and may thus induce epigenetic reprogramming that contributes to the senile phenotype and degenerative diseases. The metabolism of these compounds is particularly important when considering ageing mechanisms connected with different levels of initial physiological reactivity and able to initiate individual programmed ageing, depending on the intensity of oxygen consumption, metabolic peculiarities, and behavioural reactions.
    Keywords:  ageing mechanisms; anti-ageing therapy; bioenergetic mechanisms of ageing; individual ageing processes; individual physiological reactivity; tricarboxylic acid cycle intermediates
    DOI:  https://doi.org/10.3390/biom14030260
  9. Cells. 2024 Mar 07. pii: 473. [Epub ahead of print]13(6):
    The Mitochondrial Connection: The Nek Kinases' New Functional Axis in Mitochondrial Homeostasis.
    Fernanda L Basei, Ivan Rosa E Silva, Pedro R Firmino Dias, Camila C Ferezin, Andressa Peres de Oliveira, Luidy K Issayama, Livia A R Moura, Fernando Riback da Silva, Jörg Kobarg.
      Mitochondria provide energy for all cellular processes, including reactions associated with cell cycle progression, DNA damage repair, and cilia formation. Moreover, mitochondria participate in cell fate decisions between death and survival. Nek family members have already been implicated in DNA damage response, cilia formation, cell death, and cell cycle control. Here, we discuss the role of several Nek family members, namely Nek1, Nek4, Nek5, Nek6, and Nek10, which are not exclusively dedicated to cell cycle-related functions, in controlling mitochondrial functions. Specifically, we review the function of these Neks in mitochondrial respiration and dynamics, mtDNA maintenance, stress response, and cell death. Finally, we discuss the interplay of other cell cycle kinases in mitochondrial function and vice versa. Nek1, Nek5, and Nek6 are connected to the stress response, including ROS control, mtDNA repair, autophagy, and apoptosis. Nek4, in turn, seems to be related to mitochondrial dynamics, while Nek10 is involved with mitochondrial metabolism. Here, we propose that the participation of Neks in mitochondrial roles is a new functional axis for the Nek family.
    Keywords:  Nek kinase family functions; cell cycle; cellular signaling; mitochondrial homeostasis
    DOI:  https://doi.org/10.3390/cells13060473
  10. Sports Med. 2024 Mar 25.
    Exercise-Regulated Mitochondrial and Nuclear Signalling Networks in Skeletal Muscle.
    Elizabeth G Reisman, John A Hawley, Nolan J Hoffman.
      Exercise perturbs energy homeostasis in skeletal muscle and engages integrated cellular signalling networks to help meet the contraction-induced increases in skeletal muscle energy and oxygen demand. Investigating exercise-associated perturbations in skeletal muscle signalling networks has uncovered novel mechanisms by which exercise stimulates skeletal muscle mitochondrial biogenesis and promotes whole-body health and fitness. While acute exercise regulates a complex network of protein post-translational modifications (e.g. phosphorylation) in skeletal muscle, previous investigations of exercise signalling in human and rodent skeletal muscle have primarily focused on a select group of exercise-regulated protein kinases [i.e. 5' adenosine monophosphate-activated protein kinase (AMPK), protein kinase A (PKA), Ca2+/calmodulin-dependent protein kinase (CaMK) and mitogen-activated protein kinase (MAPK)] and only a small subset of their respective protein substrates. Recently, global mass spectrometry-based phosphoproteomic approaches have helped unravel the extensive complexity and interconnection of exercise signalling pathways and kinases beyond this select group and phosphorylation and/or translocation of exercise-regulated mitochondrial and nuclear protein substrates. This review provides an overview of recent advances in our understanding of the molecular events associated with acute endurance exercise-regulated signalling pathways and kinases in skeletal muscle with a focus on phosphorylation. We critically appraise recent evidence highlighting the involvement of mitochondrial and nuclear protein phosphorylation and/or translocation in skeletal muscle adaptive responses to an acute bout of endurance exercise that ultimately stimulate mitochondrial biogenesis and contribute to exercise's wider health and fitness benefits.
    DOI:  https://doi.org/10.1007/s40279-024-02007-2
  11. Aging Cell. 2024 Mar 30. e14154
    Subcellular structure, heterogeneity, and plasticity of senescent cells.
    Thais Cardoso Bitencourt, Jose Eduardo Vargas, Andrew Oliveira Silva, Lucas Rosa Fraga, Eduardo Filippi-Chiela.
      Cellular senescence is a state of permanent growth arrest. It can be triggered by telomere shortening (replicative senescence) or prematurely induced by stresses such as DNA damage, oncogene overactivation, loss of tumor suppressor genes, oxidative stress, tissue factors, and others. Advances in techniques and experimental designs have provided new evidence about the biology of senescent cells (SnCs) and their importance in human health and disease. This review aims to describe the main aspects of SnCs phenotype focusing on alterations in subcellular compartments like plasma membrane, cytoskeleton, organelles, and nuclei. We also discuss the heterogeneity, dynamics, and plasticity of SnCs' phenotype, including the SASP, and pro-survival mechanisms. We advance on the multiple layers of phenotypic heterogeneity of SnCs, such as the heterogeneity between inducers, tissues and within a population of SnCs, discussing the relevance of these aspects to human health and disease. We also raise the main challenges as well alternatives to overcome them. Ultimately, we present open questions and perspectives in understanding the phenotype of SnCs from the perspective of basic and applied questions.
    Keywords:  SASP; cellular senescence; dynamics; heterogeneity; subcellular structure
    DOI:  https://doi.org/10.1111/acel.14154
  12. Mol Biol Cell. 2024 Mar 27. mbcE23080332
    Stress-induced microautophagy is coordinated with lysosome biogenesis and regulated by PIKfyve.
    Alison D Klein, Kayla L Petruzzi, Chan Lee, Michael Overholtzer.
      Lysosome turnover and biogenesis are induced in response to treatment of cells with agents that cause membrane rupture, but whether other stress conditions engage similar homeostatic mechanisms is not well understood. Recently we described a form of selective turnover of lysosomes that is induced by metabolic stress or by treatment of cells with ionophores or lysosomotropic agents, involving the formation of intraluminal vesicles within intact organelles through microautophagy. Selective turnover involves non-canonical autophagy and the lipidation of LC3 onto lysosomal membranes, as well as the autophagy gene-dependent formation of intraluminal vesicles. Here we find a form of microautophagy induction that requires activity of the lipid kinase PIKfyve and is associated with the nuclear translocation of TFEB, a known mediator of lysosome biogenesis. We show that LC3 undergoes turnover during this process, and that PIKfyve is required for the formation of intraluminal vesicles and LC3 turnover, but not for LC3 lipidation onto lysosomal membranes, demonstrating that microautophagy is regulated by PIKfyve downstream of non-canonical autophagy. We further show that TFEB activation requires non-canonical autophagy but not PIKfyve, distinguishing the regulation of biogenesis from microautophagy occurring in response to agents that induce lysosomal stress. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E23-08-0332
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:13.