bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2024‒09‒01
sixteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Mitochondrial translation is the primary determinant of secondary mitochondrial complex I deficiencies.
  2. Emerging interactions between mitochondria and NAD+ metabolism in cardiometabolic diseases.
  3. Mitochondrial dysfunction in acute kidney injury.
  4. Mitochondrial membrane lipids in the regulation of bioenergetic flux.
  5. The role of mitochondrial fusion and fission in immune-mediated inflammatory diseases.
  6. Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells.
  7. Cell-specific expression of key mitochondrial enzymes limits OXPHOS in astrocytes of the adult human neocortex and hippocampal formation.
  8. POLG-related mitochondrial disease mimicking autoimmune encephalitis.
  9. Interplay of FXN expression and lipolysis in white adipocytes plays a critical role in insulin sensitivity in Friedreich's ataxia mouse model.
  10. Pregnancy Disorders: A Potential Role for Mitochondrial Altered Homeostasis.
  11. Context-dependent roles of mitochondrial LONP1 in orchestrating the balance between airway progenitor versus progeny cells.
  12. Aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis.
  13. Glucagon promotes increased hepatic mitochondrial oxidation and pyruvate carboxylase flux in humans with fatty liver disease.
  14. Prenatal vitamin D deficiency exposure leads to long-term changes in immune cell proportions.
  15. Nicotinamide riboside modulates the reactive species interactome, bioenergetic status and proteomic landscape in a brain-region-specific manner.
  16. Dissecting the impact of differentiation stage, replicative history, and cell type composition on epigenetic clocks.
  1. iScience. 2024 Aug 16. 27(8): 110560
    Mitochondrial translation is the primary determinant of secondary mitochondrial complex I deficiencies.
    Kristýna Čunátová, Marek Vrbacký, Guillermo Puertas-Frias, Lukáš Alán, Marie Vanišová, María José Saucedo-Rodríguez, Josef Houštěk, Erika Fernández-Vizarra, Jiří Neužil, Alena Pecinová, Petr Pecina, Tomáš Mráček.
      Individual complexes of the mitochondrial oxidative phosphorylation system (OXPHOS) are not linked solely by their function; they also share dependencies at the maintenance/assembly level, where one complex depends on the presence of a different individual complex. Despite the relevance of this "interdependence" behavior for mitochondrial diseases, its true nature remains elusive. To understand the mechanism that can explain this phenomenon, we examined the consequences of the aberration of different OXPHOS complexes in human cells. We demonstrate here that the complete disruption of each of the OXPHOS complexes resulted in a decrease in the complex I (cI) level and that the major reason for this is linked to the downregulation of mitochondrial ribosomal proteins. We conclude that the secondary cI defect is due to mitochondrial protein synthesis attenuation, while the responsible signaling pathways could differ based on the origin of the OXPHOS defect.
    Keywords:  Biochemistry; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.110560
  2. Trends Endocrinol Metab. 2024 Aug 27. pii: S1043-2760(24)00191-7. [Epub ahead of print]
    Emerging interactions between mitochondria and NAD+ metabolism in cardiometabolic diseases.
    Azadeh Nasuhidehnavi, Weronika Zarzycka, Ignacy Górecki, Ying Ann Chiao, Chi Fung Lee.
      Nicotinamide adenine dinucleotide (NAD+) is an essential coenzyme for redox reactions and regulates cellular catabolic pathways. An intertwined relationship exists between NAD+ and mitochondria, with consequences for mitochondrial function. Dysregulation in NAD+ homeostasis can lead to impaired energetics and increased oxidative stress, contributing to the pathogenesis of cardiometabolic diseases. In this review, we explore how disruptions in NAD+ homeostasis impact mitochondrial function in various cardiometabolic diseases. We discuss emerging studies demonstrating that enhancing NAD+ synthesis or inhibiting its consumption can ameliorate complications of this family of pathological conditions. Additionally, we highlight the potential role and therapeutic promise of mitochondrial NAD+ transporters in regulating cellular and mitochondrial NAD+ homeostasis.
    DOI:  https://doi.org/10.1016/j.tem.2024.07.010
  3. Ren Fail. 2024 Dec;46(2): 2393262
    Mitochondrial dysfunction in acute kidney injury.
    Congcong Yao, Ziwei Li, Keke Sun, Yan Zhang, Songtao Shou, Heng Jin.
      Acute kidney injury (AKI) is a systemic clinical syndrome increasing morbidity and mortality worldwide in recent years. Renal tubular epithelial cells (TECs) death caused by mitochondrial dysfunction is one of the pathogeneses. The imbalance of mitochondrial quality control is the main cause of mitochondrial dysfunction. Mitochondrial quality control plays a crucial role in AKI. Mitochondrial quality control mechanisms are involved in regulating mitochondrial integrity and function, including antioxidant defense, mitochondrial quality control, mitochondrial DNA (mtDNA) repair, mitochondrial dynamics, mitophagy, and mitochondrial biogenesis. Currently, many studies have used mitochondrial dysfunction as a targeted therapeutic strategy for AKI. Therefore, this review aims to present the latest research advancements on mitochondrial dysfunction in AKI, providing a valuable reference and theoretical foundation for clinical prevention and treatment of this condition, ultimately enhancing patient prognosis.
    Keywords:  Acute kidney injury; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial quality control; mitophagy
    DOI:  https://doi.org/10.1080/0886022X.2024.2393262
  4. Cell Metab. 2024 Aug 13. pii: S1550-4131(24)00326-7. [Epub ahead of print]
    Mitochondrial membrane lipids in the regulation of bioenergetic flux.
    Stephen Thomas Decker, Katsuhiko Funai.
      Oxidative phosphorylation (OXPHOS) occurs through and across the inner mitochondrial membrane (IMM). Mitochondrial membranes contain a distinct lipid composition, aided by lipid biosynthetic machinery localized in the IMM and class-specific lipid transporters that limit lipid traffic in and out of mitochondria. This unique lipid composition appears to be essential for functions of mitochondria, particularly OXPHOS, by its effects on direct lipid-to-protein interactions, membrane properties, and cristae ultrastructure. This review highlights the biological significance of mitochondrial lipids, with a particular spotlight on the role of lipids in mitochondrial bioenergetics. We describe pathways for the biosynthesis of mitochondrial lipids and provide evidence for their roles in physiology, their implications in human disease, and the mechanisms by which they regulate mitochondrial bioenergetics.
    Keywords:  bioenergetics; mitochondria; phospholipids
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.024
  5. Cell Immunol. 2024 Aug 26. pii: S0008-8749(24)00067-4. [Epub ahead of print]403-404 104864
    The role of mitochondrial fusion and fission in immune-mediated inflammatory diseases.
    Yulai Fang, Shichen Min, Hong Shen.
      Mitochondria are highly dynamic organelles that maintain their homeostasis through mitochondrial dynamics. Mitochondrial fusion and fission are two important processes of mitochondrial dynamics. There is accumulating evidence that mitochondrial fusion and fission play an important role in the development of immune-mediated inflammatory diseases. This article provides a brief review of the essential role of mitochondrial fusion and fission in immune-mediated inflammatory diseases. It will provide a novel perspective and direction for the elucidation of the pathogenesis and treatment of immune-mediated inflammatory diseases.
    Keywords:  Immune-mediated inflammatory diseases; Mitochondrial fission; Mitochondrial fusion
    DOI:  https://doi.org/10.1016/j.cellimm.2024.104864
  6. Nat Commun. 2024 Aug 27. 15(1): 7378
    Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells.
    Vanessa López-Polo, Mate Maus, Emmanouil Zacharioudakis, Miguel Lafarga, Camille Stephan-Otto Attolini, Francisco D M Marques, Marta Kovatcheva, Evripidis Gavathiotis, Manuel Serrano.
      The escape of mitochondrial double-stranded dsRNA (mt-dsRNA) into the cytosol has been recently linked to a number of inflammatory diseases. Here, we report that the release of mt-dsRNA into the cytosol is a general feature of senescent cells and a critical driver of their inflammatory secretome, known as senescence-associated secretory phenotype (SASP). Inhibition of the mitochondrial RNA polymerase, the dsRNA sensors RIGI and MDA5, or the master inflammatory signaling protein MAVS, all result in reduced expression of the SASP, while broadly preserving other hallmarks of senescence. Moreover, senescent cells are hypersensitized to mt-dsRNA-driven inflammation due to their reduced levels of PNPT1 and ADAR1, two proteins critical for mitigating the accumulation of mt-dsRNA and the inflammatory potency of dsRNA, respectively. We find that mitofusin MFN1, but not MFN2, is important for the activation of the mt-dsRNA/MAVS/SASP axis and, accordingly, genetic or pharmacologic MFN1 inhibition attenuates the SASP. Finally, we report that senescent cells within fibrotic and aged tissues present dsRNA foci, and inhibition of mitochondrial RNA polymerase reduces systemic inflammation associated to senescence. In conclusion, we uncover the mt-dsRNA/MAVS/MFN1 axis as a key driver of the SASP and we identify novel therapeutic strategies for senescence-associated diseases.
    DOI:  https://doi.org/10.1038/s41467-024-51363-0
  7. Commun Biol. 2024 Aug 24. 7(1): 1045
    Cell-specific expression of key mitochondrial enzymes limits OXPHOS in astrocytes of the adult human neocortex and hippocampal formation.
    Arpád Dobolyi, Melinda Cservenák, Attila G Bagó, Chun Chen, Anna Stepanova, Krisztina Paal, Jeonghyoun Lee, Miklós Palkovits, Gavin Hudson, Christos Chinopoulos.
      The astrocyte-to-neuron lactate shuttle model entails that, upon glutamatergic neurotransmission, glycolytically derived pyruvate in astrocytes is mainly converted to lactate instead of being entirely catabolized in mitochondria. The mechanism of this metabolic rewiring and its occurrence in human brain are unclear. Here by using immunohistochemistry (4 brains) and imaging mass cytometry (8 brains) we show that astrocytes of the adult human neocortex and hippocampal formation express barely detectable amounts of mitochondrial proteins critical for performing oxidative phosphorylation (OXPHOS). These data are corroborated by queries of transcriptomes (107 brains) of neuronal versus non-neuronal cells fetched from the Allen Institute for Brain Science for genes coding for a much larger repertoire of entities contributing to OXPHOS, showing that human non-neuronal elements barely expressed mRNAs coding for such proteins. With less OXPHOS, human brain astrocytes are thus bound to produce more lactate to avoid interruption of glycolysis.
    DOI:  https://doi.org/10.1038/s42003-024-06751-z
  8. J Neurol. 2024 Aug 24.
    POLG-related mitochondrial disease mimicking autoimmune encephalitis.
    Michael Bayat, Thomas Harbo, Maryam Anzabi, Allan Bayat, Jan Lykke Scheel Thomsen.
      
    DOI:  https://doi.org/10.1007/s00415-024-12641-5
  9. Sci Rep. 2024 08 27. 14(1): 19876
    Interplay of FXN expression and lipolysis in white adipocytes plays a critical role in insulin sensitivity in Friedreich's ataxia mouse model.
    Lin Wu, Fei Huang, Lu Yang, Liu Yang, Zichen Sun, Jinghua Zhang, Siyu Xia, Hongting Zhao, Yibing Ding, Dezhi Bian, Kuanyu Li.
      Frataxin (FXN) is required for iron-sulfur cluster biogenesis, and its loss causes the early-onset neurodegenerative disease Friedreich ataxia (FRDA). Loss of FXN is a susceptibility factor in the development of diabetes, a common metabolic complication after myocardial hypertrophy in patients with FRDA. The underlying mechanism of FXN deficient-induced hyperglycemia in FRDA is, however, poorly understood. In this study, we confirmed that the FXN deficiency mouse model YG8R develops insulin resistance in elder individuals by disturbing lipid metabolic homeostasis in adipose tissues. Evaluation of lipolysis, lipogenesis, and fatty acid β-oxidation showed that lipolysis is most severely affected in white adipose tissues. Consistently, FXN deficiency significantly decreased expression of lipolytic genes encoding adipose triglyceride lipase (Atgl) and hormone-sensitive lipase (Hsl) resulting in adipocyte enlargement and inflammation. Lipolysis induction by fasting or cold exposure remarkably upregulated FXN expression, though FXN deficiency lessened the competency of lipolysis compared with the control or wild type mice. Moreover, we found that the impairment of lipolysis was present at a young age, a few months earlier than hyperglycemia and insulin resistance. Forskolin, an activator of lipolysis, or pioglitazone, an agonist of PPARγ, improved insulin sensitivity in FXN-deficient adipocytes or mice. We uncovered the interplay between FXN expression and lipolysis and found that impairment of lipolysis, particularly the white adipocytes, is an early event, likely, as a primary cause for insulin resistance in FRDA patients at later age.
    Keywords:  Adipose tissue; Frataxin; Insulin sensitivity; Lipolysis; PPARγ
    DOI:  https://doi.org/10.1038/s41598-024-71099-7
  10. Antioxidants (Basel). 2024 Aug 13. pii: 979. [Epub ahead of print]13(8):
    Pregnancy Disorders: A Potential Role for Mitochondrial Altered Homeostasis.
    Juan M Toledano, María Puche-Juarez, Jose Maria Galvez-Navas, Jorge Moreno-Fernandez, Javier Diaz-Castro, Julio J Ochoa.
      Pregnancy is a complex and challenging process associated with physiological changes whose objective is to adapt the maternal organism to the increasing energetic requirements due to embryo and fetal development. A failed adaptation to these demands may lead to pregnancy complications that threaten the health of both mothers and their offspring. Since mitochondria are the main organelle responsible for energy generation in the form of ATP, the adequate state of these organelles seems crucial for proper pregnancy development and healthy pregnancy outcomes. The homeostasis of these organelles depends on several aspects, including their content, biogenesis, energy production, oxidative stress, dynamics, and signaling functions, such as apoptosis, which can be modified in relation to diseases during pregnancy. The etiology of pregnancy disorders like preeclampsia, fetal growth restriction, and gestational diabetes mellitus is not yet well understood. Nevertheless, insufficient placental perfusion and oxygen transfer are characteristic of many of them, being associated with alterations in the previously cited different aspects of mitochondrial homeostasis. Therefore, and due to the capacity of these multifactorial organelles to respond to physiological and pathophysiological stimuli, it is of great importance to gather the currently available scientific information regarding the relationship between main pregnancy complications and mitochondrial alterations. According to this, the present review is intended to show clear insight into the possible implications of mitochondria in these disorders, thus providing relevant information for further investigation in relation to the investigation and management of pregnancy diseases.
    Keywords:  bioenergetics; fetal growth restriction; gestation; gestational diabetes mellitus; mitochondria; mitochondrial dynamics; oxidative phosphorylation; preeclampsia; pregnancy complications
    DOI:  https://doi.org/10.3390/antiox13080979
  11. Cell Stem Cell. 2024 Aug 16. pii: S1934-5909(24)00287-X. [Epub ahead of print]
    Context-dependent roles of mitochondrial LONP1 in orchestrating the balance between airway progenitor versus progeny cells.
    Le Xu, Chunting Tan, Justinn Barr, Nicole Talaba, Jamie Verheyden, Ji Sun Chin, Samvel Gaboyan, Nikita Kasaraneni, Ruth M Elgamal, Kyle J Gaulton, Grace Lin, Kamyar Afshar, Eugene Golts, Angela Meier, Laura E Crotty Alexander, Zea Borok, Yufeng Shen, Wendy K Chung, David J McCulley, Xin Sun.
      While all eukaryotic cells are dependent on mitochondria for function, in a complex tissue, which cell type and which cell behavior are more sensitive to mitochondrial deficiency remain unpredictable. Here, we show that in the mouse airway, compromising mitochondrial function by inactivating mitochondrial protease gene Lonp1 led to reduced progenitor proliferation and differentiation during development, apoptosis of terminally differentiated ciliated cells and their replacement by basal progenitors and goblet cells during homeostasis, and failed airway progenitor migration into damaged alveoli following influenza infection. ATF4 and the integrated stress response (ISR) pathway are elevated and responsible for the airway phenotypes. Such context-dependent sensitivities are predicted by the selective expression of Bok, which is required for ISR activation. Reduced LONP1 expression is found in chronic obstructive pulmonary disease (COPD) airways with squamous metaplasia. These findings illustrate a cellular energy landscape whereby compromised mitochondrial function could favor the emergence of pathological cell types.
    Keywords:  ATF4; BOK; COPD; airway homeostasis; differentiated progeny cells; influenza infection; integrated stress response; lung epithelial cells; mitochondria; progenitor basal cells
    DOI:  https://doi.org/10.1016/j.stem.2024.08.001
  12. Nat Commun. 2024 Aug 26. 15(1): 7337
    Aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis.
    Niranjana Natarajan, Jonathan Florentin, Ebin Johny, Hanxi Xiao, Scott Patrick O'Neil, Liqun Lei, Jixing Shen, Lee Ohayon, Aaron R Johnson, Krithika Rao, Xiaoyun Li, Yanwu Zhao, Yingze Zhang, Sina Tavakoli, Sruti Shiva, Jishnu Das, Partha Dutta.
      There is a large body of evidence that cellular metabolism governs inflammation, and that inflammation contributes to the progression of atherosclerosis. However, whether mitochondrial DNA synthesis affects macrophage function and atherosclerosis pathology is not fully understood. Here we show, by transcriptomic analyzes of plaque macrophages, spatial single cell transcriptomics of atherosclerotic plaques, and functional experiments, that mitochondrial DNA (mtDNA) synthesis in atherosclerotic plaque macrophages are triggered by vascular cell adhesion molecule 1 (VCAM-1) under inflammatory conditions in both humans and mice. Mechanistically, VCAM-1 activates C/EBPα, which binds to the promoters of key mitochondrial biogenesis genes - Cmpk2 and Pgc1a. Increased CMPK2 and PGC-1α expression triggers mtDNA synthesis, which activates STING-mediated inflammation. Consistently, atherosclerosis and inflammation are less severe in Apoe-/- mice lacking Vcam1 in macrophages. Downregulation of macrophage-specific VCAM-1 in vivo leads to decreased expression of LYZ1 and FCOR, involved in STING signalling. Finally, VCAM-1 expression in human carotid plaque macrophages correlates with necrotic core area, mitochondrial volume, and oxidative damage to DNA. Collectively, our study highlights the importance of macrophage VCAM-1 in inflammation and atherogenesis pathology and proposes a self-acerbating pathway involving increased mtDNA synthesis.
    DOI:  https://doi.org/10.1038/s41467-024-51780-1
  13. Cell Metab. 2024 Aug 21. pii: S1550-4131(24)00325-5. [Epub ahead of print]
    Glucagon promotes increased hepatic mitochondrial oxidation and pyruvate carboxylase flux in humans with fatty liver disease.
    Kitt Falk Petersen, Sylvie Dufour, Wajahat Z Mehal, Gerald I Shulman.
      We assessed in vivo rates of hepatic mitochondrial oxidation, gluconeogenesis, and β-hydroxybutyrate (β-OHB) turnover by positional isotopomer NMR tracer analysis (PINTA) in individuals with metabolic-dysfunction-associated steatotic liver (MASL) (fatty liver) and MASL disease (MASLD) (steatohepatitis) compared with BMI-matched control participants with no hepatic steatosis. Hepatic fat content was quantified by localized 1H magnetic resonance spectroscopy (MRS). We found that in vivo rates of hepatic mitochondrial oxidation were unaltered in the MASL and MASLD groups compared with the control group. A physiological increase in plasma glucagon concentrations increased in vivo rates of hepatic mitochondrial oxidation by 50%-75% in individuals with and without MASL and increased rates of glucose production by ∼50% in the MASL group, which could be attributed in part to an ∼30% increase in rates of mitochondrial pyruvate carboxylase flux. These results demonstrate that (1) rates of hepatic mitochondrial oxidation are not substantially altered in individuals with MASL and MASLD and (2) glucagon increases rates of hepatic mitochondrial oxidation.
    Keywords:  MASL; MASLD; NAFLD; NASH; citrate synthase flux; gluconeogenesis; hepatic mitochondrial oxidation; magnetic resonance spectroscopy; pyruvate carboxylase flux; β-hydroxybutyrate
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.023
  14. Sci Rep. 2024 08 27. 14(1): 19899
    Prenatal vitamin D deficiency exposure leads to long-term changes in immune cell proportions.
    Koki Ueda, Shu Shien Chin, Noriko Sato, Miyu Nishikawa, Kaori Yasuda, Naoyuki Miyasaka, Betelehem Solomon Bera, Laurent Chorro, Reanna Doña-Termine, Wade R Koba, David Reynolds, Ulrich G Steidl, Gregoire Lauvau, John M Greally, Masako Suzuki.
      Vitamin D deficiency is a common deficiency worldwide, particularly among women of reproductive age. During pregnancy, it increases the risk of immune-related diseases in offspring later in life. However, how the body remembers exposure to an adverse environment during development is poorly understood. Herein, we explore the effects of prenatal vitamin D deficiency on immune cell proportions in offspring using vitamin D deficient mice established by dietary manipulation. We found that prenatal vitamin D deficiency alters immune cell proportions in offspring by changing the transcriptional properties of genes downstream of vitamin D receptor signaling in hematopoietic stem and progenitor cells of both the fetus and adults. Moreover, further investigations of the associations between maternal vitamin D levels and cord blood immune cell profiles from 75 healthy pregnant women and their term offspring also confirm that maternal vitamin D levels in the second trimester significantly affect immune cell proportions in the offspring. These findings imply that the differentiation properties of hematopoiesis act as long-term memories of prenatal vitamin D deficiency exposure in later life.
    DOI:  https://doi.org/10.1038/s41598-024-70911-8
  15. Neurobiol Dis. 2024 Aug 22. pii: S0969-9961(24)00245-6. [Epub ahead of print]200 106645
    Nicotinamide riboside modulates the reactive species interactome, bioenergetic status and proteomic landscape in a brain-region-specific manner.
    Alejandro Marmolejo-Garza, Laurent Chatre, Deborah L Croteau, Alejandro Herron-Bedoya, Minh Danh Anh Luu, Benoit Bernay, Julien Pontin, Vilhelm A Bohr, Erik Boddeke, Amalia M Dolga.
      Nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD+), has robust cognitive benefits and alleviates neuroinflammation in Alzheimer's Disease (AD) mouse models without decreasing beta-amyloid plaque pathology. Such effects may be mediated by the reactive species interactome (RSI), at the metabolome level. In this study, we employed in vitro and in vivo models of oxidative stress, aging and AD to profile the effects of NR on neuronal survival, RSI, and the whole proteome characterization of cortex and hippocampus. RSI analysis yielded a complex modulation upon NR treatment. We constructed protein co-expression networks and correlated them to NR treatment and all measured reactive species. We observed brain-area specific effects of NR on co-expressed protein modules of oxidative phosphorylation, fatty acid oxidation, and neurotransmitter regulation pathways, which correlated with RSI components. The current study contributes to the understanding of modulation of the metabolome, specifically after NR treatment in AD and how it may play disease-modifying roles.
    Keywords:  Aging; Alzheimer's disease; Bioenergetics; Metabolism; Mitochondria; Neurodegeneration; Nicotinamide riboside; Reactive species Interactome
    DOI:  https://doi.org/10.1016/j.nbd.2024.106645
  16. Stem Cell Reports. 2024 Aug 06. pii: S2213-6711(24)00218-2. [Epub ahead of print]
    Dissecting the impact of differentiation stage, replicative history, and cell type composition on epigenetic clocks.
    Rebecca Gorelov, Aaron Weiner, Aaron Huebner, Masaki Yagi, Amin Haghani, Robert Brooke, Steve Horvath, Konrad Hochedlinger.
      Epigenetic clocks, built on DNA methylation patterns of bulk tissues, are powerful age predictors, but their biological basis remains incompletely understood. Here, we conducted a comparative analysis of epigenetic age in murine muscle, epithelial, and blood cell types across lifespan. Strikingly, our results show that cellular subpopulations within these tissues, including adult stem and progenitor cells as well as their differentiated progeny, exhibit different epigenetic ages. Accordingly, we experimentally demonstrate that clocks can be skewed by age-associated changes in tissue composition. Mechanistically, we provide evidence that the observed variation in epigenetic age among adult stem cells correlates with their proliferative state, and, fittingly, forced proliferation of stem cells leads to increases in epigenetic age. Collectively, our analyses elucidate the impact of cell type composition, differentiation state, and replicative potential on epigenetic age, which has implications for the interpretation of existing clocks and should inform the development of more sensitive clocks.
    Keywords:  DNA methylation; adult Stem; aging; cell Proliferation; differentiation; epigenetic clocks
    DOI:  https://doi.org/10.1016/j.stemcr.2024.07.009
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