bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2022‒08‒14
seventeen papers selected by
Rich Giadone
Harvard University
  1. Proteolysis dysfunction in the process of aging and age-related diseases.
  2. Crosstalk between Biomolecular Condensates and Proteostasis.
  3. Evolutionary Aspects of the Unfolded Protein Response.
  4. Newly synthesized mRNA escapes translational repression during the acute phase of the mammalian unfolded protein response.
  5. A Pipeline for Natural Small Molecule Inhibitors of Endoplasmic Reticulum Stress.
  6. TRIM family proteins: roles in proteostasis and neurodegenerative diseases.
  7. Endoplasmic reticulum stress induces Alzheimer's disease-like phenotypes in the neuron derived from the induced pluripotent stem cell with D678H mutation on amyloid precursor protein.
  8. A CRISPRi/a platform in human iPSC-derived microglia uncovers regulators of disease states.
  9. Activating translation with phase separation.
  10. Molecular mechanism for the synchronized electrostatic coacervation and co-aggregation of alpha-synuclein and tau.
  11. Endoplasmic Reticulum-Associated Protein Degradation.
  12. Protein aggregation rate depends on mechanical stability of fibrillar structure.
  13. A genetic model for in vivo proximity labelling of the mammalian secretome.
  14. Longevity lessonsMethuselah's Zoo: What Nature Can Teach Us About Living Longer, Healthier Lives Steven N. Austad MIT Press, 2022. 320 pp.
  15. Mechanisms involved in hematopoietic stem cell aging.
  16. Artemisia argyi exhibits anti-aging effects through decreasing the senescence in aging stem cells.
  17. Exogenous Klotho ameliorates extracellular matrix degradation and angiogenesis in intervertebral disc degeneration via inhibition of the Rac1/PAK1/MMP-2 signaling axis.
  1. Front Aging. 2022 ;3 927630
    Proteolysis dysfunction in the process of aging and age-related diseases.
    Natalia Frankowska, Katarzyna Lisowska, Jacek M Witkowski.
      In this review, we discuss in detail the most relevant proteolytic systems that together with chaperones contribute to creating the proteostasis network that is kept in dynamic balance to maintain overall functionality of cellular proteomes. Data accumulated over decades demonstrate that the effectiveness of elements of the proteostasis network declines with age. In this scenario, failure to degrade misfolded or faulty proteins increases the risk of protein aggregation, chronic inflammation, and the development of age-related diseases. This is especially important in the context of aging-related modification of functions of the immune system.
    Keywords:  aging; autophagy; chaperones; lysosome; proteases; proteostasis; ubiquitin-proteasome system
    DOI:  https://doi.org/10.3389/fragi.2022.927630
  2. Cells. 2022 Aug 04. pii: 2415. [Epub ahead of print]11(15):
    Crosstalk between Biomolecular Condensates and Proteostasis.
    Emmanuel Amzallag, Eran Hornstein.
      Proper homeostasis of the proteome, referred to as proteostasis, is maintained by chaperone-dependent refolding of misfolded proteins and by protein degradation via the ubiquitin-proteasome system and the autophagic machinery. This review will discuss a crosstalk between biomolecular condensates and proteostasis, whereby the crowding of proteostasis factors into macromolecular assemblies is often established by phase separation of membraneless biomolecular condensates. Specifically, ubiquitin and other posttranslational modifications come into play as agents of phase separation, essential for the formation of condensates and for ubiquitin-proteasome system activity. Furthermore, an intriguing connection associates malfunction of the same pathways to the accumulation of misfolded and ubiquitinated proteins in aberrant condensates, the formation of protein aggregates, and finally, to the pathogenesis of neurodegenerative diseases. The crosstalk between biomolecular condensates and proteostasis is an emerging theme in cellular and disease biology and further studies will focus on delineating specific molecular pathways involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases.
    Keywords:  ALS; amyotrophic lateral sclerosis; biomolecular condensation; membraneless organelles; neurodegeneration; proteostasis; ubiquitin proteasome system
    DOI:  https://doi.org/10.3390/cells11152415
  3. Cold Spring Harb Perspect Biol. 2022 Aug 08. pii: a041262. [Epub ahead of print]
    Evolutionary Aspects of the Unfolded Protein Response.
    Kazutoshi Mori.
      The unfolded protein response (UPR) is activated when unfolded proteins accumulate in the endoplasmic reticulum (ER). The basic mechanism of the UPR in maintaining ER homeostasis has been clarified from yeast to humans. The UPR is triggered by one or more transmembrane proteins in the ER. The number of canonical UPR sensors/transducers has increased during evolution, from one (IRE1) in yeast to three (IRE1, PERK, and ATF6) in invertebrates and five (IRE1α, IRE1β, PERK, ATF6α, and ATF6β) in vertebrates. Here, I initially describe the four major changes that have occurred during evolution: (1) advent of PERK in metazoans; (2) switch in transcription factor downstream of IRE1 in metazoans; (3) switch in regulator of ER chaperone induction in vertebrates; and (4) increase in the number of ATF6-like local factors in vertebrates. I then discuss the causes of the phenotypes of vertebrate knockout animals and refer to regulated IRE1-dependent decay of mRNAs.
    DOI:  https://doi.org/10.1101/cshperspect.a041262
  4. PLoS One. 2022 ;17(8): e0271695
    Newly synthesized mRNA escapes translational repression during the acute phase of the mammalian unfolded protein response.
    Mohammed R Alzahrani, Bo-Jhih Guan, Leah L Zagore, Jing Wu, Chien-Wen Chen, Donny D Licatalosi, Kristian E Baker, Maria Hatzoglou.
      Endoplasmic Reticulum (ER) stress, caused by the accumulation of misfolded proteins in the ER, elicits a homeostatic mechanism known as the Unfolded Protein Response (UPR). The UPR reprograms gene expression to promote adaptation to chronic ER stress. The UPR comprises an acute phase involving inhibition of bulk protein synthesis and a chronic phase of transcriptional induction coupled with the partial recovery of protein synthesis. However, the role of transcriptional regulation in the acute phase of the UPR is not well understood. Here we analyzed the fate of newly synthesized mRNA encoding the protective and homeostatic transcription factor X-box binding protein 1 (XBP1) during this acute phase. We have previously shown that global translational repression induced by the acute UPR was characterized by decreased translation and increased stability of XBP1 mRNA. We demonstrate here that this stabilization is independent of new transcription. In contrast, we show XBP1 mRNA newly synthesized during the acute phase accumulates with long poly(A) tails and escapes translational repression. Inhibition of newly synthesized RNA polyadenylation during the acute phase decreased cell survival with no effect in unstressed cells. Furthermore, during the chronic phase of the UPR, levels of XBP1 mRNA with long poly(A) tails decreased in a manner consistent with co-translational deadenylation. Finally, additional pro-survival, transcriptionally-induced mRNAs show similar regulation, supporting the broad significance of the pre-steady state UPR in translational control during ER stress. We conclude that the biphasic regulation of poly(A) tail length during the UPR represents a previously unrecognized pro-survival mechanism of mammalian gene regulation.
    DOI:  https://doi.org/10.1371/journal.pone.0271695
  5. Front Pharmacol. 2022 ;13 956154
    A Pipeline for Natural Small Molecule Inhibitors of Endoplasmic Reticulum Stress.
    Daniela Correia da Silva, Patrícia Valentão, Paula B Andrade, David M Pereira.
      The homeostasis of eukaryotic cells is inseverable of that of the endoplasmic reticulum (ER). The main function of this organelle is the synthesis and folding of a significant portion of cellular proteins, while it is also the major calcium reservoir of the cell. Upon unresolved ER stress, a set of stress response signaling pathways that are collectively labeled as the unfolded protein response (UPR) is activated. Prolonged or intense activation of this molecular machinery may be deleterious. It is known that compromised ER homeostasis, and consequent UPR activation, characterizes the pathogenesis of neurodegenerative diseases. In an effort to discover new small molecules capable of countering ER stress, we subjected a panel of over 100 natural molecules to a battery of assays designed to evaluate several hallmarks of ER stress. The protective potential of these compounds against ER stress was evaluated at the levels of calcium homeostasis, key gene and protein expression, and levels of protein aggregation in fibroblasts. The most promising compounds were subsequently tested in neuronal cells. This framework resulted in the identification of several bioactive molecules capable of countering ER stress and deleterious events associated to it. Delphinidin stands out as the most promising candidate against neurodegeneration. This compound significantly inhibited the expression of UPR biomarkers, and displayed a strong potential to inhibit protein aggregation in the two aforementioned cell models. Our results indicate that natural products may be a valuable resource in the development of an effective therapeutic strategy against ER stress-related diseases.
    Keywords:  drug discovery; endoplasmic reticulum stress; natural products; neurodegeneration; unfolded protein response
    DOI:  https://doi.org/10.3389/fphar.2022.956154
  6. Open Biol. 2022 Aug;12(8): 220098
    TRIM family proteins: roles in proteostasis and neurodegenerative diseases.
    Yan Zhu, Lukman O Afolabi, Xiaochun Wan, Joong Sup Shim, Liang Chen.
      Neurodegenerative diseases (NDs) are a diverse group of disorders characterized by the progressive degeneration of the structure and function of the central or peripheral nervous systems. One of the major features of NDs, such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), is the aggregation of specific misfolded proteins, which induces cellular dysfunction, neuronal death, loss of synaptic connections and eventually brain damage. By far, a great amount of evidence has suggested that TRIM family proteins play crucial roles in the turnover of normal regulatory and misfolded proteins. To maintain cellular protein quality control, cells rely on two major classes of proteostasis: molecular chaperones and the degradative systems, the latter includes the ubiquitin-proteasome system (UPS) and autophagy; and their dysfunction has been established to result in various physiological disorders including NDs. Emerging evidence has shown that TRIM proteins are key players in facilitating the clearance of misfolded protein aggregates associated with neurodegenerative disorders. Understanding the different pathways these TRIM proteins employ during episodes of neurodegenerative disorder represents a promising therapeutic target. In this review, we elucidated and summarized the diverse roles with underlying mechanisms of members of the TRIM family proteins in NDs.
    Keywords:  chaperone; neurodegenerative diseases; protein aggregation; proteostasis; trim proteins; ubiquitin–proteasome system
    DOI:  https://doi.org/10.1098/rsob.220098
  7. J Neurochem. 2022 Aug 09.
    Endoplasmic reticulum stress induces Alzheimer's disease-like phenotypes in the neuron derived from the induced pluripotent stem cell with D678H mutation on amyloid precursor protein.
    Tania Devina, Yu-Hui Wong, Chiao-Wan Hsiao, Yu-Jui Li, Cheng-Chang Lien, Irene Han-Juo Cheng.
      Alzheimer's disease (AD), a progressive neurodegenerative disorder, is mainly caused by the interaction of genetic and environmental factors. The impact of environmental factors on the genetic mutation in the amyloid precursor protein (APP) is not well characterized. We hypothesized that Endoplasmic Reticulum (ER) stress would promote disease for the patient carrying the APP D678H mutation. Therefore, we analyzed the impact of a familial AD mutation on amyloid precursor protein (APP D678H) under ER stress. Induced pluripotent stem cell (iPSC) from APP D678H mutant carrier was differentiated into neurons, which were then analyzed for AD-like changes. Immunocytochemistry and whole-cell patch-clamp recording revealed that the derived neurons on day 28 after differentiation showed neuronal markers and electrophysiological properties similar to those of mature neurons. However, the APP D678H mutant neurons did not have significant alterations in the levels of amyloid-β (Aβ) and phosphorylated tau (pTau) compared to its isogenic wild-type neuron. Only under ER stress, the neurons with the APP D678H mutation had more Aβ and pTau via immune detection assays. The higher level of Aβ in the APP D678H mutant neurons was probably due to the increased level of β-site APP cleaving enzyme (BACE1) and decreased level of Aβ degrading enzymes under ER stress. Increased Aβ and pTau under ER stress reduced the N-methyl-D-aspartate receptor (NMDAR) in Western blot analysis and altered electrophysiological properties in the mutant neurons. Our study provides evidence that the interaction between genetic mutation and ER stress would induce AD-like changes.
    Keywords:  APP D678H mutation; Endoplasmic reticulum stress; Familial Alzheimer’s disease (FAD); Induced pluripotent stem cell (iPSC)
    DOI:  https://doi.org/10.1111/jnc.15687
  8. Nat Neurosci. 2022 Aug 11.
    A CRISPRi/a platform in human iPSC-derived microglia uncovers regulators of disease states.
    Nina M Dräger, Sydney M Sattler, Cindy Tzu-Ling Huang, Olivia M Teter, Kun Leng, Sayed Hadi Hashemi, Jason Hong, Giovanni Aviles, Claire D Clelland, Lihong Zhan, Joe C Udeochu, Lay Kodama, Andrew B Singleton, Mike A Nalls, Justin Ichida, Michael E Ward, Faraz Faghri, Li Gan, Martin Kampmann.
      Microglia are emerging as key drivers of neurological diseases. However, we lack a systematic understanding of the underlying mechanisms. Here, we present a screening platform to systematically elucidate functional consequences of genetic perturbations in human induced pluripotent stem cell-derived microglia. We developed an efficient 8-day protocol for the generation of microglia-like cells based on the inducible expression of six transcription factors. We established inducible CRISPR interference and activation in this system and conducted three screens targeting the 'druggable genome'. These screens uncovered genes controlling microglia survival, activation and phagocytosis, including neurodegeneration-associated genes. A screen with single-cell RNA sequencing as the readout revealed that these microglia adopt a spectrum of states mirroring those observed in human brains and identified regulators of these states. A disease-associated state characterized by osteopontin (SPP1) expression was selectively depleted by colony-stimulating factor-1 (CSF1R) inhibition. Thus, our platform can systematically uncover regulators of microglial states, enabling their functional characterization and therapeutic targeting.
    DOI:  https://doi.org/10.1038/s41593-022-01131-4
  9. Science. 2022 Aug 12. 377(6607): 712-713
    Activating translation with phase separation.
    Anne Ramat, Martine Simonelig.
      Ribonucleoprotein granules allow activation of translation to complete mouse spermatogenesis.
    DOI:  https://doi.org/10.1126/science.add6323
  10. Nat Commun. 2022 Aug 06. 13(1): 4586
    Molecular mechanism for the synchronized electrostatic coacervation and co-aggregation of alpha-synuclein and tau.
    Pablo Gracia, David Polanco, Jorge Tarancón-Díez, Ilenia Serra, Maruan Bracci, Javier Oroz, Douglas V Laurents, Inés García, Nunilo Cremades.
      Amyloid aggregation of α-synuclein (αS) is the hallmark of Parkinson's disease and other synucleinopathies. Recently, Tau protein, generally associated with Alzheimer's disease, has been linked to αS pathology and observed to co-localize in αS-rich disease inclusions, although the molecular mechanisms for the co-aggregation of both proteins remain elusive. We report here that αS phase-separates into liquid condensates by electrostatic complex coacervation with positively charged polypeptides such as Tau. Condensates undergo either fast gelation or coalescence followed by slow amyloid aggregation depending on the affinity of αS for the poly-cation and the rate of valence exhaustion of the condensate network. By combining a set of advanced biophysical techniques, we have been able to characterize αS/Tau liquid-liquid phase separation and identified key factors that lead to the formation of hetero-aggregates containing both proteins in the interior of the liquid protein condensates.
    DOI:  https://doi.org/10.1038/s41467-022-32350-9
  11. Cold Spring Harb Perspect Biol. 2022 Aug 08. pii: a041247. [Epub ahead of print]
    Endoplasmic Reticulum-Associated Protein Degradation.
    Logesvaran Krshnan, Michael L van de Weijer, Pedro Carvalho.
      Misfolded, potentially toxic proteins in the lumen and membrane of the endoplasmic reticulum (ER) are eliminated by proteasomes in the cytosol through ER-associated degradation (ERAD). The ERAD process involves the recognition of substrates in the lumen and membrane of the ER, their translocation into the cytosol, ubiquitination, and delivery to the proteasome for degradation. These ERAD steps are performed by membrane-embedded ubiquitin-ligase complexes of different specificity that together cover a wide range of substrates. Besides misfolded proteins, ERAD further contributes to quality control by targeting unassembled and mislocalized proteins. ERAD also targets a restricted set of folded proteins to influence critical ER functions such as sterol biosynthesis, calcium homeostasis, or ER contacts with other organelles. This review describes the ubiquitin-ligase complexes and the principles guiding protein degradation by ERAD.
    DOI:  https://doi.org/10.1101/cshperspect.a041247
  12. J Chem Phys. 2022 Aug 07. 157(5): 055101
    Protein aggregation rate depends on mechanical stability of fibrillar structure.
    Tran Thi Minh Thu, Mai Suan Li.
      The formation of the fibrillar structure of amyloid proteins/peptides is believed to be associated with neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Since the rate of aggregation can influence neurotoxicity, finding the key factors that control this rate is of paramount importance. It was recently found that the rate of protein aggregation is related to the mechanical stability of the fibrillar structure such that the higher the mechanical stability, the faster the fibril is formed. However, this conclusion was supported by a limited dataset. In this work, we expand the previous study to a larger dataset, including the wild type of Aβ42 peptide and its 20 mutants, the aggregation rate of which was measured experimentally. By using all-atom steered molecular dynamics (SMD) simulations, we can assess the mechanical stability of the fibril structure, which is characterized by the rupture force, pulling work, and unbinding free energy barrier. Our result confirms that mechanical stability is indeed related to the aggregation rate. Since the estimation of the aggregation rate using all-atom simulations is almost forbidden by the current computational capabilities, our result is useful for predicting it based on information obtained from fast SMD simulations for fibrils.
    DOI:  https://doi.org/10.1063/5.0088689
  13. Open Biol. 2022 Aug;12(8): 220149
    A genetic model for in vivo proximity labelling of the mammalian secretome.
    Rui Yang, Amanda S Meyer, Ilia A Droujinine, Namrata D Udeshi, Yanhui Hu, Jinjin Guo, Jill A McMahon, Dominique K Carey, Charles Xu, Qiao Fang, Jihui Sha, Shishang Qin, David Rocco, James Wohlschlegel, Alice Y Ting, Steven A Carr, Norbert Perrimon, Andrew P McMahon.
      Organ functions are highly specialized and interdependent. Secreted factors regulate organ development and mediate homeostasis through serum trafficking and inter-organ communication. Enzyme-catalysed proximity labelling enables the identification of proteins within a specific cellular compartment. Here, we report a BirA*G3 mouse strain that enables CRE-dependent promiscuous biotinylation of proteins trafficking through the endoplasmic reticulum. When broadly activated throughout the mouse, widespread labelling of proteins was observed within the secretory pathway. Streptavidin affinity purification and peptide mapping by quantitative mass spectrometry (MS) proteomics revealed organ-specific secretory profiles and serum trafficking. As expected, secretory proteomes were highly enriched for signal peptide-containing proteins, highlighting both conventional and non-conventional secretory processes, and ectodomain shedding. Lower-abundance proteins with hormone-like properties were recovered and validated using orthogonal approaches. Hepatocyte-specific activation of BirA*G3 highlighted liver-specific biotinylated secretome profiles. The BirA*G3 mouse model demonstrates enhanced labelling efficiency and tissue specificity over viral transduction approaches and will facilitate a deeper understanding of secretory protein interplay in development, and in healthy and diseased adult states.
    Keywords:  BirA; TurboID; inter-organ communication; proximity-labelling; secretome; serum proteins
    DOI:  https://doi.org/10.1098/rsob.220149
  14. Science. 2022 Aug 12. 377(6607): 718
    Longevity lessonsMethuselah's Zoo: What Nature Can Teach Us About Living Longer, Healthier Lives Steven N. Austad MIT Press, 2022. 320 pp.
    Charles Brenner.
      Animal aging could hold clues to healthier human life spans.
    DOI:  https://doi.org/10.1126/science.add9130
  15. Cell Mol Life Sci. 2022 Aug 08. 79(9): 473
    Mechanisms involved in hematopoietic stem cell aging.
    Takeshi Fujino, Shuhei Asada, Susumu Goyama, Toshio Kitamura.
      Hematopoietic stem cells (HSCs) undergo progressive functional decline over time due to both internal and external stressors, leading to aging of the hematopoietic system. A comprehensive understanding of the molecular mechanisms underlying HSC aging will be valuable in developing novel therapies for HSC rejuvenation and to prevent the onset of several age-associated diseases and hematological malignancies. This review considers the general causes of HSC aging that range from cell-intrinsic factors to cell-extrinsic factors. In particular, epigenetics and inflammation have been implicated in the linkage of HSC aging, clonality, and oncogenesis. The challenges in clarifying mechanisms of HSC aging have accelerated the development of therapeutic interventions to rejuvenate HSCs, the major goal of aging research; these details are also discussed in this review.
    Keywords:  Aging; Clonal hematopoiesis; Hematological malignancy; Hematopoietic stem cell; Rejuvenation
    DOI:  https://doi.org/10.1007/s00018-022-04356-5
  16. Aging (Albany NY). 2022 Aug 09. 14(undefined):
    Artemisia argyi exhibits anti-aging effects through decreasing the senescence in aging stem cells.
    Tsung-Jung Ho, Debakshee Goswami, Wei-Wen Kuo, Chia-Hua Kuo, Shih Cheng Yen, Pi-Yu Lin, Shinn-Zong Lin, Dennis Jine-Yuan Hsieh, Marthandam Asokan Shibu, Chih-Yang Huang.
      Aging is accompanied by functional loss of many cellular pathways, creating an increased risk of many age-related complications (ARC). Aging causes stem cell exhaustion with a concomitant increase in cellular dysfunction. Recently, interest in senotherapeutics has been growing rapidly to promote healthy aging and as an intervention for ARCs. This research focused on screening the senomorphic properties of Artemisia argyi, as an emerging strategy for longevity, and prevention or treatment of ARCs. In this study, we aimed to find the clinical efficacy of daily consumption of Artemisia argyi water extract (AAW) on aging. In vitro 0.1μM Doxorubicin induced senescent human adipose derived mesenchymal stem cells was treated with different concentrations of AAW to show its anti-aging effect. 15 months old SHR rats (n=6) were treated with 7.9 mg/ml AAW for 4 weeks and anti-aging effect was evaluated. In vitro study showed the protective effect of AAW in telomere shortening and helps in maintaining a balance in the expression of anti-aging protein Klotho and TERT. AAW effectively reduced mitochondrial superoxide and also provided a protective shield against senescence markers like over-expression of p21 and formation of double strand breaks, which is known to cause premature aging. Moreover, animal studies indicated that AAW promoted the expression of Klotho in naturally aging rats. In addition, AAW successfully restored the decline cardiac function and improved the grip strength and memory of aging rat. These findings showed that therapeutic targeting of senescent stem cells by AAW restored stem cell homeostasis and improves overall health.
    Keywords:  Artemisia argyi; anti-aging; antioxidant; klotho; stem cell
    DOI:  https://doi.org/10.18632/aging.204210
  17. Mech Ageing Dev. 2022 Aug 08. pii: S0047-6374(22)00097-5. [Epub ahead of print]207 111715
    Exogenous Klotho ameliorates extracellular matrix degradation and angiogenesis in intervertebral disc degeneration via inhibition of the Rac1/PAK1/MMP-2 signaling axis.
    Yu-Yang Yi, Hao Chen, Shu-Bao Zhang, Hao-Wei Xu, Xin-Yue Fang, Shan-Jin Wang.
      Intervertebral disc degeneration (IDD) is highly ubiquitous in the aged population and is an essential factor for low back pain and spinal disability. Because of the association between IDD and senescence, we investigated the ability of the anti-aging drug Klotho to inhibit age-dependent advancement of nucleus pulposus cell (NPC) degeneration. The results indicated that 400 pM exogenous Klotho significantly ameliorated extracellular matrix degradation and angiogenesis. Moreover, we demonstrated that the suppression of angiogenesis and extracellular matrix catabolism was related to inhibition of the Ras-related C3 botulinum toxin substrate 1 (Rac1)/PAK1 axis and matrix metalloproteinase 2 protein expression by exogenous Klotho cotreatment with a Rac1 inhibitor, gene overexpression in NPCs, and stimulation of human umbilical vein endothelial cells with conditioned medium from NPCs. The treatment also preserved the NPC phenotype, viability, and matrix content. In conclusion, these results suggest that the new anti-aging drug Klotho is a potential treatment strategy to mitigate IDD, and thus, provides an innovative understanding of the molecular mechanism of IDD. DATA AVAILABILITY: All data supporting the findings of this study are available from the corresponding authors upon reasonable request.
    Keywords:  Angiogenesis; Extracellular matrix; Intervertebral disc degeneration; Klotho; Senescence
    DOI:  https://doi.org/10.1016/j.mad.2022.111715
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