The Double-Edged Role of Extracellular Vesicles in the Hallmarks of Aging
Abstract
:1. Extracellular Vesicles in Aging
1.1. What Are Extracellular Vesicles?
1.2. Where Do EVs Come from in Aging Studies?
2. EVs and the Hallmarks of Aging
2.1. What Are the Hallmarks of Aging?
2.2. Primary Hallmarks
2.2.1. EVs and Genomic Instability
2.2.2. EVs and Telomere Attrition
2.2.3. EVs and Epigenetic Alterations
2.2.4. EVs and Loss of Proteostasis
2.3. Antagonistic Hallmarks
2.3.1. EVs and Deregulated Nutrient Sensing
2.3.2. EVs and Mitochondrial Dysfunction
2.3.3. EVs and Cellular Senescence
2.4. Integrative Hallmarks
2.4.1. EVs and Stem Cell Exhaustion
2.4.2. EVs and Altered Intercellular Communication
3. Conclusions and Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Hallmark | Pro-/Anti- | IVV/IVT | EVs’ Receptor | EVs’ Donor | EV Cargo | Cell-Level and Organismal-Level Effects | Ref. | |
---|---|---|---|---|---|---|---|---|
P R I M A R Y | Genomic instability | Pro- | IVT | Human mononuclear cells from healthy donors | K-562 cell line (lymphoblasts) | NA | Inhibited tumor suppressor genes P53 and RIZ1. Activated cytidine deaminase and ROS, leading to DNA breakage and recombination Treated cells exhibit a leukemia-like malignant phenotype | [55] |
IVT | HUVECs | RAS-3 cell line (intestinal epithelial cell line containing c-HRAS oncogene) | BCR-ABL1 mRNA | Increased the level of DNA damage response markers, such as the phosphorylation of histone γH2AX Increased oncogenic transformation potential | [54] | |||
Anti- | IVV | Intestinal epithelial cells | BM-MSCs | NA | Limited intestinal epithelial cells’ ROS accumulation and DNA damage Alleviated ulcerative colitis injury | [56] | ||
IVT | FDC-P1 cell line (bone marrow hematopoietic cells) | BM-MSCs | miR106b-3, miR155-5p, and miR210-5p | Rescued radiation-associated DNA damage | [57] | |||
IVT | Renal epithelial cells | h-UCMSCs (human umbilical cord MSCs) | NA | Decreased DNA damage foci and senescence | [52] | |||
IVT | Microglia from adult rats (primary culture) | ADSCs | NA | Activation of SIRT1 Reduced levels of caspase-3, MDA, 8-OHdG, and TNF-α Promoted the recovery of SOD, catalase, and IL-10 Ameliorated radiation-induced brain injury | [58] | |||
IVT | Nucleus pulposus cells | iMSCs | miR-105-5p | SIRT6 activation Rejuvenated senescent nucleus pulposus cells and attenuated intervertebral disc degeneration | [59] | |||
Telomere attrition | Pro- | IVT | Peripheral blood mononuclear cells | TRF2-induced BJ-5ta fibroblasts | cfTERRA | Stimulated the transcription of inflammatory cytokine genes (TNFα, IL6, and C-X-C chemokine 10) | [71] | |
IVT | Breast cancer cells | Irradiated breast cancer cells | Proteins and RNAs | Reduced telomere length Reduced telomerase activity | [73] | |||
Anti- | IVT IVV | BM-MSCs Ovariectomized mice MRL/lpr mice (systemic lupus-erythrematosus-like) | Stem cells from human exfoliated deciduous teeth (SHED) | miR-346 | Increased Tert mRNA expression and telomerase activity Increased hematopoietic niche formation and osteoblast differentiation Recovered bone volume and alleviate osteoporosis | [74,75] | ||
IVT IVV | T cells and T cells deficient in telomerase (TERT KO cells) | Autologous-antigen-presenting cells (polymorphonuclear cells) | Telomeric DNA | Increased telomere length by Rad51 recombination factor Increased T cell proliferation rates and delayed senescence, increase in central memory T cells Increased mice survival after viral infection | [78] | |||
IVV | Old mice | Serum of young mice | Several miRNAs (miR-126b-5p) | Upregulated telomerase-complex-related genes (Men1 and Mre11a) in the liver and lungs | [76] | |||
Epigenetic alterations | Pro- | IVT | Human mononuclear cells from healthy donors | K-562 cell line (lymphoblasts) | NA | Global DNA hypermethylation, including promoters of the tumor suppressor genes P53 and RIZ1, and the upregulation of methyltransferases | [55] | |
IVT | HUVECs | Senescent HUVECs | miR-21-5p and miR-217 | Downregulation of DNA methyltransferase 1 and SIRT1 Expression of SASP molecules and cell cycle inhibitors | [82] | |||
Anti- | IVV | Old mice | Young ADSCs | miRNAs | Reduced epigenetic clocks of the liver and kidney Improved renal function and increase healthspan | [77] | ||
Loss of proteostasis | Pro- | IVT | N2a cells (neural-crest-derived cell line) | Amyloid beta peptide (Aβ) | Responsible for the release of Aβ into the extracellular milieu Involved in the pathogenesis of AD | [88] | ||
Anti- | IVT IVV | Podocytes | ADSCs | miR-486 | Promoted autophagy Attenuated diabetic nephropathy | [89] | ||
IVV | Renal tissue | BM-MSCs | NA | Autophagy induction through the mTOR signaling pathway Attenuated diabetic nephropathy | [90] | |||
IVT IVV | Hepatic tissue and HSC-T6 cells | ADSCs | miRNA-181-5p | Autophagy activation Prevented liver fibrosis | [91] | |||
IVT IVV | Cardiomyocytes | BM-MSCs | NA | Autophagy activation via AMPK/mTOR or Akt/mTOR Rescued myocardial ischemia/reperfusion injury | [92] | |||
IVT | SH-SY5Y cell line (from neuroblastoma cell line) | h-UCMSCs | NA | Induced autophagy in neural tissue Improved Parkinson’s disease features | [93] | |||
IVT IVV | Neurons under glucose–oxygen deprivation Mice exposed to cerebral ischemia | ADSCs | miR-25-3p | Reduced autophagy and cell death by modulating p53-BNIP3 signaling Reduced infarct size and improve neurological recovery | [94] | |||
A N T A G O N I S T I C | Deregulated nutrient sensing | Pro- | IVT | Young MSCs | Old MSC-EVs | NA | Increased mTOR pathways | |
Anti- | IVV | Old mice | Plasma from young mice | miR-126b-5p and miR-466c-5p | Reduced mTOR and IGF1R levels in the lungs and liver | [76] | ||
IVV | Old mice | BM-MSCs | NA | Reduced mTOR and IGF1R levels in the parietal cortex Promoted microglial M2 polarization | [101] | |||
IVT | Cardiomyocytes | BM-MSCs | NA | AMPK activation results in increased autophagy Rescued myocardial ischemia/reperfusion injury | [92] | |||
IVT | Old MSCs | Young MSCs | miR-188-3p | Rictor targeting downregulates mTOR pathways and increases AMPK pathways. Improved pluripotency of MSCs | [27] | |||
IVV | Old mice | Plasma from young mice | eNAMPT | Increased NAD+ bioavailability in tissues Increased lifespan and healthspan | [22] | |||
Mitochondrial dysfunction | Pro- | IVT | Old mice | mtDNA | mtDNA in mitovesicles declines with age Cell-free mtDNA causes chronic inflammation | [113] | ||
IVT | Lung epithelial cells | Idiopathic pulmonary fibrosis—lung fibroblasts | miR-23b-3p, miR-494-3p | Suppressed SIRT3 expression Increased mitochondrial ROS and mitochondrial damage | [114] | |||
Pro- Anti- | IVT | HeLA cells | Plasma from young and old mice | NA | Improved (young EVs’) or worsened (old EVs’) oxygen consumption rates | [113] | ||
Anti- | IVT | MDPSCs from old mice | Serum from young and old mice | α-Klotho transcripts | Increased basal oxygen consumption rates Improved mitochondrial ultrastructure | [115] | ||
IVT | MDPSCs | Oxidatively injured myotubes | NA | Increased basal oxygen consumption rates and spare respiratory capacity | [116] | |||
IVV IVT | mtDNA-deficient L929 Rho0 cells Mice with multiple sclerosis | NSCs | Functional mitochondria | EV-transferred mitochondria replaced the cell’s own, improving mitochondrial function Increased cell survival When taken up by immune cells, decreased inflammation Ameliorated clinical deficits | [117] | |||
IVV IVT | Mice with ARDS-like damage Primary human airway epithelial and pulmonary endothelial cells | MSCs | Functional mitochondria | Restored cell barrier integrity and levels of oxidative phosphorylation Restored mitochondrial respiration in lung tissue Reduced lung injury in ARDS | [118] | |||
IVV IVT | Hypoxia-injured iPSC-derived cardiomyocytes Mice with myocardial infarction | Autologous-stem-cell-derived cardiomyocytes | Functional mitochondria PGC-1α | Improved mitochondrial function Increased mitogenesis Significantly improved post-infarction cardiac function | [119] | |||
IVV | Mice with acute kidney injury | MSCs | TFAM | Stabilized mtDNA via the formation of the TFAM–mtDNA complex Reversed mtDNA deletion and mitochondrial oxidative phosphorylation defects Attenuated renal damage | [120] | |||
IVV | Mice with AD | MSCs, SHP2-enriched | 2 SHP | Selective induction of mitophagy in neural cells Decreased apoptosis and inflammation Decreased synaptic loss and cognitive decline are reduced | [121] | |||
Cellular senescence | Pro- | IVT | MSCS | Senescent MSCs | miR-31 | Inhibited osteogenic differentiation via Frizzled-3 factor knockout Inhibited proliferation | [138] | |
IVT IVV | BMSCs | Senescent muscle cells | miR-34a | Senescence induction and decreased SIRT1 expression | [139] | |||
IVT | HFFF2 human foreskin primary fibroblasts | Senescent HFFF2 expressing an empty vector or oncogenic H-RAS (iC and iRAS cells) | IFITM3 | Senescence induction via paracrine transmission | [140] | |||
IVV | HFFF2 human foreskin primary fibroblasts | Senescent HFFF2 expressing an empty vector or oncogenic H-RAS (iC and iRAS cells) | NA | Senescence induction through the NF-κB/IKK pathway | [141] | |||
Anti- | IVT | Fibroblasts from old mice or progeroid mice | Fibroblasts from young mice | GSTM-2 | Senescence markers decreased (p16, p21, SA-ß-Gal and yH2AX) Reduced ROS and lipid peroxidation levels | [27] | ||
IVT | Senescent MSCs | MSCs | Peroxiredoxins | Decreased senescence and ROS | [143] | |||
IVV IVT | Ercc1−/− mice MSCs from old mice Progeroid MDPSCs (Zmpste24−/−) | hESC-derived BM-MSCs | miRNAs | Decreased senescence in vivo in kidney, liver, lung, and brain Decreased senescence in vitro (p16, p21, p53, PTEN, MYC, IL-1, and IL-6) through a possible senomorphic effect (downregulation of SASP factors) Increased the lifespan of Ercc1−/− mice | [144] | |||
IVT | UV-radiated dermal fibroblasts | h-UCMSCs Dermal fibroblasts | NA | Decreased senescence Promoted the expressions of GPX-1 as well as Col-1 and decreased the expression of MMP-1 | [145] | |||
IVV IVT | Old mice Senescent C2C12 myoblasts | Young ADSCs | miR-125b-5p, miR-let7c-5p, and miR-214-3p | Decreased senescence in vivo in kidney and muscle (laminB1, yH2AX) through a possible senomorphic effect (downregulation of SASP factors) Decreased senescence in vitro (SA-ß-Gal, SASP factors) with no selective increase in apoptosis | [77] | |||
I N T E G R A T I V E | Stem cell exhaustion | Anti- | IVT | MSCs from old mice Progeroid MDPSCs | hESC-derived BM-MSCs | miRNAs | Decreased senescence of BM-MSCs Decreased senescence of MDPSCs and increased differentiation | [144] |
IVV | Old mice | hESCs | Proteins modulating anti-aging genes | Promoted proliferation and osteogenic differentiation of BM-MSCs Alleviated age-related bone loss | [34] | |||
IVV | Old mice | Hypothalamic NSCs from young mice | miRNA | Improved healthspan (physical tests, memory, and socialty) Rescued hypothalamic NSCs’ senescence | [36,155] | |||
IVV | Old mice | ESCs | SMADs 4-5 | Activation of the MYT1–Egln3–Sirt1 axis Improved hNSCs’ stemness | [156] | |||
IVV | Ovariectomized mice | SHED | miR-346 | Increased BM-MSCs’ proliferation and stemness Recovered bone volume and alleviate osteoporosis | [74] | |||
IVV | Old mice | Young ADSCs | miRNAs | Increased proliferation and reduced fibrosis of renal tubules Improved renal function Higher cross-sectional area of muscle fibers, predominancy of type II fibers, and higher protein content Improved physical condition, decreased frailty scores, and increased healthspan | [77] | |||
IVT | MDPSCs from old mice | Serum from young and old mice | α-Klotho transcripts | Increased myogenic differentiation potential | [115] | |||
IVT | Senescent DP-MSCs (passage or hyperoxia pretreatment) | DP-MSCs | miR-302b | Increased expression of the pluripotency factors OCT4, SOX2, KLF4, and cMYC via HIF-1α activation A metabolic shift towards highly glycolytic and low oxidative profiles Recovered stemness | [32] | |||
Altered intercellular communication | Anti- | IVT IVV | Cardiomyocytes, H9c2 myoblasts, cardiac fibroblasts, and HAPI cells | ADSCs | NA | Promoted macrophage M2 polarization and decreased LPS-induced inflammation Attenuated hypoxic damage | [163] | |
IVT | Osteoarthritic osteoblasts | ADSCs | NA | Reduced the levels of inflammatory mediators (IL-6 and PGE2) | [164] | |||
IVV | Intestinal epithelial cells | BM-MSCs | NA | Reduced IL-17A, RORγt, and IL-23 | [56] | |||
IVV | Serum, CNS, and salivary glands | Young mice serum | NA | Reduced the levels of inflammatory mediators (IL-6, IL-1β, and TNF-a) Reduced CD4+IFN-γ+ T cells Reduced CNS-penetrating CD3+ T cells and macrophages, as well as MHC-II expression by microglia Reduced chronic autoimmune predisposition | [165] |
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Romero-García, N.; Huete-Acevedo, J.; Mas-Bargues, C.; Sanz-Ros, J.; Dromant, M.; Borrás, C. The Double-Edged Role of Extracellular Vesicles in the Hallmarks of Aging. Biomolecules 2023, 13, 165. https://doi.org/10.3390/biom13010165
Romero-García N, Huete-Acevedo J, Mas-Bargues C, Sanz-Ros J, Dromant M, Borrás C. The Double-Edged Role of Extracellular Vesicles in the Hallmarks of Aging. Biomolecules. 2023; 13(1):165. https://doi.org/10.3390/biom13010165
Chicago/Turabian StyleRomero-García, Nekane, Javier Huete-Acevedo, Cristina Mas-Bargues, Jorge Sanz-Ros, Mar Dromant, and Consuelo Borrás. 2023. "The Double-Edged Role of Extracellular Vesicles in the Hallmarks of Aging" Biomolecules 13, no. 1: 165. https://doi.org/10.3390/biom13010165
APA StyleRomero-García, N., Huete-Acevedo, J., Mas-Bargues, C., Sanz-Ros, J., Dromant, M., & Borrás, C. (2023). The Double-Edged Role of Extracellular Vesicles in the Hallmarks of Aging. Biomolecules, 13(1), 165. https://doi.org/10.3390/biom13010165