title: Aging-related anatomical and biochemical changes in lymphatic collectors impair lymph transport, fluid homeostasis, and pathogen clearance.
abstract: The role of lymphatic vessels is to transport fluid, soluble molecules, and immune cells to the draining lymph nodes. Here, we analyze how the aging process affects the functionality of the lymphatic collectors and the dynamics of lymph flow. Ultrastructural, biochemical, and proteomic analysis indicates a loss of matrix proteins, and smooth muscle cells in aged collectors resulting in a decrease in contraction frequency, systolic lymph flow velocity, and pumping activity, as measured in vivo in lymphatic collectors. Functionally, this impairment also translated into a reduced ability for in vivo bacterial transport as determined by time-lapse microscopy. Ultrastructural and proteomic analysis also indicates a decrease in the thickness of the endothelial cell glycocalyx and loss of gap junction proteins in aged lymph collectors. Redox proteomic analysis mapped an aging-related increase in the glycation and carboxylation of lymphatic's endothelial cell and matrix proteins. Functionally, these modifications translate into apparent hyperpermeability of the lymphatics with pathogen escaping from the collectors into the surrounding tissue and a decreased ability to control tissue fluid homeostasis. Altogether, our data provide a mechanistic analysis of how the anatomical and biochemical changes, occurring in aged lymphatic vessels, compromise lymph flow, tissue fluid homeostasis, and pathogen transport.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
authors.forename: Valerio
authors.initials: V
authors.lastname: Zolla
authors.affiliation: Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, TX, 76501, USA.
authors.forename: Irina Tsoy
authors.initials: IT
authors.lastname: Nizamutdinova
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Scharf
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
authors.forename: Cristina C
authors.initials: CC
authors.lastname: Clement
authors.affiliation: Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, TX, 76501, USA.|Department of Physiology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Maejima
authors.affiliation: Department of Biomedical Engineering, Texas A&M University, College Station, TX, 77843, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Akl
authors.affiliation: Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, TX, 76501, USA.|Department of Physiology, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagai
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, Zurich, CH-8093, Switzerland.
authors.forename: Paola
authors.initials: P
authors.lastname: Luciani
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, Zurich, CH-8093, Switzerland.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Leroux
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, Zurich, CH-8093, Switzerland.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Halin
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
authors.forename: Sabriya
authors.initials: S
authors.lastname: Stukes
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Tiwari
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
authors.forename: Arturo
authors.initials: A
authors.lastname: Casadevall
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.|Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
authors.forename: David
authors.initials: D
authors.lastname: Entenberg
authors.affiliation: Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, TX, 76501, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Zawieja
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.|Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
authors.forename: John
authors.initials: J
authors.lastname: Condeelis
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.|Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Fooksman
authors.affiliation: Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, TX, 76501, USA.
authors.forename: Anatoliy A
authors.initials: AA
authors.lastname: Gashev
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.|Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Santambrogio
mesh_terms: D000375:Aging / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000648:ultrastructure; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism / Q000648:ultrastructure; D019276:Glycocalyx / Q000737:chemistry / Q000378:metabolism; D006031:Glycosylation; D016908:Gram-Positive Bacterial Infections / Q000378:metabolism / Q000382:microbiology; D006706:Homeostasis; D008196:Lymph / Q000378:metabolism*; D008198:Lymph Nodes / Q000378:metabolism* / Q000382:microbiology / Q000648:ultrastructure; D042601:Lymphatic Vessels / Q000737:chemistry* / Q000378:metabolism / Q000382:microbiology / Q000648:ultrastructure; D008297:Male; D008643:Mesentery / Q000378:metabolism / Q000382:microbiology / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D020102:Mycobacterium smegmatis / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000648:ultrastructure; D020543:Proteome / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013211:Staphylococcus aureus / Q000502:physiology; D059008:Time-Lapse Imaging
chemical_list: D017630:Connexins; D016326:Extracellular Matrix Proteins; D020543:Proteome
keywords: aging; lymphatics; mass spectrometry; oxidative stress; proteomics