title: Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease.
abstract: Telomere dysfunction limits the proliferative capacity of human cells by activation of DNA damage responses, inducing senescence or apoptosis. In humans, telomere shortening occurs in the vast majority of tissues during aging, and telomere shortening is accelerated in chronic diseases that increase the rate of cell turnover. Yet, the functional role of telomere dysfunction and DNA damage in human aging and diseases remains under debate. Here, we identified marker proteins (i.e., CRAMP, stathmin, EF-1alpha, and chitinase) that are secreted from telomere-dysfunctional bone-marrow cells of late generation telomerase knockout mice (G4mTerc(-/-)). The expression levels of these proteins increase in blood and in various tissues of aging G4mTerc(-/-) mice but not in aging mice with long telomere reserves. Orthologs of these proteins are up-regulated in late-passage presenescent human fibroblasts and in early passage human cells in response to gamma-irradiation. The study shows that the expression level of these marker proteins increases in the blood plasma of aging humans and shows a further increase in geriatric patients with aging-associated diseases. Moreover, there was a significant increase in the expression of the biomarkers in the blood plasma of patients with chronic diseases that are associated with increased rates of cell turnover and telomere shortening, such as cirrhosis and myelodysplastic syndromes (MDS). Analysis of blinded test samples validated the effectiveness of the biomarkers to discriminate between young and old, and between disease groups (MDS, cirrhosis) and healthy controls. These results support the concept that telomere dysfunction and DNA damage are interconnected pathways that are activated during human aging and disease.
authors.affiliation: Institute of Molecular Medicine and Max Planck Research Group on Stem Cell Aging and Department of Internal Medicine III, University of Ulm, 89081 Ulm, Germany.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Eric
authors.initials: E
authors.lastname: Schiffer
authors.forename: Zhangfa
authors.initials: Z
authors.lastname: Song
authors.forename: Jianwei
authors.initials: J
authors.lastname: Wang
authors.forename: Petra
authors.initials: P
authors.lastname: Zürbig
authors.forename: Kathrin
authors.initials: K
authors.lastname: Thedieck
authors.forename: Suzette
authors.initials: S
authors.lastname: Moes
authors.forename: Heike
authors.initials: H
authors.lastname: Bantel
authors.forename: Nadja
authors.initials: N
authors.lastname: Saal
authors.forename: Justyna
authors.initials: J
authors.lastname: Jantos
authors.forename: Meiken
authors.initials: M
authors.lastname: Brecht
authors.forename: Paul
authors.initials: P
authors.lastname: Jenö
authors.forename: Michael N
authors.initials: MN
authors.lastname: Hall
authors.forename: Klaus
authors.initials: K
authors.lastname: Hager
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Hartmut
authors.initials: H
authors.lastname: Hecker
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.forename: Andrzej
authors.initials: A
authors.lastname: Bartke
authors.forename: Christoph
authors.initials: C
authors.lastname: Meissner
authors.forename: Harald
authors.initials: H
authors.lastname: Mischak
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Ju
authors.forename: K Lenhard
authors.initials: KL
authors.lastname: Rudolph
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis*; D017209:Apoptosis / Q000528:radiation effects; D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D054804:Cathelicidins; D016922:Cellular Senescence / Q000528:radiation effects; D002688:Chitinases / Q000096:biosynthesis*; D004249:DNA Damage / Q000528:radiation effects; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism* / Q000473:pathology; D005720:Gamma Rays / Q000009:adverse effects; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009190:Myelodysplastic Syndromes / Q000378:metabolism* / Q000473:pathology; D020648:Peptide Elongation Factor 1 / Q000096:biosynthesis*; D050777:Stathmin / Q000096:biosynthesis*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000528:radiation effects
chemical_list: D023181:Antimicrobial Cationic Peptides; D015415:Biomarkers; D054804:Cathelicidins; D020648:Peptide Elongation Factor 1; C493995:STMN1 protein, human; D050777:Stathmin; D019098:Telomerase; D002688:Chitinases