TY - JOUR
T1 - Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease
AU - Jiang, Hong
AU - Schiffer, Eric
AU - Song, Zhangfa
AU - Wang, Jianwei
AU - Zürbig, Petra
AU - Thedieck, Kathrin
AU - Moes, Suzette
AU - Bantel, Heike
AU - Saal, Nadja
AU - Jantos, Justyna
AU - Brecht, Meiken
AU - Jenö, Paul
AU - Hall, Michael N.
AU - Hager, Klaus
AU - Manns, Michael P.
AU - Hecker, Hartmut
AU - Ganser, Arnold
AU - Döhner, Konstanze
AU - Bartke, Andrzej
AU - Meissner, Christoph
AU - Mischak, Harald
AU - Ju, Zhenyu
AU - Rudolph, K. Lenhard
PY - 2008/8/12
Y1 - 2008/8/12
N2 - 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-1α, 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 γ-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.
AB - 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-1α, 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 γ-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.
UR - http://www.scopus.com/inward/record.url?scp=49649090009&partnerID=8YFLogxK
U2 - 10.1073/pnas.0801457105
DO - 10.1073/pnas.0801457105
M3 - Journal articles
C2 - 18695223
AN - SCOPUS:49649090009
SN - 0027-8424
VL - 105
SP - 11299
EP - 11304
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 32
ER -