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-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.

Cell intrinsic and extrinsic mechanisms of stem cell aging depend on telomere status

“…These markers show an increased expression in various tissues and blood plasma of aging telomere dysfunctional mice but not in wildtype controls. The same biomarkers significantly increase during human aging and aging-associated disease (Jiang et al 2008). Together these results support the hypothesis that accumulation of telomere dysfunction and DNA damage contribute to human aging, but have little impact on aging of wild type mice with long telomere reserves.…”

“…Telomere dysfunction increased the influence of environmental alterations limiting the function of HSCs in aging mice. Experimental evidence for an accumulation of telomere dysfunction in aging humans (Jiang et al 2008) and clinical data (Table 1) support the hypothesis that environmental alterations induced by telomere dysfunction could contribute to the decline in stem cell function in human aging.…”

“…Together, these data strongly indicate that human telomere reserves are limited. New experimental data indicate that increasing levels of biomarkers of telomere dysfunction and DNA damage characterize human aging and aging-associated disease (Jiang et al 2008). Given the pivotal role of telomeres and adult stem cells for tissues maintenance and repair, it appears to be of utmost importance to understand the functional consequences of telomere dysfunction on stem cell levels.…”

“…Given the pivotal role of telomeres and adult stem cells for tissues maintenance and repair, it appears to be of utmost importance to understand the functional consequences of telomere dysfunction on stem cell levels. The characterization of stem cell aging in wild type mice cannot address this critical question since laboratory wild type mouse strains have very long telomeres compared to humans 4 (Prowse and Greider, 1995) and inbred laboratory wildtype mice do not experience significant levels of telomere dysfunction during aging (Jiang et al 2008). In fact, there is experimental evidence that the decline in stem cell function in wild type laboratory mouse strains is mainly driven by telomere-independent mechanisms (Allsopp et al, 2003).…”

“…Proteomic analysis on cell extrinsic proteins in culture supernatant of bone marrow from telomere dysfunctional mice has identified a new set of biomarker showing increased expression in response to telomere dysfunction in aging mTerc-/-mice (Jiang et al 2008). Interestingly, these biomarkers showed increased expression in human cells in response to telomere dysfunction and irradiation induced DAN damage.…”