Sepsis induces Telomere Shortening: a Potential Mechanism Responsible for Delayed Pathophysiological Events in Sepsis Survivors?

Abstract

Sepsis survivors suffer from additional morbidities, including higher disk of readmissions, nervous system disturbances and cognitive dysfunction, and increased mortality, even several years after the initial episode of sepsis. In many ways, the phenotype of sepsis survivors resembles the phenotype associated with accelerated aging. Since telomere shortening is a hallmark of aging, we investigated whether sepsis also leads to telomere shortening. Male balb/c mice were divided into two groups: the control group received 100 μl of normal saline intraperitoneally; the sepsis group received 15 mg/kg of bacterial lipopolysaccharide i.p. After 48 hours, animals were sacrificed to collect blood, spleen and kidney. The human component of our study utilized blood samples obtained from patients in the Trauma Department and samples collected 7 days later in those patients who developed sepsis. Telomere length was measured by quantitative PCR. Since oxidative stress is a known inducer of telomere shortening, thiobarbituric acid reactive substances and superoxide dismutase (SOD) activity were analyzed in order to evaluate oxidative stress burden. Induction of endotoxemia in mice resulted in significant telomere shortening in spleen and kidney.Blood cells from patients that progressed to sepsis also exhibited a statistically significant reduction of telomere length. Endotoxemia in mice also induced an earlyonset increase in oxidative stress markers, but was not associated with a downregulation of telomerase protein expression. We conclude that endotoxemia and sepsis induce telomere shortening in various tissues and hypothesize that this may contribute to the pathogenesis of the delayed pathophysiological events in sepsis survivors.

Decreased Thymic Output Contributes to Immune Defects in Septic Patients

“…In contrast, we found decreased telomere length in CD4+ T cells but not CD8+ T cells of septic patients, despite upregulated telomerase and moreover despite upregulated shelterin complexes, which protect telomeres from shortening. Similarly to our study, decreased telomere length was also observed in a mouse model of sepsis and in human peripheral blood cells of septic patients, which was explained as possibly resulting from oxidative stress or the release of several inflammatory factors [38]. In this case, increased telomerase activity cannot compensate for these mechanisms.…”

Telomere Length Changes during Critical Illness: A Prospective, Observational Study

“…Findings from a recent small study of septic patients ( n = 9) showed that significant reductions in telomere length may also occur over short time periods, namely over one week [20]. However, the correlation between changes of leukocyte telomere length in this acute setting of critically ill, metabolically stressed patients and outcome has not been evaluated to date.…”

Septic Shock and the Aging Process: A Molecular Comparison

“…In the long term, these plausible DNA mutations and deletions can significantly impact patient quality of life and predispose the survivors of inflammatory catastrophes to several morbid consequences. In this regard, a recent publication from our group showed that sepsis induces telomere shortening ( 55 ), confirming that inflammation affects telomere length ( 56 ) and that stress-induced premature senescence is a telomere-dependent process ( 57 ). Despite that, however, the other evidence in the literature addressing this topic is controversial and/or indirect.…”