Septic Shock and the Aging Process: A Molecular Comparison

Abstract

Aging is a continuous process promoted by both intrinsic and extrinsic factors that each trigger a multitude of molecular events. Increasing evidence supports a central role for inflammation in this progression. Here, we discuss how the low-grade chronic inflammation that characterizes aging is tightly interconnected with other important aspects of this process, such as DNA damage, mitochondrial dysfunction, and epigenetic changes. Similarly, inflammation also plays a critical role in many morbid conditions that affect patients who are admitted to Intensive Care. Although the inflammatory response is low grade and persistent in healthy aging while it is acute and severe in critically ill states, we hypothesize that both situations have important interconnections. Here, we performed an extensive review of the literature to investigate this potential link. Because sepsis is the most extensively studied disease and is the leading cause of death in Critical Care, we focus our discussion on comparing the inflammatory profile of healthy older people with that of patients in septic shock to explain why we believe that both situations have synergistic effects, leading to critically ill aged patients having a worse prognosis when compared with critically ill young patients.

Mechanisms of Ataxia Telangiectasia Mutated (ATM) Control in the DNA Damage Response to Oxidative Stress, Epigenetic Regulation, and Persistent Innate Immune Suppression Following Sepsis

“…Numerous studies indicate that induction of emergency hematopoiesis, the rapid activation and differentiation of HSCs within the bone marrow (BM) environment, and even depletion of HSCs occur during sepsis [85][86][87]. In addition, recent studies provide evidence that during the acute phase of sepsis, epigenetic changes are made to HSC nuclear chromatin [88]. This critically important piece of the emerging picture provides a mechanism for how innate immune cells of sepsis survivors remain permanently suppressed.…”

The PARP inhibitor olaparib exerts beneficial effects in mice subjected to cecal ligature and puncture and in cells subjected to oxidative stress without impairing DNA integrity: A potential opportunity for repurposing a clinically used oncological drug for the experimental therapy of sepsis

“…Since septic shock is, to a large extent, a disease of the elderly [1, 2], and since in aged organisms some of the p athophysiological mechanisms are not only quantitatively but also qualitatively different from the mechanisms that occur in young adult organisms [2,22,[28][29][30], we have also investigated the effect of ola par ib in aged mice (72 weeks old Fig. 19.…”

Transcriptome analysis of six tissues obtained post‐mortem from sepsis patients

“…19 Cellular senescence, genomic instability, telomere attrition, loss of proteostasis, epigenetic alterations and mitochondrial dysfunction constitute six of the nine classical hallmarks of ageing, 20 providing evidence that most mechanisms that characterize the ageing process have a role in the pathophysiology of septic shock. 21 With the exception of 'oxidative stress-induced senescence', the inhibition of these Reactome pathways disturbs cell homeostasis and leads to accelerated ageing.…”