Alpha Ketoglutarate Enhances Geroprotection In Surgery (AEGIS)

Overview

One of the most common major surgeries that older patients undergo is coronary artery bypass grafting surgery (CABG), which is performed in approximately 400,000 patients in the United States each year. CABG invokes a massive surgical stress response, with systemic epinephrine increasing 33-fold and norepinephrine increasing 3-fold. Initially, local tissue injury results in a sterile inflammation, releasing damage-associated molecular patterns (DAMPS). DAMPS activate neutrophils, bringing a cascade of cytokines, complement, and coagulation changes. Activation of nociceptors results in a neurometabolic response involving the sympathetic nervous system and hypothalamus-pituitary axis. This brings about systemic effects including changes in basal metabolic rate, hyperglycemia, lipolysis, negative nitrogen balance, and release of cytokines and complement. Although the surgical stress response is essential for wound healing and is usually self-limiting, an exaggerated response may occur resulting in multiple organ dysfunction. The acute phase of the surgical stress response is often followed by secondary insults that may be either sterile or pathogen-induced (such as postoperative infection).In the "two-hit" model of surgical stress response, there is an exaggerated response even to minor insults in vulnerable individuals who were primed by the initial stress response. Changes in the microbiome may also occur, developing a "pathobiome" that may enter the systemic circulation. If left unchecked, this second hit may result in the development of systemic inflammatory response syndrome (SIRS) and multi-organ failure. Chronological ageing changes the innate and adaptive immunity of patients. Biological hallmarks of aging such as genomic instability, mitochondrial damage, glycation of proteins, and cellular senescence all result in increased oxidative stress and systemic inflammation. Aging brings about a pro-inflammatory innate immune responsiveness that often occurs even in the absence of an inflammatory threat. This is termed inflammaging. Paradoxically, inflammaging is associated with an increased risk of infection and poor response to stressful events. At the same time, there is an age-associated loss of T-cell function, particularly in naïve CD8 T-cells. This deficit is termed immunosenescence and is characterised by reduced pathogen recognition, chemotaxis, and phagocytosis.

Within 24 hours of surgery, single-cell mass cytometry identified signalling changes in immune cell subsets that characterise the phenotypic and functional immune response to surgery. These signals accounted for 40-60% of observed patient variability, and strong correlations were found between these immune signatures with the speed of recovery from fatigue, pain, and functional impairment. In another study, Fragiadakis found that the preoperative immune state was also predictive of recovery from surgery, with toll-like receptor (TLR) 4 signalling in cluster of differentiation (CD) 14+ monocytes accounting for 50% of observed variance in clinical recovery. Furthermore, the group showed that patients undergoing an intermediate risk cardiac surgery had a significantly higher risk of developing multi-organ failure when their cytokine response profile was highly proinflammatory after stimulation with Escherichia coli-derived lipopolysaccharide . Another study showed that patients' immune response after surgery and immune profile before surgery predicted the development of surgical site complications in abdominal surgery. Taken together, these studies were consistent in suggesting that immune profiles play a major role in surgical resilience. Therefore, it is postulated that giving a geroprotector in the perioperative period can mitigate the aging-related immune changes and prevent a dysfunctional surgical stress response, directly impacting surgical resilience. AKG is a geroprotector that benefits patients undergoing cardiac surgery. Plasma concentrations of AKG are reduced in patients with ischemic heart disease and it is possible that this aggravates myocardial ischemic injury during CABG. AKG supplementation during cardiopulmonary bypass significantly decreased ischaemic injury markers (creatine kinase MB and troponin T) by 30-50% in patients undergoing heart surgery, secondary to improved myocardial oxygen extraction. AKG has beneficial effects beyond its cardiac effects. AKG is an intermediate in the Krebs cycle which is involved in various metabolic and cellular pathways as a signalling molecule, energy source, and precursor of amino acid synthesis. AKG is an anti-oxidative agent and a significant source of cellular adenosine triphosphate (ATP). Therefore, AKG plays an important role in multiple metabolic processes, and has been shown to preserve skeletal muscle, improve renal function, and protect neurological function. AKG is also a regulator of cell signalling pathways that maintain energy homeostasis, including mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK). By reducing the triggers of oxidative stress and hypoxia, AKG can moderate inflammation. AKG also has immune-modulatory properties. It modulates monocyte and neutrophil function by increasing phagocytosis and reactive oxygen species (ROS) intermediate production, macrophages by enhancing cytokine production, and lymphocytes by enhancing their proliferation. Hypothesis Inflammaging and immunosenescence renders the older patient vulnerable to a dysfunctional surgical stress response.