Tryptophan Metabolism and Inflammaging

Today's open access research on tryptophan and its role in age-related immune dysfunction is particularly interesting in the context of ongoing research into the changes that take place in gut microbiota with age. Other recent work has examined the way in which tryptophan production by gut microbes declines precipitously with age, as this is one of a number of compounds produced by bacteria, such as butyrate, indole, and proprionate, that are influential on long term health. It is a slow process, but researchers are uncovering the specific mechanisms linking age-related changes in gut microbe populations with declining health. The overall size of effect of gut microbes on heath might be in the same ballpark as that of exercise, but this is only suggested by the evidence to date, not rigorously established.

Given detrimental changes in gut microbes, declining production of beneficial compounds, and a rise in chronic inflammation due to a rise in the presence of harmful microbes, what might be done about all of this? One possibility is supplementation with the various identified compounds, not all of which can make it past the stomach without some form of protection. Some have been tested, with varying results. Another is fecal microbiota transplant, which has produced some quite eye-opening results on life span and measures of health in short-lived species such as killifish. As a treatment for severe conditions in which pathological microbes have taken hold in a patient's intestine, this approach to therapy has done quite well to date. It has not yet been assessed as a way to restore - even temporarily - a more youthful set of gut microbes in older people, however, as the animal evidence suggests it might.

Tryptophan Metabolism in Inflammaging: From Biomarker to Therapeutic Target

Age-related changes of the innate immune system are common and include shifts in the composition of immune cell populations, paralleled by the development of a chronic inflammatory state referred to as inflammaging. This is characterized by an imbalance between pro- and anti-inflammatory responses and fluctuations of inflammatory cytokines. The rate of inflammaging, quantified by measuring these markers, is strongly associated with age-related disability, disease, and mortality. It is theorized that inflammaging is driven by endogenous ligands released upon age-related tissue damage and can be aggravated by food excess and attenuated by caloric restriction, suggesting relevant cross-talk between metabolic and immune functioning.

Understanding how inflammaging is controlled could aid in the development of diagnostic and therapeutic tools for many age-related diseases associated with inflammation. Tryptophan (Trp) metabolism is associated with aging and produces metabolites that control inflammation, regulate energy homeostasis, and modulate behavior. The essential amino acid Trp fuels the synthesis of kynurenine (Kyn), serotonin (5-HT) and indoles. The Kyn pathway of Trp is the most active pathway of Trp metabolism and produces metabolites including kynurenic acid and nicotinamide adenine dinucleotide (NAD+). While indoleamine 2,3-dioxygenase (IDO) plays a minor role in Trp metabolism under normal circumstances, IDO-dependent Trp metabolism is strongly activated in response to interferons and other cytokines that are released upon inflammation. Inflammation-related IDO activity is often measured by the Kyn/Trp ratio in blood in diseases characterized by excessive or chronic inflammation including infections, autoimmune disorders, cardiovascular disease, and cancer.

Trp metabolism controls hyperinflammation and induces long term immune tolerance. These effects pivot on the ability of IDO to alter the local and systemic Kyn/Trp balance. This balance directly affects metabolic and immune signaling pathways that drive an anti-inflammatory response. The Kyn/Trp ratio, measured in blood, is robustly associated with aging in humans. The fact that this association is already evident in healthy young adults, and persists throughout life, implies that the age-dependent increase in the Kyn/Trp ratio is not secondary to the onset of disease but rather represents a physiological age-related change. Taken together, these observational data suggests that the Kyn/Trp ratio could provide a valuable marker for the rate of (physiological) inflammaging. As inflammaging is involved in the onset of age-related diseases, a marker for inflammaging should also predict the onset of age-related diseases. This is the case for the Kyn/Trp ratio.

Age-related changes to the microbiome were associated with increased expression of enzymes involved in microbial Trp metabolism. This highlights the importance of microbiota-dependent Trp metabolism and suggest that activation of intestinal IDO and age-related changes in microbiome composition can deplete the body of health-promoting indoles while affecting the systemic Kyn/Trp balance. In addition, it provides relevant evidence that links metabolic inflammation to gastrointestinal Trp metabolism and metabolic health.

Comments

It is a mystery to me why fecal transplant is so expensive

Posted by: JohnD at December 7th, 2019 11:01 AM

Probably because thats the good shite...

Posted by: Cuberat at December 7th, 2019 7:30 PM

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