1Division of Medical Biochemistry, Biocenter, Medical University Innsbruck, Austria 2Department of Prevention and Sports Medicine, TUM, Munich, Germany 3Division of Biological Chemistry, Biocenter, Medical University Innsbruck, Austria 4Department of Sport Science, Medical Section, University Innsbruck, Austria
Muscle atrophy is an unfortunate effect of aging and many diseases and can compromise physical function and impair vital metabolic processes. Low levels of muscular fitness together with insufficient dietary intake are major risk factors for illness and mortality from all causes. Ultimately, muscle wasting contributes significantly to weakness, disability, increased hospitalization, immobility, and loss of independence. However, the extent of muscle wasting differs greatly between individuals due to differences in the aging process per se as well as physical activity levels. Interventions for sarcopenia include exercise and nutrition because both have a positive impact on protein anabolism but also enhance other aspects that contribute to well-being in sarcopenic older adults, such as physical function, quality of life, and anti-inflammatory state. The process of aging is accompanied by chronic immune activation, and sarcopenia may represent a consequence of a counter-regulatory strategy of the immune system. Thereby, the kynurenine pathway is induced, and elevation in the ratio of kynurenine to tryptophan concentrations, which estimates the tryptophan breakdown rate, is often linked with inflammatory conditions and neuropsychiatric symptoms. A combined exercise program consisting of both resistance-type and endurance-type exercise may best help to ameliorate the loss of skeletal muscle mass and function, to prevent muscle aging comorbidities, and to improve physical performance and quality of life. In addition, the use of dietary protein supplementation can further augment protein anabolism but can also contribute to a more active lifestyle, thereby supporting well-being and active aging in the older population.
Figure 1. Age-related decline of endurance and strength performance in trained versus untrained subjects
Age-related decline in the anaerobic threshold (VO2AT) in Master’s mountain runners and sedentary subjects (A) and peak power in Master’s weight lifters and sedentary control subjects (B); (modified from ref. 58, 59).
Figure 2. The induction of indoleamine 2,3-dioxygenase 1 (IDO1) by aging
The process of aging involves pro-inflammatory pathways which include activation of the T-cell-macrophage axis in the framework of the cell-mediated (Th1-type) immune response in which the formation of Th1-type cytokine interferon-γ (IFN-γ) is of utmost relevance. IFN-γ stimulates a broad spectrum of biochemical pathways that are directed to stop unwanted growth of pathogens or malignant cells. Among them, the conversion of essential amino acid tryptophan to kynurenine is a key element, which on the one hand is involved in a feedback inhibition of T-cell activation via regulatory T-cells and thus immunosuppressive. On the other hand, the catabolites generated by this strategy can impact on the central nervous system when neuroactive compounds accumulate and pro-inflammatory cascades including the formation of reactive oxygen species (ROS) interfere with neuroendocrine signaling, which controls mood and behavior.
Figure 3. Tryptophan breakdown limits the availability of tryptophan for serotonin synthesis and increases the downstream production of neuroactive metabolites
Enhanced tryptophan breakdown by the enzymes tryptophan 2,3-dioxygenase (tryptophan pyrrolase, TDO) and/or indoleamine 2,3-dioxygenase-1 (IDO-1) can affect several body compartments including the brain. Thereby, various intermediate catabolites such as kynurenic acid, picolinic acid, and quinolinic acid are formed on the route to nicotinamide adenine dinucleotides. Tryptophan shortage during/after the pro-inflammatory response may reduce the availability of the essential amino acid for the biosynthesis of muscle proteins and can thus contribute to sarcopenia development with older age. For the transport of tryptophan and kynurenine into the brain to cross the blood-brain barrier (BBB), the leucine-preferring L1 system is utilized in competition with the so-called large neutral amino acids (LNAA). Once arrived in the brain, astrocytes are able to convert kynurenine to neuroprotective kynurenic acid, whereas glial cells primarily produce its neurotoxic counterpart quinolinic acid. Alternatively, tryptophan is converted by the tryptophan 5-monooxygenase to 5-hydroxytryptophan, which decarboxylates to the product serotonin (5-hydroxytryptamin), an important neurotransmitter and precursor of the sleep hormone melatonin. If brain tryptophan is low, serotonin also decreases and can disturb memory and cognition as well as sleep and mood, which finally increase the risk of development of dementia and depression.
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