The Paper of the Month for November is ‘Fatigue in older persons: the role of nutrition‘. The blog is written by authors Dr Domenico Azzolino and Professor Matteo Cesari, and the paper is published in the Proceedings of the Nutrition Society and is free to access.

Fatigue is a symptom resulting from the weakening or depletion of one's physical and/or mental resources, ranging from a general state of lethargy to a specific, work-induced burning sensation within one's muscles. It is a highly prevalent feeling but still remains an often-neglected unmet clinical need. Fatigue is frequently reported by older people, but it can also occur earlier in life in association with a range of conditions, including emotional stress, depression, burnout, lack of sleep, and/or physical distress. Additionally, it has been reported to be the most complained and frequently long-lasting symptom in the context of COVID-19.

In this regard, nutrition may represent the biological substratum on which acting to properly address the symptom of fatigue. In fact, fatigue may mirror the exhaustion of the metabolic reserves of the individual, a sort of alert launched by the organisms in response to a stressor. When energy and protein intakes become inadequate to meet demands, catabolic pathways are activated to provide energy with consequent symptoms like fatigue and tiredness. Thus, the first-line approach is to ensure an adequate amount of energy and nutrients to our body. 

Notwithstanding, fatigue remains a complex symptom with multiple causal mechanisms. Among all, inflammation and mitochondrial dysfunction represent the most promising pathways to better understand the complexity of the symptom. Mitochondria represent the hub of energy production through oxidative phosphorylation, in which nutrients are processed to generate ATP. Inflammation could predispose to mitochondrial dysfunction with the production of mitochondrial damage-associated molecular patterns that, in turn, can lead to the release of cytokines, chemokines, nitric oxide and reactive oxygen species, further promoting mitochondrial damage, and establishing a vicious circle.

Fatigue is observed in some conditions characterised by micronutrient deficiencies, and some vitamins and minerals are pivotal for mitochondrial functioning. Nutritional interventions aimed at counteracting inflammation and mitochondrial dysfunction seem to be a promising strategy. However, to date, no single food (including the so-called ‘superfoods’) has been shown to provide the so-called “energy boost” and significantly relieving fatigue.

Creatine supplementation has been indicated as an interesting approach. It is mainly stored in muscles in the form of phosphocreatine, which acts as an energy shuttle, transferring a high-energy phosphate group to adenosine diphosphate to regenerate ATP during muscle contraction. β-hydroxy-β-methylbutyrate, a metabolite of leucine, has been indicated as a promising agent that may increase resistance to fatigue. Beneficial effects of acetyl l-carnitine and vitamin D (in those who are deficient) on mental and physical fatigue have also been reported. 

Coenzyme Q plays an important role in the mitochondrial electron transport chain, and coenzyme Q10 has shown antioxidant and anti-inflammatory properties. NADH is also involved in the mitochondrial function and regulation of inflammation. NADH and coenzyme Q10 supplementations have been reported to reduce fatigue in patients with chronic fatigue syndrome. Low concentrations of selenium have been associated with anxiety, depression and tiredness. Some seleno-proteins (i.e., glutathione peroxidases, thioredoxin reductases) seem to be effective at controlling oxidative stress and inflammation and might also be of interest for reducing fatigue. Finally, n-3 fatty acids have been indicated as potentially beneficial in inflammatory conditions and might be worth exploring in the management of fatigue.