Long-COVID-19 autonomic dysfunction: An integrated view in the framework of inflammaging

The recently identified syndrome known as Long COVID (LC) is characterized by a constellation of debilitating conditions that impair both physical and cognitive functions, thus reducing the quality of life and increasing the risk of developing the most common age-related diseases. These conditions are linked to the presence of symptoms of autonomic dysfunction, in association with low cortisol levels, suggestive of reduced hypothalamicpituitary-adrenal (HPA) axis activity, and with increased pro-inflammatory condition. Alterations of dopamine and serotonin neurotransmitter levels were also recently observed in LC. Interestingly, at least some of the proposed mechanisms of LC development overlap with mechanisms of Autonomic Nervous System (ANS) imbalance, previously detailed in the framework of the aging process. ANS imbalance is characterized by a proinflammatory sympathetic overdrive, and a concomitant decreased anti-inflammatory vagal parasympathetic activity, associated with reduced anti-inflammatory effects of the HPA axis and cholinergic anti-inflammatory pathway (CAP). These neuro-immune-endocrine system imbalanced activities fuel the vicious circle of chronic inflammation, i.e. inflammaging. Here, we refine our original hypothesis that ANS dysfunction fuels inflammaging and propose that biomarkers of ANS imbalance could also be considered biomarkers of inflammaging, recognized as the main risk factor for developing age-related diseases and the sequelae of viral infections, i.e. LC.