Autonomic nervous system imbalance during aging contributes to impair endogenous anti-inflammaging strategies

Abstract

Inflammaging refers to the age-related low grade, sterile, chronic, systemic, and long-lasting subclinical, proinflammatory status, currently recognized as the main risk factor for development and progression of the most common age-related diseases (ARDs). Extensive investigations were focused on a plethora of proinflammatory stimuli that can fuel inflammaging, underestimating and partly neglecting important endogenous anti-inflammaging mechanisms that could play a crucial role in such age-related proinflammatory state. Studies on autonomic nervous system (ANS) functions during aging highlighted an imbalance toward an overactive sympathetic nervous system (SNS) tone, promoting proinflammatory conditions, and a diminished parasympathetic nervous system (PNS) activity, playing anti-inflammatory effects mediated by the so called cholinergic anti-inflammatory pathway (CAP). At the molecular level, CAP is characterized by signals communicated via the vagus nerve (with the possible involvement of the splenic nerves) through acetylcholine release to downregulate the inflammatory actions of macrophages, key players of inflammaging. Notably, decreased vagal function and increased burden of activated/senescent macrophages (macrophaging) probably precede the development of several age-related risk factors and diseases, while increased vagal function and reduced macrophaging could be associated with relevant reduction of risk profiles. Hypothalamic–pituitary–adrenal axis (HPA axis) is another pathway related to ANS promoting some anti-inflammatory response mainly through increased cortisol levels. In this perspective review, we highlighted that CAP and HPA, representing broadly “anti-inflammaging” mechanisms, have a reduced efficacy and lose effectiveness in aged people, a phenomenon that could contribute to fuel inflammaging. In this framework, strategies aimed to re-balance PNS/SNS activities could be explored to modulate systemic inflammaging especially at an early subclinical stage, thus increasing the chances to reach the extreme limit of human lifespan in healthy status.

Role of the autonomic nervous system in young, middle-aged, and older individuals with essential hypertension and sleep-related changes in neurocardiac regulation

“…The overflow of norepinephrine to the heart and kidney is increased in patients with essential hypertension 42 , particularly in patients aged < 40 years 43 . In younger patients, heightened renal sympathetic nerve activity correlates with elevated levels of renal renin secretion and arterial plasma renin activity, whereas in older patients, the increase in sympathetic nerve activity and norepinephrine release may vary 44 . In an animal study, severe, self-sustaining salt hypertension in young Dahl rats was associated with enhanced sympathetic nervous system activity, reduced nitric oxide levels, weakened baroreflex response, and increased residual BP, all indicating extensive remodeling of resistance blood vessels; these findings differed from those observed in adult Dahl rats 45 .…”

“…Moreover, there is a decline in baroreceptor function, reflex efficiency, and renal excretory capacity, potentially significantly promoting the development of hypertension 47 , 48 . However, age-related alterations in sympathetic nervous system and parasympathetic nervous system don’t progress linearly, indicating complex interrelationships among factors 44 . Therefore, both aging and autonomic imbalance contribute to the pathogenesis of hypertension in older individuals, with autonomic imbalance playing a more significant role in younger patients with hypertension 47 , 49 .…”

Similar Patterns of Dysautonomia in Myalgic Encephalomyelitis/Chronic Fatigue and Post-COVID-19 Syndromes

“…Sympathetic hyper-activation also favors pro-inflammatory and prothrombotic effects [ 42 ] driven by cytokines, chemokines and other biologically active mediators, while the parasympathetic branch of the autonomic nervous system plays an anti-inflammatory role mediated by the so-called cholinergic anti-inflammatory pathway. This pathway is characterized by signals communicated via the vagus nerve (with the possible involvement of the splenic nerves) through acetylcholine release to down-regulate the inflammatory actions of macrophages, which are key players in inflammaging [ 44 ]. The hypothalamic–pituitary–adrenal axis is another pathway related to the ANS, which promotes some anti-inflammatory responses mainly through increased cortisol levels (notably, this mechanism is also impaired in ME/CFS [ 45 ]).…”