Aged brain and neuroimmune responses to COVID-19: post-acute sequelae and modulatory effects of behavioral and nutritional interventions

Abstract

Advanced age is one of the significant risk determinants for coronavirus disease 2019 (COVID-19)-related mortality and for long COVID complications. The contributing factors may include the age-related dynamical remodeling of the immune system, known as immunosenescence and chronic low-grade systemic inflammation. Both of these factors may induce an inflammatory milieu in the aged brain and drive the changes in the microenvironment of neurons and microglia, which are characterized by a general condition of chronic inflammation, so-called neuroinflammation. Emerging evidence reveals that the immune privilege in the aging brain may be compromised. Resident brain cells, such as astrocytes, neurons, oligodendrocytes and microglia, but also infiltrating immune cells, such as monocytes, T cells and macrophages participate in the complex intercellular networks and multiple reciprocal interactions. Especially changes in microglia playing a regulatory role in inflammation, contribute to disturbing of the brain homeostasis and to impairments of the neuroimmune responses. Neuroinflammation may trigger structural damage, diminish regeneration, induce neuronal cell death, modulate synaptic remodeling and in this manner negatively interfere with the brain functions.In this review article, we give insights into neuroimmune interactions in the aged brain and highlight the impact of COVID-19 on the functional systems already modulated by immunosenescence and neuroinflammation. We discuss the potential ways of these interactions with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and review proposed neuroimmune mechanisms and biological factors that may contribute to the development of persisting long COVID conditions. We summarize the potential mechanisms responsible for long COVID, including inflammation, autoimmunity, direct virus-mediated cytotoxicity, hypercoagulation, mitochondrial failure, dysbiosis, and the reactivation of other persisting viruses, such as the Cytomegalovirus (CMV). Finally, we discuss the effects of various interventional options that can decrease the propagation of biological, physiological, and psychosocial stressors that are responsible for neuroimmune activation and which may inhibit the triggering of unbalanced inflammatory responses. We highlight the modulatory effects of bioactive nutritional compounds along with the multimodal benefits of behavioral interventions and moderate exercise, which can be applied as postinfectious interventions in order to improve brain health.

Management of cognitive impairment associated with post-COVID-19 syndrome: recommendations for primary care

“…Behavioral interventions mentioned by Müller and Di Benedetto ( Muller and Di Benedetto, 2023 ) comprise mind-body interventions, musical therapy, and meditation. These interventions, which are of low to moderate cost, can be conducted as self-practice at home and can alleviate symptoms of PCS.…”

“…Although controlled clinical trials focusing on patients with PCS are currently lacking, the use of probiotics and prebiotics may be considered as a supportive measure ( Catalano et al, 2022 ). Additionally, immunomodulatory effects of probiotics may help in restoring the gut microbiome altered during viral infections ( Muller and Di Benedetto, 2023 ).…”

Aging brain: exploring the interplay between bone marrow aging, immunosenescence, and neuroinflammation

“…Astrocytes, the most abundant glial cells in the CNS, undergo significant changes with aging, leading to alterations in their morphology, gene expression, and functional properties ( 81 , 82 ). Concurrently, aging is associated with dysregulation of the immune system, characterized by alterations in immune cell populations, increased production of pro-inflammatory cytokines, and impaired immune responses ( 72 ).…”

From aging to long COVID: exploring the convergence of immunosenescence, inflammaging, and autoimmunity

“…As mentioned above, the Long COVID is a multifaceted condition and the mechanisms underlying autoimmunity in Long COVID are complex and not fully understood ( 72 , 73 , 75 ). Several possible mechanisms have been considered and are summarized in Figure 2 that may contribute to the development of autoimmune-like features in Long COVID patients.…”

“…This prolonged viral antigen presence could continually stimulate the immune system, leading to inflammatory conditions, immune dysregulation, and the development of autoantibodies ( Figure 2D ). In some individuals, this immune response may not return to its normal state even after the virus is cleared, leading to chronic inflammation and autoimmunity ( Figure 2B ) ( 44 , 71 , 75 , 76 ). The concept of inflammaging, characterized by chronic low-grade inflammation, resonates with the persistent inflammation encountered in Long COVID patients.…”