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Murdaca, G.; Paladin, F.; Casciaro, M.; Vicario, C.M.; Gangemi, S.; Martino, G. Neuro-Inflammaging and Psychopatological Distress. Encyclopedia. Available online: (accessed on 05 December 2023).
Murdaca G, Paladin F, Casciaro M, Vicario CM, Gangemi S, Martino G. Neuro-Inflammaging and Psychopatological Distress. Encyclopedia. Available at: Accessed December 05, 2023.
Murdaca, Giuseppe, Francesca Paladin, Marco Casciaro, Carmelo Mario Vicario, Sebastiano Gangemi, Gabriella Martino. "Neuro-Inflammaging and Psychopatological Distress" Encyclopedia, (accessed December 05, 2023).
Murdaca, G., Paladin, F., Casciaro, M., Vicario, C.M., Gangemi, S., & Martino, G.(2023, June 26). Neuro-Inflammaging and Psychopatological Distress. In Encyclopedia.
Murdaca, Giuseppe, et al. "Neuro-Inflammaging and Psychopatological Distress." Encyclopedia. Web. 26 June, 2023.
Neuro-Inflammaging and Psychopatological Distress

Inflammaging is a low degree of chronic and systemic tissue inflammation associated with aging, and is intimately linked to pro-inflammatory mediators. These substances are involved in the pathogenesis of chronic inflammatory diseases and related psychopathological symptoms. Aging and inflammation have been defined in their interplay since the 1991 New York Academy of Sciences conference by a group of researchers. It ihas been suggested that  biological, chemical, and physics damage led to a chronic inflammatory process. The link between the molecular and cellular balance capable of permitting a physiological healthy aging or a cognitive impairment is still unclear. The innate immune system plays a crucial role in the inflammatory processes, usually reduced at advanced ages. In the elderly, senescent microglia augment the production of proinflammatory mediators with reduced chemotaxis and phagocytosis capacities, particularly of amyloid-β fibrils. The raised systemic inflammatory state and peripheral immunosenescence interfere with neuronal immune cell activity and reactivity.

chronic inflammatory diseases inflammaging pro-inflammatory cytokines

1. Introduction

In recent decades there has been a progressive increase in the prevalence of chronic diseases, mainly due to an ever-increasing life expectancy. Aging and chronic diseases find their fil rouge in chronic inflammation.

Aging and inflammation have been defined in their interplay since the 1991 New York Academy of Sciences conference by a group of researchers [1]. Among these, Claudio Franceschi conceptualized the word "inflammaging". He and his group elaborated that a constantly growing survival together with the aging process affected by a biological, chemical, and physics damage led to a chronic inflammatory process. Longevity is a characteristic of modern industrialized society, and successful aging is the key to countering destructive processes due to several causes and contributing to organ damage. Franceschi et al. also speculated a series of defensive systems against chronic inflammatory injuries in the elderly, called "anti-inflammaging". They evaluated centenarians who were able to escape the diseases typical of advanced ages. These kinds of subjects were defined as "escapers" [2][3].

Although different tissues and organs are usually targeted by long-term inflammation, one of the most sensitive due to its limited renewal capacity is the brain. Neurodegenerative diseases are a direct consequence. The link between the molecular and cellular balance capable of permitting a physiological healthy aging or a cognitive impairment is still unclear.

The actual models suggest that exposure during lifespan to several exogenous and endogenous insults triggers an immune response, inducing a state of chronic physiological inflammation that is protective for long-term survival at certain levels. As mentioned above, a systemic inflammatory state defines a phenotype typical of successful aging. Also, neurodegeneration is affected by an age-related increase in inflammation, with simultaneous adaptive activation of anti-inflammation procedures [4].

The innate immune system plays a crucial role in the inflammatory processes, usually reduced at advanced ages. Sometimes, also hyperreactivity could be age-associated. Microglia are main actors among the resident immune cells in the brain. In the elderly, senescent microglia augment the production of proinflammatory mediators with reduced chemotaxis and phagocytosis capacities, particularly of amyloid-β fibrils [5]. Geriatric microglia amass mitochondrial DNA with detrimental effects on cells leading to ROS accumulation and sustaining further damages.

Also, the reduced effectiveness of the adaptive immune system contributes to declined immune response versus biological threats [6].

The raised systemic inflammatory state and peripheral immunosenescence interfere with neuronal immune cell activity and reactivity. The consequence is a chronic low-grade inflammatory condition called neuro-inflammaging. The activated glia in a loop sustained by cytokines, oxidative stress, and damage is mainly involved in memory loss and cognitive decline. Immunosenescence and inflammaging induce brain suffering, with the subsequent spread of clinical psychological signs and symptoms such as cognitive impairment, behavior alteration, or mental disorders [7].

This pervasive process of aging, known as "inflammaging", is characterized by a low degree of chronic and systemic tissue inflammation, revealed by high levels of some biomarkers such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFa) [1]. Growing evidence has drawn attention to the potential role of these and other inflammatory mediators in the pathogenesis of chronic inflammatory diseases and related psychopathological symptoms, such as depression, anxiety, and alexithymia as pervasive and worsening symptoms and signs of the organic pathology. Chronic neuroinflammation plays a primary pathophysiological role in developing neurotoxic alterations of those brain regions involved in emotional regulation, contributing i.e. to the development of major depressive disorder (MDD) [8].

Based on the role of the neuro-inflammatory process, this assessment focuses on the connection between chronic inflammatory diseases commonly found in older individuals (known as neuro-inflammaging) and psychopathological symptoms. The emphasis is on comprehending the immune-pathogenetic mechanisms involved and exploring the potential application of immunomodulatory drugs in addressing clinical psychological indicators [7].

2. Correlation between Depression and Other Psychopathological Disorders in Chronic Inflammatory Diseases

According to Maes’ “theory of cytokine-induced depression” [9], inflammatory factors play a crucial role in the onset symptoms of psychopathological diseases as they are capable of altering the metabolism of biogenic monoamines involved in their pathogenesis, i.e., dopamine, noradrenaline and serotonin in the mesencephalic nuclei [10][11].
It follows that both depression and some chronic inflammatory diseases such as cardiovascular diseases, respiratory diseases, metabolic disorders and autoimmune diseases have the same immunological background. These chronic diseases represent not only the risk factors for a depressive episode, but also factors of resistance to psychoactive therapies and favoring relapses of episodes of deteriorated mood [12][13]. Recent studies have in fact highlighted how the use of mood stabilizers was associated with lower IL-6 levels at the follow-up of patients with major depressive disorder [14].
Subsequent studies have shown associations between cytokine production and the presence of both depressive and anxious symptoms, in relation to adjustments for favoring factors such as smoking and alcohol intake. Specifically, lipopolysaccharide-stimulated inflammation (LPS) was more consistently associated with anxiety levels in which the presence of pro-inflammatory factors such as IL-6, IL-8, IL-10, IL-18, MCP-1, MMP2 and TNF-β prevails, with respect to depressive symptoms, in which molecules such as IL-8, MCP-1 and MMP2 prevail [15][16][17][18].
Similarly, patients with elevated CRP levels appear to be associated with greater symptom severity, a specific pattern of depressive symptoms, and worse response to treatment. Additionally, approximately one-third of depressed patients exhibited low-grade inflammatory status (i.e., CRP > 3.0 mg/L), suggesting the presence of a different subgroup of Major Depressive Disorder (MDD) with distinct etiopathogenesis, and prognosis, which could potentially respond to anti-inflammatory treatments [19][20].
Depressive disorders are predominantly associated with some chronic inflammatory/autoimmune diseases. This is what happens, for example, in rheumatoid arthritis, where depression represents an important co-morbidity which is more represented, compared to the general population [21].
Even in patients with chronic obstructive pulmonary disease (COPD) with depression in comorbidities there was an increase in the concentration of inflammatory markers such as IL-1 and TNF-α salivary and a decrease in salivary cortisol. In particular, IL-1 and TNF-α showed a significant positive correlation with the severity of depression, while salivary cortisol showed a negative correlation with the severity of depression in the COPD patients [22].
Another relevant factor that has been shown to negatively influence the extent of depressive symptoms and which seems to share the inflammatory pattern and the correlation with various chronic inflammatory diseases, is represented by alexithymia, the difficulty in identifying, recognizing, distinguish, and express the own and others feelings [23][24][25][26]. Similarly, with specific regard to alexithymia, recent studies highlighted a pathogenetic correlation with specific inflammatory markers such as TNF-α and IL-6 exists [27][28][29][30][31][32]. Finally, it should be mentioned the literature reporting the negative influence of chronotype on depressive symptoms [33], which also significantly predicts the risk to develop anxiety disorders [34] and inflammatory diseases, such as Irritable Bowel Syndrome [35]. All these studies have associated late chronotype with a higher risk for the above-mentioned clinical conditions.


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