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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., (© 2023. The Author(s).)

Both reactive oxygen species (ROS) from redox-biology and pro-inflammatory cytokines from innate immunity/and other sources, in addition to their role in redox-biology, and in defense and repair, have long been regarded as potentially harmful factors associated with oxidative stress and inflammatory states. However, their important physiological functions as signaling molecules have been demonstrated to be of importance, also in Geroscience, particularly when ROS are at balanced basal levels (redox-biology) and pro-inflammatory cytokines are at very low levels (cold-inflammaging). Under these conditions, both of these components (alone or in combination) may act as signaling/response molecules involved in regulating/maintaining or restoring adaptive homeostasis during aging, particularly in the early phases of even very-mild non-damaging internal or external environmental stimuli that could nevertheless elicit low-grade warnings-signals for homeostatic stability. If signals potentially perturbing homeostasis persist, the levels of ROS and pro-inflammatory mediators increase resulting in a switch from adaptive to maladaptive responses which may lead to oxidative stress and overt-inflammaging (or even to an overt inflammatory state), thus paving the way to the risks of aging-related diseases (ARDs). Conversely, upon adaptive-responses, low-levels of ROS and very-low-levels of pro-inflammatory-cytokines, alone or in combination, can result in an amplified capacity to prevent or slow-down overt-inflammaging (2-fold to 4-fold increase of pro-inflammatory cytokines) thus maintaining or restoring homeostasis. Therefore, these signaling molecules may also have the sequential incremental potential to prevent or slow the subsequent decline of adaptive homeostasis that will occur later in the lifespan. These scenarios may lead us to conceive of, and conceptualize, both these molecules and their basal-low levels, as well as their dynamics and the time-course of responses, as 'potential important pillars of adaptive-homeostasis in aging' since the earliest phases of the occurrence of any even very- mild environmental potential imbalance., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The age-related pro-inflammatory state, discovered and called 'inflammaging' by Franceschi et al. (2000) plays an important role in the pathogenesis of age-related chronic diseases. A substantial body of data established that inflammaging is accompanied by a '2-fold to 4-fold' increase in plasma levels of pro-inflammatory mediators in healthy elderly people, when compared to the healthy adult population. This review focuses on the pre-inflammaging phase, here we reported as 'cold-inflammaging', a state where plasma levels of cytokines are slightly increased, but below the lower limit of 2-fold increase established for inflammaging. Slightly altered cytokine levels by innate immunity are known to be associated with homeostasis imbalances, this functional pleiotropy of cytokines as signal transducers, have a physiological counterpart, representing an adaptive process aimed at restoring (or achieving a new) homeostatic stability. If a dyshomeostatic state persists, the cytokine response by innate immunity increases and becomes a driver of inflammaging. A scenario where cytokines are characterised as major players in homeostasis imbalances at the beginning (cold-inflammaging) and then in chronic low-grade pro-inflammatory-state (inflammaging). Other important drivers of inflammaging are cellular senescence with its senescence-associated secretory phenotype, the altered gut microbiota, and the age-related dysregulation in the production of endogenous molecular waste (Garb-aging). The main purpose of this review being to thoroughly investigate each step of the pathway from cold-inflammaging to overt-inflammaging, because aging, cold-inflammaging, overt-inflammaging and the pathogenesis of age-related diseases have been shown to share some established basic pillars of geroscience that largely converge on inflammaging., (© 2022 John Wiley & Sons Australia, Ltd.)

Previous studies on the longevity effect of pyrroloquinoline quinine (PQQ) on nematode worms have revealed that PQQ can enhance the antioxidant capacity of nematode worms, thus extending the lifespan of the worms. The induction and development of cellular senescence are closely connected with inflammatory reactions. The aim of this study was to determine the effect of PQQ and ageing factors on senescent cells. To this end, we cultivated human embryonic lung fibroblasts in nutrient solution with or without tumour necrosis factor-alpha (TNF-α) to establish an inflammaging model in vitro. The cells were preincubated with or without PQQ to determine if PQQ had any anti-inflammaging effect. More senescent cells were detected with the addition of TNF-α than without (P < .01). The ratio of senescent cells to non-senescent cells in the TNF-α group was greater than that in the control group (P < .01). When cells were preincubated with PQQ prior to TNF-α treatment, there were fewer senescent cells than those in the control group, which was not pretreated with PQQ (P < .05). The same tendency was noted with regard to p21, p16, and Jagged1. In summary, we used TNF-α, a well-known pro-inflammatory cytokine associated with inflammaging, to establish an in vitro inflammaging model and provided evidence that PQQ delays TNF-α -induced cellular senescence and has anti-inflammaging properties., (© 2019 John Wiley & Sons Australia, Ltd.)

Inflamm-aging is a challenging and promising new branch of aging-related research fields that includes areas such as immunosenescence. Increasing evidence indicates that inflamm-aging is intensively associated with many aging diseases, such as Alzheimer's disease, atherosclerosis, heart disease, type II diabetes, and cancer. Mounting studies have focused on the role of inflamm-aging in disease progression and many advances have been made in the last decade. However, the underlying mechanisms by which inflamm-aging affects pathological changes and disease development are still unclear. Here, we review studies of inflamm-aging that explore the concept, pathological features, mechanisms, intervention, and the therapeutic strategies of inflamm-aging in disease progression.

Age is an independent risk factor of cardiovascular disease, even in the absence of other traditional factors. Emerging evidence in experimental animal and human models has emphasized a central role for two main mechanisms of age-related cardiovascular disease: oxidative stress and inflammation. Excess reactive oxygen species (ROS) and superoxide generated by oxidative stress and low-grade inflammation accompanying aging recapitulate age-related cardiovascular dysfunction, that is, left ventricular hypertrophy, fibrosis, and diastolic dysfunction in the heart as well as endothelial dysfunction, reduced vascular elasticity, and increased vascular stiffness. We describe the signaling involved in these two main mechanisms that include the factors NF-κB, JunD, p66(Shc), and Nrf2. Potential therapeutic strategies to improve the cardiovascular function with aging are discussed, with a focus on calorie restriction, SIRT1, and resveratrol.

The aim of the study was to investigate the effect of icariin (ICA) on cardiac aging through its effects on the SIRT6 enzyme and on the NF-κB pathway. Investigating the effect of ICA on the enzymatic activity of histone deacetylase SIRT6 revealed a concentration of 10−8 mol/L ICA had a maximum activating effect on histone deacetylase SIRT6 enzymatic activity. Western analysis showed that ICA upregulated SIRT6 protein expression and downregulated NF-κB (p65) protein expression in animal tissues and cell models. ICA upregulated the expression of SIRT6 and had an inhibitory effect on NF-κB inflammatory signaling pathways as shown by decreasing mRNA levels of the NF-κB downstream target genes TNF-α, ICAM-1, IL-2, and IL-6. Those effects were mediated directly or indirectly by SIRT6. We provided evidence that inflammaging may involve a novel link between the effects of ICA on SIRT6 (a regulator of aging) and NF-κB (a regulator of inflammation). [ABSTRACT FROM AUTHOR]

Particulate matter (PM)-induced airway inflammation contributes to the development and exacerbation of chronic airway diseases. Circular RNA (circRNA) is a new class of non-coding RNA that participates in gene regulation in various respiratory diseases, but the regulatory role of circRNA in PM-induced airway inflammation has not been fully elucidated. In this study, we performed the human circRNA microarray to reveal differentially expressed circRNAs in PM-induced human bronchial epithelial cells (HBECs). A total of 176 upregulated and 15 downregulated circRNAs were identified. Of these, a new circRNA termed circTXNRD1 was upregulated by PM exposure in a dose- and time-dependent manner. Knockdown of circTXNRD1 significantly attenuated PM-induced expression of proinflammatory cytokine interleukin 6 (IL-6). CircRNA pull-down, dual-luciferase reporter assay and fluorescence in situ hybridization showed that circTXNRD1 acted as an endogenous sponge to decrease miR-892a levels in HBECs. Downregulation of miR-892a could increase cyclooxygenase-2 (COX-2) expression and eventually promote IL-6 secretion in PM-induced HBECs. Taken together, our findings reveal circTXNRD1 as a novel inflammatory mediator in PM-induced inflammation in HBECs via regulating miR-892a/COX-2 axis. These results provide new insight into the biological mechanism underlying PM-induced inflammation in chronic airway diseases. [Display omitted] • The differential circRNAs expression profile was identified in PM-exposed HBECs. • The circTXNRD1 was significantly upregulated by PM in HBECs. • The circTXNRD1 promoted PM-induced inflammation via miR-892a/COX-2 axis in HBECs. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) is a new infectious respiratory disease, which has caused a pandemic that has become the world's leading public health emergency, threatening people of all ages worldwide, especially the elderly. Complications of COVID-19 are closely related to an upregulation of the inflammatory response revealed by the pro-inflammatory profile of plasma cytokines (to the point of causing a cytokine storm), which is also a contributing cause of the associated coagulation disorders with venous and arterial thromboembolisms, causing multiple organ dysfunction and failure. In severe fulminant cases of COVID-19, there is an activation of coagulation and consumption of clotting factors leading to a deadly disseminated intravascular coagulation (DIC). It is well established that human immune response changes with age, and also that the pro-inflammatory profile of plasma cytokines is upregulated in both healthy and diseased elderly people. In fact, normal aging is known to be associated with a subclinical, sterile, low-grade, systemic pro-inflammatory state linked to the chronic activation of the innate immune system, a phenomenon known as "inflammaging". Inflammaging may play a role as a condition contributing to the co-occurrence of the severe hyper-inflammatory state (cytokine storm) during COVID-19, and also in other severe infections (sepsis) in older people. Moreover, we must consider the impact of inflammation on coagulation due to the crosstalk between inflammation and coagulation. The systemic inflammatory state and coagulation disorders are closely related, a phenomenon that here we call "coagul-aging" (Giunta S.). In this review, we discuss the various degrees of inflammation in older adults after being infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the adverse effects of aging on the inflammatory response and coagulation system. It is important to note that although there is no gender difference in susceptibility to COVID-19 infection, however, due to differences in angiotensin-converting enzyme 2 (ACE2) expression, innate immunity, and comorbidities, older men exhibit more severe disease and higher mortality than older women. There are currently no FDA-approved specific antiviral drugs that can be used against the virus. Therapies used in patients with COVID-19 consist of remdesivir, dexamethasone, low-molecular-weight heparin, in addition to monoclonal antibodies against the spike protein of SARS-CoV-2 in the early phase of the disease. Future pharmacological research should also consider targeting the possible role of the underlying scenario of inflammaging in healthy older people to prevent or mitigate disease complications. It is worth mentioning that some specific cytokine antagonists and traditional Chinese medicine preparations can reduce the elderly's inflammatory state. • The elderly have seriously been threatened in this COVID-19 epidemic, especially older men. • Inflammaging and coagul-aging are important factors for the poor prognosis of the elderly. • Some specific cytokine antagonists and traditional Chinese medicine preparations can alleviate the inflammatory state. [ABSTRACT FROM AUTHOR]