Inflammaging

Inflammaging was coined by Franceschi et al. in 2000, representing a newer dimension to aging studies and decrees that the aging process has a chronic progressive proinflammatory phenotype (Franceschi et al., 2000). Inflammaging plays an increasingly important role in the rate of aging and age-related diseases. Research in this area has attracted attention of academics in diverse fields of study that have made significant impacts in the past decade. In this thematic issue, we present manuscripts representing varied fields of study that capture aspects of inflammaging. We also discuss the relationship of inflammaging with various diseases described below that suggest potential novel interventions to delay or prevent inflammaging-related diseases.

Briefly, from a theoretical perspective, inflammaging is the expansion of the network theory of aging and the remodeling theory of aging (Franceschi, 1989, Franceschi et al., 1995). The network theory of aging hypothesizes that aging is indirectly controlled by the network of cellular and molecular defense mechanisms. The remodeling theory, which was implied to explain immunosenescence, is the gradually adaptive process of the body with a net result controlling malignant damage resulting in a trade-off with immunity. In the process of aging, some scholars suggest that the process where adaptive immunity declines is called immunosenescence, whereas when innate immunity is activated causing an increased pro-inflammatory state be termed inflammaging (Salminen et al., 2008). Others regard the chronic inflammatory process with age as inflammaging (Mishto et al., 2003), while others proposed the oxidation-inflammation theory of aging (De la Fuente and Miquel, 2009). Despite the lack of agreement on definitions and terminology, the prevailing consensus that the primary feature of inflammaging is an increase in the proinflammatory status with advancing age.

Although chronic inflammation is well established with obesity and metabolic syndrome (Monteiro and Azevedo, 2010), study populations are usually not focused on aged populations. In the elderly population, the relationship of obesity and disease-specific mortality remains controversial. In the first manuscript in this thematic issue of Immunological Investigations, Crotti et al. consider the long-standing association of obesity and inflammaging in a well-characterized Italian cohort of elderly individuals. This prospective study utilized nearly 5,000 patient subjects and compared BMI and mortality risk where they hypothesized that low-grade inflammation (LGI) may increase the mortality risk. Interestingly, these observed that overweight elderly individuals had a decreased risk of mortality, whereas severely obese elderly populations had an increased risk of death.

The next original manuscript considers specific molecular mechanisms where proinflammatory mediators may be differentially regulated with age. Specifically, microRNAs (miRNAs) regulate gene expression usually by binding the 3ʹ untranslated region (3ʹUTR) of target genes. Recent evidence suggests that miRNAs may regulate immune cells in aged mice (Olivieri et al., 2014). In the next paper in this thematic issue, the authors show that miR-350-3p contributes to age-associated impairment of IL-6 production by macrophages (Huiyang,C., Xu,W, Shusheng, Y.). Aging-associated miRNAs are largely negative regulators of the immune innate response and target central nodes of aging-associated networks, in particular, NF-κB, the downstream effector of TLR signals that leads to induction of proinflammatory responses. In the manuscript by Huiying et al., they address the role of miR-350-3p in regulation of IL-6 expression in aged vs. young mice where miRNA-350-3p decreases with age, permitting increased IL-6 expression with age. Their findings provide new evidence for age-specific therapeutic targets in inflammaging.

In the next paper, a review article by Amsterdam and Ostrov (2018), the impact that the microbiome has on the immunosenescence is presented. Although it has long been appreciated the gut microbiome educates the immune system (Belkaid and Hand, 2014, Belkaid and Harrison, 2017, Molloy et al., 2012), considerably less appreciated is how the gut microbiome can shape the immune system with age. The gut microbiome is known to be different in the elderly populations, and this review highlights the interaction ofthe human microbiome and the immune system and immunosenescence with age. These changes highlight the implications of age-related immunosenescence in health and disease in this expanding elderly population.

The next review article by Shahrokhi et al. considers the role of inflammaging in Alzheimer’s disease. Although inflammaging has long been considered part of the etiology of Alzheimer’s, the role of specific immune cytokines is still an active area of investigation (Wyss-Coray and Rogers, 2012). This review discusses the plausible role of damage-associated molecular patterns (DAMPs) in initiation of age-associated inflammation and considers the specific role of IL-17A and IL-23 in the Alzheimer’s degenerative process. Their discussion also includes novel insights into how this neuroinflammation can be therapeutically addressed in future studies.

Fontana et al. (2018) review the biological markers of oxidative stress in cardiovascular diseases. The cellular mechanisms involved in the pathogenesis of myocardial ischemia/reperfusion injury are complex and involve the interaction of a number of cell types, including coronary endothelial cells, circulating blood cells (e.g., leukocytes, platelets), and cardiac myocytes, most of which are capable of generating reactive oxygen species (ROS) (Lefer and Granger, 2000). These ROS have the potential to injure vascular cells and cardiac myocytes directly, and can initiate a series of local chemical reactions and genetic alterations that ultimately result in an amplification of the initial ROS-mediated cardiomyocyte dysfunction and/or cytotoxicity. A key component of the amplification cascade that leads to irreversible tissue damage is the production of factors that promote the recruitment and activation of circulating inflammatory cells (Lefer and Granger, 2000). Despite understanding of this mechanism, oxidative stress biomarker studies have measured a diverse array of inflammatory mediators by a variety of methods, making it difficult to make conclusions that can be generalized. The authors discuss the issues that have led to the interest in anti-oxidant foods yet the direct proof of oxidative stress by validated biomarker studies is still lacking.

The final review of this thematic issue, by Kirkwood et al. (2018) discuss the role of inflammaging on the age-related expansion of a specific myeloid cell population called myeloid-derived suppressor cells (MDSCs) and how this population can contribute bone loss and fragility. We and others have shown that MDSCs can directly become osteoclasts and resorb bone matrix under specific conditions (Sawant and Ponnazhagan, 2013, Steinkamp et al., 2018). In this context, we discuss how MDSCs are potentially engaged in reduction of bone mass/strength independent of loss of sex steroids in aged mice and potentially humans.

In summary, all the topics selected to be published in this thematic issue on inflammaging, address important questions and concerns related to the involvement of the immune system in health and disease during the aging process. The role that inflammaging plays in the pathophysiology of a disease process will dictate the direction of age-dependent therapeutics that may be beneficial for the diagnosis or treatment of these pathologies.

Conflict of Interest

None is declared

Additional information

Funding

This work was supported by the National Institutes of Health (NIH) grant [1 R01 DE028258-01].