Aging, Obesity, and Inflammatory Age-Related Diseases

Abstract

The increase in the prevalence of obesity represents a worldwide phenomenon in all age groups and is pathologically and genetically correlated with several metabolic and cardiovascular diseases, representing the most frequent age-related diseases. Obesity superimposed on aging drastically increases chronic low-grade inflammation (inflammaging), which is an important link between obesity, insulin resistance, and age-associated diseases. Immune cells of both the innate and the adaptive immune systems infiltrate the adipose tissue (AT) and during obesity induce inflammatory responses associated with metabolic switches and changes in phenotypes and function of immune cell subsets. Obesity poses new health problems especially when it occurs in the context of other diseases, many of them frequently affect elderly subjects. An emerging problem is the decreased proportion of patients with obesity achieving clinical response to therapy. In this review, we will discuss the reciprocal influences of immune cell and AT inflammation in aging and age-associated diseases and the complex relationship of nutrient and energy-sensing homeostatic checkpoints, which contribute to shape the phenotype of the AT. We will specifically examine type-2 diabetes, rheumatoid arthritis, osteoarthritis, cognitive impairment, and dementia, where obesity plays a significant role, also in shaping some clinical aspects.

Keywords: aging; inflammation; obesity; rheumatoid arthritis; type-2 diabetes.

Figure 1

Model for regulation of inflammatory pathways in the obese adipose tissue (AT). Adipocytes (AD) in the obese AT are highly inflammatory and secrete several pro-inflammatory cytokines and chemokines, which recruit immune cells, thus contributing to the establishment and maintenance of local and systemic inflammation. Among these inflammatory mediators, tumor necrosis factor (TNF)-α released by both AD and immune cells induces lipolysis and release of free fatty acids (FFAs), which activate tissue-resident macrophages (MΦ) to release cytokines and chemokines. FFAs are also released in blood and cause both insulin resistance and inflammation in major insulin target tissues. Immune cells recruited to the obese AT differentiate into inflammatory subsets and secrete additional pro-inflammatory mediators. We hypothesize that these cells would generate suboptimal immune responses in obese individuals by circulating to peripheral lymphoid organs. Pathogenic antibodies may be secreted by B cells in the AT. These antibodies may form immune complexes with “self”-antigens, which in turn activate complement and Fc receptors on immune cells, leading to enhanced local inflammation, remodeling of the AT, impairment of adipocyte function and nutrient metabolism, and exacerbation of obesity-associated conditions. These antibodies can also exert additional detrimental effects both locally and systemically targeting distinct clusters of self proteins. One mechanisms for the release of “self”-antigens in the obese AT is the decreased supply of oxygen, resulting in areas of hypoxia, which leads to further release of pro-inflammatory cytokines, as well as to the release of “self”-antigens, such as intracellular proteins, cell-free DNA, and lipids.