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Although classically considered an energy storage organ, it is becoming increasingly clear that adipose tissue is also an immunologically responsive organ that contributes to systemic inflammation. Adipose tissue remodeling and redistribution into abdominal fat are common features of age-related adipose tissue dysfunction. Importantly, these physiological changes can occur independently of obesity. In addition to increased visceral adiposity, ectopic lipid accumulation in tissues, including bone marrow, the thymus, liver, and muscle increases during healthy aging and can upset normal tissue homeostasis [71].

As adipose tissue inappropriately accumulates in tissues and lymphoid organs, it disrupts tissue architecture, function, and perhaps essential cell-cell communication. Adipose tissue secretes cytokine-like molecules, known as adipokines, such as leptin and adiponectin that modulate immune cell function. Besides these secreted factors, the adipose tissue itself contains a unique immune phenotype [72]. Under steady-state conditions, the adipose contains primarily anti-inflammatory macrophages, γδ T cells, and other innate immune cells with tissue maintenance and reparative properties. However, during aging, the composition of the adipose-resident immune populations become skewed and heavily enriched for proinflammatory macrophages, B cells, and memory T cells [73–75].

Mouse studies indicate that adipose-resident macrophages exhibit particularly intriguing changes during aging. Unlike obesity, in which proinflammatory macrophages increase numerically, aging is accompanied by an overall reduction in the proportion of macrophages in visceral adipose tissue, although the population still manifests a generally proinflammatory phenotype [73]. The macrophages that remain occupy several distinct niches, including crown-like structures surrounding dead or dying adipocytes, scattered in the parenchyma, and lining sympathetic nerves within the adipose tissue [29]. The “aged” macrophages gain a unique transcriptional profile that includes upregulation of enzymes monoamine oxidase A (Maoa) and catechol-O-methyltransferase (Comt) that degrade catecholamines, leading to impaired lipolysis during fasting. This phenotype may also be driven by chronic low-grade inflammation by macrophages, as NLRP3 inflammasome-deficient old mice are protected from lipolysis resistance. Notably, NLRP3-deficient mice are also protected from numerous age-related inflammatory diseases, including aspects of immunosenescence [76, 77], sarcopenia [78], and experimental lung fibrosis [79], highlighting its role as a potential driver of age-related inflammation. While human studies show transcriptional activation of inflammasome gene signatures during aging [78], more studies are needed to formally understand how these proinflammatory immune complexes promote immune senescence during aging.