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.
Mechanisms of Dysfunction in Innate Immune Cells during Aging
For the numerous innate immune defects that develop with age, the impact of tissue milieu on innate immune cells may have particular relevance, but data from humans are limited, and additional novel approaches are desperately needed. Multiple mechanisms that cause cell-intrinsic defects have been identified in experiments using innate immune cells isolated from peripheral blood of elderly and adult donors. Notably, these mechanisms may occur simultaneously within particular cells, or across multiple populations, ultimately disarming the proper function of the aged innate immune system.
Altered Transcription after Stimulation
Transcriptional programming coordinates the proinflammatory programs needed for innate immune control of pathogens. PBMC from healthy aged participants had elevated baseline type 1 interferon gene signature compared to PBMC from younger adults, and levels could not be further induced by influenza vaccination [80]. Younger adult PBMC also showed increased oxidative phosphorylation and mitochondrial biogenesis programs that were absent in older adult PBMC, particularly in older adults that did not respond to vaccination. Circulating isolated monocyte subsets from elderly individuals showed altered transcriptional profiles in response to ex vivo TLR ligand stimulation including exaggerated superoxide and oxidative stress program signatures [81]. A large multicohort analysis showed that baseline gene expression predicts influenza vaccination response in young adults. Fifteen genes (upregulated: RAB24, GRB2, DPP3, ACTB, MVP, DPP7, ARPC4, PLEKHB2, ARRB1; down-regulated: PTPN22, PURA, SP4, CASP6, NUDCD2) were identified in young adults classified as “high responders” to influenza vaccination. These nine upregulated genes were not induced in older individuals, and no genes in older adults were differentially expressed in low and high responders, suggesting distinct responses lead to lower vaccine response in older individuals [82]. Hematopoietic stem cells (HSCs) from older individuals exhibit hypermethylation of the IRF8 locus [83], and thus epigenetic regulatory mechanisms may link the well-known myeloid skewing of HSCs with impaired IFN induction with age [26]. These age-related impairments may contribute to impaired vaccine response and the increased susceptibility of older persons to IAV infection.
Impaired Mer Signaling
TAM receptors (Tyro3, Axl, and Mer) are a family of receptor tyrosine kinases that play critical roles in tissue homeostasis by recognizing and inducing phagocytosis of apoptotic cells. TAMs are also negative regulators of TLR-mediated immune responses that broadly inhibit both TLR and TLR-induced cytokine receptor cascades to limit inflammation [84]. The importance of TAMs in immune activation is illustrated by the observation that reduced levels of TAMs in humans and in a TAM-deficient mouse model are associated with susceptibility to autoimmune disease and higher or chronic inflammation [85–87]. Monocytes from older donors showed elevated expression of TAM receptors but impaired activation of the Mer pathway following binding of the ligand Protein S, leading to impaired signaling through AKT [88]. The elevated expression of TAM receptors in monocytes from older adults has important implications for dysregulation of immune responses in aging, in particular as the Mer pathway is critical for clearance of apoptotic cells that contribute to inflammation in aging [89, 90]. Defective TAM signaling in alveolar macrophages in old mice may also explain impaired phagocytic clearance of apoptotic PMNs and increased mortality during influenza infection [91]. Further, TAMs play a key role in mediating autophagy [84, 85], and the reduced efficiency of autophagy in aging has been shown to contribute to accumulation of damaged proteins in cells [92]. The importance of TAMs in aging may be especially significant in tissue, where levels of Mer are highest, and may present avenues for modulation of chronic tissue inflammation noted in aging.
Reduced RIG-I Signaling
Innate immune cells rely on intracellular sensors known as PRRs to recognize pathogen-associated molecular patterns. One such PRR induced during viral infection by recognition of 5′-triphosphate (5′-ppp) is the RIG-I which induces type 1 IFN to control viral infections. Recent studies of DCs detected lower levels of RIG-I from older human subjects [40], and monocytes from older subjects have significantly diminished IFN-α/β responses to RIG-I stimulation [25]. Total human PBMCs exhibit impaired IFN responses to 5′-ppp RNA transfection relative to younger controls 6 h after stimulation, although in this complex cell population responses were comparable after 24 h [93]. Studies of potential mechanisms mediating these age-associated findings revealed that monocytes from older adults exhibit decreased expression of the adaptor protein TRAF3 as a consequence of