Opinion Metabolic Alterations in Aging Macrophages: Ingredients for Inflammaging? Adriaan A. van Beek, 1,2,3 Jan Van den Bossche, 4,5 Pier G. Mastroberardino, 6 Menno P.J. de Winther, 5,7 and Pieter J.M. Leenen 3, * Aging is a complex process with an impact on essentially all organs. Declined cellular repair causes increased damage at genomic and proteomic levels upon aging. This can lead to systemic changes in metabolism and pro-inflammatory cytokine production, resulting in low-grade inflammation, or ‘inflammaging’. Tissue macrophages, gatekeepers of parenchymal homeostasis and integrity, are prime inflammatory cytokine producers, as well as initiators and regulators of inflammation. In this opinion piece, we summarize intrinsic alterations in macrophage phenotype and function with age. We propose that alternatively activated macrophages (M2-like), which are yet pro-inflammatory, can accu- mulate in tissues and promote inflammaging. Age-related increases in endo- plasmic reticulum stress and mitochondrial dysfunction might be cell-intrinsic forces driving this unusual phenotype. Macrophages and Inflammaging Systemic decline during aging is characterized by various changes at the cellular level, summarized in a landmark review [1]. These features comprise genomic instability, epigenetic (see Glossary) changes, increased protein misfolding, mitochondrial dysfunction, and dysregulated nutrient sens- ing. Moreover, the ability to restore homeostasis via proteasomal degradation, the unfolded protein response (UPR) and autophagy decrease with aging, leading to fragile conditions in which cells lose proper function and either die or enter a senescent state [2,3]. This can be accompanied by systemically increased pro-inflammatory factors such as IL-1, IL-6, IL-8, TNF, and C-reactive protein [4]. While these mediators serve a homeostatic role in acute inflammation, their chronic elevation has been associated with diseases such as diabetes, atherosclerosis, or autoimmunity. In some cases, senescent tissue cells can secrete a variety of inflammatory cytokines and chemokines, a phenomenon described as the senescence-associated secretory pheno- type (SASP) [5] . It is undecided whether these SASP-positive parenchymal cells are the major cellular sources of ‘inflammaging’ mediators, or whether activated immune cells are critical contributors to the increasing concentrations of such mediators in the steady state during aging. Macrophages are critical regulators of processes aimed at maintaining homeostasis and prominently contribute to inflammatory and immune responses, but also help maintain meta- bolic stability [6]. Direct evidence on the role of macrophages in determining life span and inflammaging is scarce. A study in Drosophila showed a link between reduction in life span by a lipid-rich diet and increase of the macrophage-derived cytokine encoded by upd3 [7]. Silencing of upd3 in macrophages rescued insulin sensitivity and life span [7]. In addition, long-term selective elimination of macrophages in aging mice has been shown to inhibit peripheral nerve degeneration and reduction in muscle strength [8]. Moreover, macrophage depletion in aged mice can prevent strongly increased pro-inflammatory cytokine concentrations and deaths of Highlights Aging is associated at the cellular level with several adaptations, fueled by increasing damage and reduced capacity for repair. This generates a condition of low-grade inflammation, called ‘ inflammaging’ . Macrophages are prime cells in initia- tion and regulation of inflammatory processes and may thus play major roles in inflammaging. Macrophage polarization and activa- tion, induced by intrinsic or extrinsic conditions, are reflected in and regu- lated by the cells’ metabolic and epi- genetic profiles. Age-induced changes in macro- phages are diverse and, in general, may represent pro-inflammatory acti- vation of cells with an alternatively acti- vated (M2-like) phenotype. 1 Top Institute Food and Nutrition, Nieuwe Kanaal 9A, 6709 PA Wageningen, The Netherlands 2 Cell Biology and Immunology Group, Wageningen University, De Elst 1, 6709 PG Wageningen, The Netherlands 3 Department of Immunology, Erasmus University Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands 4 Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Amsterdam Cardiovascular Sciences, Cancer Center Amsterdam, De Boelelaan 1117, Amsterdam, Netherlands 5 Amsterdam UMC, University of Amsterdam, Experimental Vascular Biology, Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, TREIMM 1536 No. of Pages 15 Trends in Immunology, Month Year, Vol. xx, No. yy https://doi.org/10.1016/j.it.2018.12.007 1 © 2018 Elsevier Ltd. All rights reserved.