Abstract
Differences in lipid metabolism associate with age-related disease development and lifespan. Inflammation is a common link between metabolic dysregulation and aging. Saturated fatty acids (FAs) initiate pro-inflammatory signalling from many cells including monocytes; however, no existing studies have quantified age-associated changes in individual FAs in relation to inflammatory phenotype. Therefore, we have determined the plasma concentrations of distinct FAs by gas chromatography in 26 healthy younger individuals (age<30years) and 21 healthy FA individuals (age>50years). Linear mixed models were used to explore the association between circulating FAs, age and cytokines. We showed that plasma saturated, poly- and mono-unsaturated FAs increase with age. Circulating TNF-α and IL-6 concentrations increased with age, whereas IL-10 and TGF-β1 concentrations decreased. Oxidation of MitoSOX Red was higher in leucocytes from FA adults, and plasma oxidized glutathione concentrations were higher. There was significant colinearity between plasma saturated FAs, indicative of their metabolic relationships. Higher levels of the saturated FAs C18:0 and C24:0 were associated with lower TGF-β1 concentrations, and higher C16:0 were associated with higher TNF-α concentrations. We further examined effects of the aging FA profile on monocyte polarization and metabolism in THP1 monocytes. Monocytes preincubated with C16:0 increased secretion of pro-inflammatory cytokines in response to phorbol myristate acetate-induced differentiation through ceramide-dependent inhibition of PPARγ activity. Conversely, C18:1 primed a pro-resolving macrophage which was PPARγ dependent and ceramide dependent and which required oxidative phosphorylation. These data suggest that a midlife adult FA profile impairs the switch from proinflammatory to lower energy, requiring anti-inflammatory macrophages through metabolic reprogramming.
Highlights
During aging, there is a redistribution of body fat away from subcutaneous stores to other depots including muscle and viscera (Pararasa et al, 2014)
Visceral adipose tissue is less efficient in storing fatty acid (FA) and there is a concomitant increase in circulating free fatty acids (FFA) that promote insulin resistance leading to elevated blood glucose concentrations and risk for type 2 diabetes (T2DM) (Carlsson et al, 2000; Pilz et al, 2006)
We limited our study to males to exclude the confounding effects of hormonal changes in peri-/menopausal older women; for example the decline in oestrogen concentration with age associates with monocyte activation, an increase in very low density lipoprotein (VLDL) and triglycerides and decrease of high density lipoprotein (HDL) in menopausal women
Summary
Differences in lipid metabolism associate with age-related disease development and lifespan. Saturated fatty acids (FAs) initiate pro-inflammatory signalling from many cells including monocytes; no existing studies have quantified age-associated changes in individual FAs in relation to inflammatory phenotype. We showed that plasma saturated, polyand mono-unsaturated FAs increase with age. Circulating TNF-a and IL-6 concentrations increased with age, whereas IL-10 and TGF-b1 concentrations decreased. Monocytes preincubated with C16:0 increased secretion of pro-inflammatory cytokines in response to phorbol myristate acetate-induced differentiation through ceramide-dependent inhibition of PPARc activity. C18:1 primed a pro-resolving macrophage which was PPARc dependent and ceramide dependent and which required oxidative phosphorylation. These data suggest that a midlife adult FA profile impairs the switch from proinflammatory to lower energy, requiring anti-inflammatory macrophages through metabolic reprogramming.
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