title: Age-associated changes in long-chain fatty acid profile during healthy aging promote pro-inflammatory monocyte polarization via PPARγ.
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 < 30 years) and 21 healthy FA individuals (age > 50 years). 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.
authors.affiliation: Life & Health Sciences, Aston University, Birmingham, B4 7ET, UK.|Aston Research Centre for Healthy Ageing, Aston University, Birmingham, B4 7ET, UK.
authors.forename: Chathyan
authors.initials: C
authors.lastname: Pararasa
authors.affiliation: Life & Health Sciences, Aston University, Birmingham, B4 7ET, UK.
authors.forename: John
authors.initials: J
authors.lastname: Ikwuobe
authors.affiliation: Life & Health Sciences, Aston University, Birmingham, B4 7ET, UK.
authors.forename: Shahjahan
authors.initials: S
authors.lastname: Shigdar
authors.affiliation: Engineering & Applied Sciences, Aston University, Birmingham, B4 7ET, UK.
authors.forename: Alexis
authors.initials: A
authors.lastname: Boukouvalas
authors.affiliation: Aston Research Centre for Healthy Ageing, Aston University, Birmingham, B4 7ET, UK.
authors.forename: Ian T
authors.initials: IT
authors.lastname: Nabney
authors.affiliation: Life & Health Sciences, Aston University, Birmingham, B4 7ET, UK.
authors.forename: James E
authors.initials: JE
authors.lastname: Brown
authors.affiliation: Life & Health Sciences, Aston University, Birmingham, B4 7ET, UK.|Aston Research Centre for Healthy Ageing, Aston University, Birmingham, B4 7ET, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Devitt
authors.affiliation: Life & Health Sciences, Aston University, Birmingham, B4 7ET, UK.|Aston Research Centre for Healthy Ageing, Aston University, Birmingham, B4 7ET, UK.
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Bailey
authors.affiliation: Life & Health Sciences, Aston University, Birmingham, B4 7ET, UK.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Bennett
authors.affiliation: Life & Health Sciences, Aston University, Birmingham, B4 7ET, UK.|Aston Research Centre for Healthy Ageing, Aston University, Birmingham, B4 7ET, UK.
authors.forename: Helen R
authors.initials: HR
authors.lastname: Griffiths
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D002454:Cell Differentiation; D016764:Cell Polarity; D002518:Ceramides / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D050356:Lipid Metabolism / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008297:Male; D009000:Monocytes / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
chemical_list: D002518:Ceramides; D016207:Cytokines; D005227:Fatty Acids; D047495:PPAR gamma; D014409:Tumor Necrosis Factor-alpha
keywords: anti-inflammatory; macrophage; mitochondrial ROS; oleate; oxidative phosphorylation; palmitate