Pararasa Chathyan, Ikwuobe John, Shigdar Shahjahan, Boukouvalas Alexis, Nabney Ian T, Brown James E, Devitt Andrew, Bailey Clifford J, Bennett Stuart J, Griffiths Helen R
Life & Health Sciences, Aston University, Birmingham, B4 7ET, UK.
Aston Research Centre for Healthy Ageing, Aston University, Birmingham, B4 7ET, UK.
Aging Cell. 2016 Feb;15(1):128-39. doi: 10.1111/acel.12416. Epub 2015 Nov 2.
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.
脂质代谢差异与年龄相关疾病的发展及寿命有关。炎症是代谢失调与衰老之间的常见联系。饱和脂肪酸（FAs）可引发包括单核细胞在内的许多细胞的促炎信号传导；然而，现有研究尚未量化与炎症表型相关的个体脂肪酸随年龄的变化。因此，我们通过气相色谱法测定了26名健康年轻个体（年龄<30岁）和21名健康老年个体（年龄>50岁）中不同脂肪酸的血浆浓度。使用线性混合模型来探讨循环脂肪酸、年龄和细胞因子之间的关联。我们发现血浆饱和脂肪酸、多不饱和脂肪酸和单不饱和脂肪酸随年龄增加。循环肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）浓度随年龄增加，而白细胞介素-10（IL-10）和转化生长因子-β1（TGF-β1）浓度降低。老年成年人白细胞中MitoSOX Red的氧化水平更高，血浆氧化型谷胱甘肽浓度也更高。血浆饱和脂肪酸之间存在显著共线性，表明它们的代谢关系。饱和脂肪酸C18:0和C24:0水平较高与较低的TGF-β1浓度相关，而C16:0水平较高与较高的TNF-α浓度相关。我们进一步研究了衰老脂肪酸谱对THP1单核细胞中单核细胞极化和代谢的影响。预先用C16:0孵育的单核细胞在佛波酯肉豆蔻酸酯乙酸盐诱导的分化过程中，通过神经酰胺依赖性抑制PPARγ活性，增加了促炎细胞因子的分泌。相反，C18:1诱导了一种具有促分解作用的巨噬细胞，这种巨噬细胞依赖PPARγ和神经酰胺，并且需要氧化磷酸化。这些数据表明，中年成年人的脂肪酸谱通过代谢重编程损害了从促炎状态向低能量、需要抗炎巨噬细胞状态的转变。
