Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Belfer 709, Bronx, NY 10461, USA.
J Gerontol A Biol Sci Med Sci. 2012 Dec;67(12):1321-8. doi: 10.1093/gerona/gls200. Epub 2012 Oct 22.
Human aging is associated with heightened risk of diabetes and cardiovascular disease. Increased fat mass may contribute to age-related diseases by harboring inflammatory macrophages that produce metabolically important proteins such as plasminogen activator inhibitor-1 (PAI-1). Elevated PAI-1 concentrations have been implicated in the pathogenesis of such aging-related conditions as insulin resistance, obesity, and atherosclerosis. We have previously reported that increased plasma free fatty acid (FFA) concentrations augment both circulating PAI-1 concentrations and PAI-1 production by adipose tissue macrophages (ATMs).
Because increasing age is associated with increased infiltration and reactivity of adipose macrophages, we performed euglycemic-hyperinsulinemic clamp studies and adipose tissue biopsies with and without elevated FFA concentrations in 31 nondiabetic participants stratified by age, to determine whether middle-aged individuals manifest heightened insulin resistance and PAI-1 production by ATMs in response to elevated nutrient signals relative to their young adult peers.
We observed that elevating FFA concentrations under euglycemic-hyperinsulinemic clamp conditions induced the same degree of insulin resistance in both middle-aged and younger body mass index-matched adults, whereas systemic PAI-1 concentrations were significantly increased in the middle-aged group. Likewise, elevated FFA and insulin concentrations induced larger increases in PAI-1 gene expression in the whole fat and ATMs of middle-aged compared with younger adult participants.
These studies reveal a heightened adipose inflammatory response to increased FFA and insulin availability in middle-aged individuals relative to younger adults, suggesting that increased susceptibility to the effects of fatty acid excess may contribute to the pathogenesis of age-related diseases.
人类衰老与糖尿病和心血管疾病风险增加有关。脂肪量的增加可能通过容纳产生代谢重要蛋白（如纤溶酶原激活物抑制剂-1（PAI-1）的炎性巨噬细胞而导致与年龄相关的疾病。升高的 PAI-1 浓度与胰岛素抵抗、肥胖和动脉粥样硬化等与衰老相关的病症的发病机制有关。我们之前报道过，增加血浆游离脂肪酸（FFA）浓度会增加循环 PAI-1 浓度和脂肪组织巨噬细胞（ATMs）产生的 PAI-1。
由于年龄增长与脂肪巨噬细胞的浸润和反应性增加有关，我们在 31 名非糖尿病参与者中进行了正常血糖高胰岛素钳夹研究和脂肪组织活检，这些参与者按年龄分层，有或没有升高的 FFA 浓度，以确定中年个体是否表现出对升高的营养信号的更高胰岛素抵抗和 ATMs 产生 PAI-1，与他们的年轻成年同龄人相比。
我们观察到，在正常血糖高胰岛素钳夹条件下升高 FFA 浓度会导致中年和年轻体重指数匹配成年人的胰岛素抵抗程度相同，而中年组的全身 PAI-1 浓度显著升高。同样，升高的 FFA 和胰岛素浓度会诱导中年参与者的整个脂肪和 ATMs 中 PAI-1 基因表达的更大增加。
这些研究揭示了中年个体相对于年轻成年人对升高的 FFA 和胰岛素可用性的脂肪炎症反应增强，表明对脂肪酸过量影响的易感性增加可能导致与年龄相关的疾病的发病机制。
