最近一项研究发现相比于年轻人来说，老年人的肌肉线粒体从催化脂肪酸代谢转向催化葡萄糖代谢的能力下降，而这可能是导致衰老相关的2型糖尿病发生和葡萄糖耐受性损伤的重要原因。相关研究结果发表在国际学术期刊PNAS上。
在美国，年龄大于65岁的老年人更易患2型糖尿病或葡萄糖不耐受。科学家们对其中的原因了解较少，但一些研究发现肌肉胰岛素抵抗，同时肌细胞内脂质含量增加，代谢速率下降与衰老密切相关。因此，研究人员对于探究老年人与年轻人肌肉细胞线粒体的差别非常感兴趣。
在这项研究中，研究人员首先对平均年龄为69岁的非吸烟健康老年人进行了24小时饥饿处理随后进行了口服葡萄糖测试并检测了他们的肌肉细胞脂质含量。结果表明饥饿后老年个体的血糖浓度比年轻个体更高，而其他因子如胰岛素浓度则没有差异；而口服葡萄糖之后老年个体的血糖浓度和胰岛素浓度都显著高于年轻个体；他们的肌肉细胞脂质含量也更高。
随后研究人员利用高胰岛素-正葡萄糖钳夹实验结合同位素标记的葡萄糖探究了老年人对血浆胰岛素水平增加的应答情况，结果表明老年个体对葡萄糖的代谢速率慢于年轻个体。
研究人员为了对肌肉细胞线粒体功能有更加精确的了解，他们开发了一种新的方法可以利用液相色谱-质谱技术结合同位素标记的葡萄糖对线粒体内两种关键代谢酶的催化速率变化进行研究。他们测定了肌肉线粒体内代谢产物从丙酮酸脱氢酶到柠檬酸合酶的流动速率，并将该结果与平均年龄为27岁的年轻个体进行匹配分析。结果表明饥饿后两组肌肉线粒体内代谢产物从丙酮酸脱氢酶到柠檬酸合酶的流动速率基本相同，进行了胰岛素刺激之后，年轻个体的代谢产物流动速率增加了3倍，而老年个体组没有发生变化。
这些结果表明，在进行胰岛素刺激后，年轻个体的线粒体能够从脂质氧化向葡萄糖氧化进行转变，而这种变化在老年组并不明显。这表明肌肉细胞内的胰岛素信号损伤与衰老有关，这可能是导致老年人2型糖尿病和葡萄糖不耐受高发的一个重要因素。
Effect of aging on muscle mitochondrial substrate utilization in humans
Kitt Falk Petersena, Katsutaro Morinoa,b, Tiago C. Alvesa, Richard G. Kibbeya, Sylvie Dufourb, Saki Sonoa,b, Peter S. Yooc, Gary W. Clinea, and Gerald I. Shulman
Previous studies have implicated age-associated reductions in mitochondrial oxidative phosphorylation activity in skeletal muscle as a predisposing factor for intramyocellular lipid (IMCL) accumulation and muscle insulin resistance (IR) in the elderly. To further investigate potential alterations in muscle mitochondrial function associated with aging, we assessed basal and insulin-stimulated rates of muscle pyruvate dehydrogenase (VPDH) flux relative to citrate synthase flux (VCS) in healthy lean, elderly subjects and healthy young body mass index- and activity-matched subjects. VPDH/VCS flux was assessed from the 13C incorporation from of infused [1-13C] glucose into glutamate [4-13C] relative to alanine [3-13C] assessed by LC-tandem MS in muscle biopsies. Insulin-stimulated rates of muscle glucose uptake were reduced by 25% (P < 0.01) in the elderly subjects and were associated with ?70% (P < 0.04) increase in IMCL, assessed by1H magnetic resonance spectroscopy. Basal VPDH/VCS fluxes were similar between the groups (young: 0.20 ± 0.03; elderly: 0.14 ± 0.03) and increased approximately threefold in the young subjects following insulin stimulation. However, this increase was severely blunted in the elderly subjects (young: 0.55 ± 0.04; elderly: 0.18 ± 0.02, P = 0.0002) and was associated with an ?40% (P = 0.004) reduction in insulin activation of Akt. These results provide new insights into acquired mitochondrial abnormalities associated with aging and demonstrate that age-associated reductions in muscle mitochondrial function and increased IMCL are associated with a marked inability of mitochondria to switch from lipid to glucose oxidation during insulin stimulation.