PPARγ agonists delay age-associated metabolic disease and extend longevity.
PPARγ agonists delay age-associated metabolic disease and extend longevity.
复制标题
PPARγ 激动剂可延缓与年龄相关的代谢疾病并延长寿命。
DOI：
10.1111/acel.13267
复制
发表时间：
2020-11
期刊：
影响因子：
7.8
通讯作者：
Mueller E
中科院分区：
文献类型：
--
作者：
Xu L;Ma X;Verma N;Perie L;Pendse J;Shamloo S;Marie Josephson A;Wang D;Qiu J;Guo M;Ping X;Allen M;Noguchi A;Springer D;Shen F;Liu C;Zhang S;Li L;Li J;Xiao J;Lu J;Du Z;Luo J;Aleman JO;Leucht P;Mueller E
衰老会导致由细胞衰老、组织损伤和器官功能障碍引起的多种疾病。据报道，抗炎和胰岛素增敏化合物可延缓或逆转衰老过程，预防代谢紊乱、神经退行性疾病和肌肉萎缩，提高健康寿命并延长寿命。在此，鉴于过氧化物酶体增殖物激活受体γ（PPARγ）激动剂在降低炎症和血糖方面的已知特性，我们研究了其在预防衰老和延长寿命方面的作用。我们的分子和生理学研究表明，对14个月大的小鼠长期使用低剂量的PPARγ配体罗格列酮（Rosi）可改善葡萄糖代谢和线粒体功能。这些作用与炎症减轻、组织萎缩减少、认知功能改善以及焦虑和抑郁样状况减轻相关，且对心脏和骨骼功能无任何不良影响。此外，从14个月大开始对小鼠使用Rosi治疗与寿命延长有关。对PPARγ激动剂吡格列酮（Pio）对寿命影响的回顾性分析显示，与接受不依赖PPARγ的胰岛素促泌剂格列美脲的患者相比，接受Pio的患者死亡率降低。综上所述，这些数据表明使用PPARγ激动剂促进健康衰老和延长寿命的可能性。
在本文中，我们表明长期使用低剂量的针对核受体PPARγ的抗糖尿病药物可维持代谢器官功能和认知能力，并减少抑郁和焦虑样症状。通过功能、组织学和分子分析，我们证明接受治疗的小鼠脂肪组织内稳态得到改善，肌肉减少症减轻，炎症降低，线粒体功能提高。此外，我们的寿命研究表明，噻唑烷二酮类药物（TZD）可延长小鼠寿命并提高人类的生存率。这些数据支持长期使用低剂量的PPARγ配体来对抗衰老的可能性。
Aging leads to a number of disorders caused by cellular senescence, tissue damage, and organ dysfunction. It has been reported that anti‐inflammatory and insulin‐sensitizing compounds delay, or reverse, the aging process and prevent metabolic disorders, neurodegenerative disease, and muscle atrophy, improving healthspan and extending lifespan. Here we investigated the effects of PPARγ agonists in preventing aging and increasing longevity, given their known properties in lowering inflammation and decreasing glycemia. Our molecular and physiological studies show that long‐term treatment of mice at 14 months of age with low doses of the PPARγ ligand rosiglitazone (Rosi) improved glucose metabolism and mitochondrial functionality. These effects were associated with decreased inflammation and reduced tissue atrophy, improved cognitive function, and diminished anxiety‐ and depression‐like conditions, without any adverse effects on cardiac and skeletal functionality. Furthermore, Rosi treatment of mice started when they were 14 months old was associated with lifespan extension. A retrospective analysis of the effects of the PPARγ agonist pioglitazone (Pio) on longevity showed decreased mortality in patients receiving Pio compared to those receiving a PPARγ‐independent insulin secretagogue glimepiride. Taken together, these data suggest the possibility of using PPARγ agonists to promote healthy aging and extend lifespan. In this manuscript, we show that chronic use of low doses of antidiabetic drugs that target the nuclear receptor PPARgamma preserves metabolic organ function and cognitive abilities and decreases depression‐ and anxiety‐like symptoms. Through functional, histological, and molecular analyses, we demonstrated that treated mice have improved adipose tissue homeostasis, reduced sarcopenia, decreased inflammation, and improved mitochondrial functionality. In addition, our longevity studies demonstrated lifespan extension in mice and increased survival in humans in response to TZD. These data support the possible long‐term use of low doses PPARgamma ligands to counteract aging.
登录
查看更多内容
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
158.5
作者：
Nissen, Steven E.;Wolski, Kathy
通讯作者：
Wolski, Kathy
影响因子：
4.8
作者：
Mueller, E;Drori, S;Spiegelman, BM
通讯作者：
Spiegelman, BM
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
7.8
作者：
Harrison, David E.;Strong, Randy;Miller, Richard A.
通讯作者：
Miller, Richard A.