Sphingolipids and lifespan regulation.
Sphingolipids and lifespan regulation.
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DOI：
10.1016/j.bbalip.2013.08.006
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发表时间：
2014-05
期刊：
影响因子：
--
通讯作者：
Dickson RC
中科院分区：
文献类型：
--
作者：
Huang X;Withers BR;Dickson RC
随着年龄的增长，包括癌症、2型糖尿病、心血管和免疫功能障碍以及神经退化在内的疾病变得更加普遍，再加上人类平均寿命的延长，给卫生保健系统带来了越来越大的负担。在本章中，我们专注于寻找调节鞘磷脂的方法来防止与年龄相关的疾病的发展或延缓其发病，这两者都可以改善老年、脆弱人群的健康。在过去的十年里，由于对信号转导途径和细胞过程，特别是在模式生物中的理解取得了进展，减少或延缓了衰老疾病的发生，这些在大多数真核生物中基本上是保守的，可以被调节以减少衰老迹象和延长健康寿命。在模式生物中，这种干预也必须延长寿命才能被认为是显著的，但这不是在人类身上使用的要求。在模式生物中最鼓舞人心的干预措施包括降低一个或多个鞘脂的浓度，以降低关键信号通路的活性，其中最有希望的是雷帕霉素复合体1靶蛋白(TORC1)蛋白激酶通路。调节鞘磷脂可能有助于改善老年人健康状况的其他潜在方式是通过减少氧化应激、炎症反应和生长因子信号。最后，也许调节鞘脂和延长寿命的最有趣的方法是降低丝氨酸棕榈酰基转移酶的活性，丝氨酸棕榈酰转移酶是神经鞘脂生物合成途径中的第一个酶。酵母和啮齿动物的现有数据令人鼓舞，随着我们对分子机制的深入了解，通过调节鞘磷脂来改善人类健康的策略将变得更加明显。
Diseases including cancer, type 2 diabetes, cardiovascular and immune dysfunction and neurodegeneration become more prevalent as we age, and combined with the increase in average human lifespan, place an ever increasing burden on the health care system. In this chapter we focus on finding ways of modulating sphingolipids to prevent the development of age-associated diseases or delay their onset, both of which could improve health in elderly, fragile people. Reducing the incidence of or delaying the onset of diseases of aging has blossomed in the past decade because of advances in understanding signal transduction pathways and cellular processes, especially in model organisms, that are largely conserved in most eukaryotes and that can be modulated to reduce signs of aging and increase health span. In model organisms such interventions must also increase lifespan to be considered significant, but this is not a requirement for use in humans. The most encouraging interventions in model organisms involve lowering the concentration of one or more sphingolipid so as to reduce the activity of key signaling pathways, one of the most promising being the Target of Rapamycin Complex 1 (TORC1) protein kinase pathway. Other potential ways in which modulating sphingolipids may contribute to improving the health profile of the elderly is by reducing oxidative stresses, inflammatory responses and growth factor signaling. Lastly, perhaps the most interesting way to modulate sphingolipids and promote longevity is by lowering the activity of serine palmitoyltransferase, the first enzyme in the de novo sphingolipid biosynthesis pathway. Available data in yeasts and rodents are encouraging and as we gain insights into molecular mechanisms the strategies for improving human health by modulating sphingolipids will become more apparent.
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