Dietary and genetic evidence for phosphate toxicity accelerating mammalian aging
Dietary and genetic evidence for phosphate toxicity accelerating mammalian aging
复制标题
DOI：
10.1096/fj.09-152488
复制
发表时间：
2010-09-01
期刊：
影响因子：
4.8
通讯作者：
Razzaque, M. Shawkat
中科院分区：
文献类型：
--
作者：
Ohnishi, Mutsuko;Razzaque, M. Shawkat
确定加速衰老过程的因素可以为减缓这一过程提供重要的治疗靶点。磷酸盐稳态失调已在各种骨骼、心脏和肾脏疾病中被注意到，但磷酸盐毒性在哺乳动物衰老中的确切作用尚未明确定义。磷酸盐在体内分布广泛，参与细胞信号传导、能量代谢、核酸合成以及通过尿液缓冲维持酸碱平衡。在这项研究中，我们使用体内遗传方法来确定磷酸盐毒性在哺乳动物衰老中的作用。klotho基因敲除小鼠（klotho(-/-)）寿命短，表现出许多与早衰一致的物理、生化和形态学特征，包括脊柱后突、运动不协调、性腺功能减退、不育、严重骨骼肌萎缩、肺气肿和骨质减少，以及皮肤、肠道、胸腺和脾脏的全身性萎缩。分子和生化分析表明，磷酸钠共转运体（NaPi2a）的肾脏活性增加导致klotho（-/-）小鼠严重的高磷血症。通过产生NaPi2a和klotho双敲除(NaPi2a（-/-)/klotho(-/-)）菌株，从基因上降低klotho（-/-）小鼠的血清磷酸盐水平，可改善早衰样特征。NaPi2a(-/-)/klotho（-/-）双敲除小鼠恢复了生殖能力，恢复了体重，减轻了器官萎缩，抑制了异位钙化，从而延长了生存期。更重要的是，当高磷饮食在NaPi2a(-/-)/klotho（-/-）小鼠中诱导高磷血症时，出现了类似早衰的特征，清楚地表明磷酸盐毒性是导致klotho（-/-）小鼠早衰的主要原因。我们的饮食和基因操作研究的结果为磷酸盐毒性加速衰老过程提供了体内证据，并提出了磷酸盐在哺乳动物衰老中的新作用。-Ohnishi， M, Razzaque， M. S.磷酸盐毒性加速哺乳动物衰老的饮食和遗传证据。中国生物医学工程学报，2009,32(2):444 - 444。www.fasebj.org
Identifying factors that accelerate the aging process can provide important therapeutic targets for slowing down this process. Misregulation of phosphate homeostasis has been noted in various skeletal, cardiac, and renal diseases, but the exact role of phosphate toxicity in mammalian aging is not clearly defined. Phosphate is widely distributed in the body and is involved in cell signaling, energy metabolism, nucleic acid synthesis, and the maintenance of acid-base balance by urinary buffering. In this study, we used an in vivo genetic approach to determine the role of phosphate toxicity in mammalian aging. Klotho-knockout mice (klotho(-/-)) have a short life span and show numerous physical, biochemical, and morphological features consistent with premature aging, including kyphosis, uncoordinated movement, hypogonadism, infertility, severe skeletal muscle wasting, emphysema, and osteopenia, as well as generalized atrophy of the skin, intestine, thymus, and spleen. Molecular and biochemical analyses suggest that increased renal activity of sodium-phosphate cotransporters (NaPi2a) leads to severe hyperphosphatemia in klotho(-/-) mice. Genetically reducing serum phosphate levels in klotho(-/-) mice by generating a NaPi2a and klotho double-knockout (NaPi2a(-/-)/klotho(-/-)) strain resulted in amelioration of premature aging-like features. The NaPi2a(-/-)/klotho(-/-) double-knockout mice regained reproductive ability, recovered their body weight, reduced their organ atrophy, and suppressed ectopic calcifications, with the resulting effect being prolonged survival. More important, when hyperphosphatemia was induced in NaPi2a(-/-)/klotho(-/-) mice by feeding with a high-phosphate diet, premature aging-like features reappeared, clearly suggesting that phosphate toxicity is the main cause of premature aging in klotho(-/-) mice. The results of our dietary and genetic manipulation studies provide in vivo evidence for phosphate toxicity accelerating the aging process and suggest a novel role for phosphate in mammalian aging.-Ohnishi, M., Razzaque, M. S. Dietary and genetic evidence for phosphate toxicity accelerating mammalian aging. FASEB J. 24, 3562-3571 (2010). www.fasebj.org