Larrick James W, Mendelsohn Andrew R
Panorama Research Institute, Sunnydale, California.
Regenerative Sciences Institute, Sunnydale, California.
Rejuvenation Res. 2020 Apr;23(2):171-175. doi: 10.1089/rej.2020.2335.
Diminished integrity of the intestinal epithelial barrier with advanced age is believed to contribute to aging-associated dysfunction and pathologies in animals. In mammals, diminished gut integrity contributes to inflammaging, the increase in inflammatory processes observed in old age. Recent work suggests that expression of intestinal alkaline phosphatase (IAP) plays a key role in maintaining gut integrity. IAP expression decreases with increasing age in mice and humans. Absence of IAP leads to liver inflammation and shortened life-spans in mice lacking the IAP gene. In normal mice, exogenous supplemental IAP reverses age-induced barrier dysfunction, improves aging-associated metabolic dysfunction, prevents microbiome dysbiosis (imbalance), and extends life-span. Consistent with IAP playing a conserved role in maintaining gut integrity, increased dietary IAP increases aging-diminished physical performance in flies. IAP helps maintain gut integrity in part by supporting the expression of tight junction proteins that maintain the intestinal epithelial barrier and by inactivating bacterial pro-inflammatory factors such as lipopolysaccharides (LPS) by dephosphorylation. Recombinant IAP is in late clinical trials for sepsis-associated acute kidney injury, suggesting it may soon become available as a therapeutic. Taken together, these reports support the idea that directly increasing IAP levels by supplemental recombinant IAP or by indirectly increasing IAP levels using dietary means to induce endogenous IAP may slow the development of aging-associated pathologies.
随着年龄增长，肠道上皮屏障完整性受损被认为会导致动物出现与衰老相关的功能障碍和病理变化。在哺乳动物中，肠道完整性受损会导致炎症衰老，即老年时观察到的炎症过程增加。最近的研究表明，肠道碱性磷酸酶（IAP）的表达在维持肠道完整性方面起着关键作用。在小鼠和人类中，IAP的表达会随着年龄的增长而降低。缺乏IAP会导致缺乏IAP基因的小鼠出现肝脏炎症并缩短寿命。在正常小鼠中，外源性补充IAP可逆转年龄诱导的屏障功能障碍，改善与衰老相关的代谢功能障碍，预防微生物群失调（失衡），并延长寿命。与IAP在维持肠道完整性方面发挥保守作用一致，增加饮食中的IAP可提高果蝇因衰老而下降的身体性能。IAP有助于维持肠道完整性，部分原因是支持维持肠道上皮屏障的紧密连接蛋白的表达，并通过去磷酸化使细菌促炎因子如脂多糖（LPS）失活。重组IAP正在进行与脓毒症相关的急性肾损伤的后期临床试验，这表明它可能很快作为一种治疗药物上市。综上所述，这些报告支持这样一种观点，即通过补充重组IAP直接提高IAP水平或通过饮食手段间接提高IAP水平以诱导内源性IAP，可能会减缓与衰老相关的病理变化的发展。
