贝勒医学院生理与生物物理系Ergun Sahin研究组宣布他们发现了端粒功能障碍导致Sirtuin抑制，进而导致端粒依赖疾病。相关论文发表在2019年6月出版的《Cell Metabolism》杂志上。

该研究团队证明，端粒酶敲除小鼠肝脏端粒缩短导致所有7种sirtuins的p53依赖抑制。p53通过micrornas（mir34a、26a和145）转录后调节非线粒体sirtuins（sirt1、2、6和7），而线粒体sirtuins（sirt3、4和5）在转录水平以过氧化物酶体增殖物激活受体γ辅激活物1αβ依赖性方式调节。给予NAD(+)前体烟酰胺单核苷酸维持端粒长度，抑制DNA损伤和p53，改善线粒体功能，在功能上以部分依赖sirt1的方式挽救肝纤维化。这些研究证实，sirtuins是端粒功能失调的下游靶点，并表明单独或与其他sirtuins联合增加Sirt1活性可稳定端粒并减轻端粒依赖疾病。

研究人员表示，端粒缩短与干细胞衰退、纤维化疾病和过早衰老有关，其机制尚不完全清楚。

附：英文原文

Title: Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease

Author: Hisayuki Amano, Arindam Chaudhury, Cristian Rodriguez-Aguayo, Milton Finegold, Joseph A. Baur, Ergun Sahin

Issue&Volume: Jun 04, 2019 Volume 29Issue 6

Abstract: Telomere shortening is associated with stem cell decline, fibrotic disorders, and premature aging through mechanisms that are incompletely understood. Here, we show that telomere shortening in livers of telomerase knockout mice leads to a p53-dependent repression of all seven sirtuins. P53 regulates non-mitochondrial sirtuins (Sirt1, 2, 6, and 7) post-transcriptionally through microRNAs (miR-34a, 26a, and 145), while the mitochondrial sirtuins (Sirt3, 4, and 5) are regulated in a peroxisome proliferator-activated receptor gamma co-activator 1 alpha-/beta-dependent manner at the transcriptional level. Administration of the NAD(+) precursor nicotinamide mononucleotide maintains telomere length, dampens the DNA damage response and p53, improves mitochondrial function, and, functionally, rescues liver fibrosis in a partially Sirt1-dependent manner. These studies establish sirtuins as downstream targets of dysfunctional telomeres and suggest that increasing Sirt1 activity alone or in combination with other sirtuins stabilizes telomeres and mitigates telomere-dependent disorders.

DOI: https://doi.org/10.1016/j.cmet.2019.03.001

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30129-9nn