Accumulation of prelamin A induces premature aging through mTOR overactivation
Xumeng Pan
School of Stomatology, China Medical University, Shenyang, China
Search for more papers by this authorCorresponding Author
Bo Jiang
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Correspondence
Yi Liu, School of stomatology, China Medical University, Shenyang, China.
Email: [email protected]
Bo Jiang and Liu Cao, Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, No. 77, Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, China.
Email: [email protected] (B. J.) [email protected] (L. C.)
Search for more papers by this authorXuan Wu
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Search for more papers by this authorHongde Xu
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Search for more papers by this authorSunrun Cao
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Search for more papers by this authorNing Bai
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Search for more papers by this authorXiaoman Li
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Search for more papers by this authorFei Yi
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Search for more papers by this authorQiqiang Guo
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Search for more papers by this authorWendong Guo
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Search for more papers by this authorXiaoyu Song
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Search for more papers by this authorFang Meng
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Search for more papers by this authorXining Li
Department of Pathology, Huzhou University, Huzhou, China
Search for more papers by this authorCorresponding Author
Yi Liu
School of Stomatology, China Medical University, Shenyang, China
Correspondence
Yi Liu, School of stomatology, China Medical University, Shenyang, China.
Email: [email protected]
Bo Jiang and Liu Cao, Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, No. 77, Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, China.
Email: [email protected] (B. J.) [email protected] (L. C.)
Search for more papers by this authorCorresponding Author
Liu Cao
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Correspondence
Yi Liu, School of stomatology, China Medical University, Shenyang, China.
Email: [email protected]
Bo Jiang and Liu Cao, Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, No. 77, Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, China.
Email: [email protected] (B. J.) [email protected] (L. C.)
Search for more papers by this authorXumeng Pan
School of Stomatology, China Medical University, Shenyang, China
Search for more papers by this authorCorresponding Author
Bo Jiang
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Correspondence
Yi Liu, School of stomatology, China Medical University, Shenyang, China.
Email: [email protected]
Bo Jiang and Liu Cao, Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, No. 77, Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, China.
Email: [email protected] (B. J.) [email protected] (L. C.)
Search for more papers by this authorXuan Wu
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Search for more papers by this authorHongde Xu
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Search for more papers by this authorSunrun Cao
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Search for more papers by this authorNing Bai
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Search for more papers by this authorXiaoman Li
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Search for more papers by this authorFei Yi
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Search for more papers by this authorQiqiang Guo
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Search for more papers by this authorWendong Guo
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Search for more papers by this authorXiaoyu Song
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Search for more papers by this authorFang Meng
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Search for more papers by this authorXining Li
Department of Pathology, Huzhou University, Huzhou, China
Search for more papers by this authorCorresponding Author
Yi Liu
School of Stomatology, China Medical University, Shenyang, China
Correspondence
Yi Liu, School of stomatology, China Medical University, Shenyang, China.
Email: [email protected]
Bo Jiang and Liu Cao, Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, No. 77, Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, China.
Email: [email protected] (B. J.) [email protected] (L. C.)
Search for more papers by this authorCorresponding Author
Liu Cao
Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, China
Correspondence
Yi Liu, School of stomatology, China Medical University, Shenyang, China.
Email: [email protected]
Bo Jiang and Liu Cao, Institute of Translational Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, No. 77, Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, China.
Email: [email protected] (B. J.) [email protected] (L. C.)
Search for more papers by this authorAbstract
Hutchinson-Gilford progeria syndrome (HGPS) arises when a truncated form of farnesylated prelamin A accumulates at the nuclear envelope, leading to misshapen nuclei. Previous studies of adult Zmpste24-deficient mice, a mouse model of progeria, have reported a metabolic response involving inhibition of the mTOR (mammalian target of rapamycin) kinase and activation of autophagy. However, exactly how mTOR or autophagy is involved in progeria remains unclear. Here, we investigate this question by crossing Zmpste24+/− mice with mice hypomorphic in mTOR (mTOR△/+), or mice heterozygous in autophagy-related gene 7 (Atg7+/−). We find that accumulation of prelamin A induces premature aging through mTOR overactivation and impaired autophagy in newborn Zmpste24−/− mice. Zmpste24−/− mice with genetically reduced mTOR activity, but not heterozygosity in Atg7, show extended lifespan. Moreover, mTOR inhibition partially restores autophagy and S6K1 activity. We also show that progerin interacts with the Akt phosphatase to promote full activation of the Akt/mTOR signaling pathway. Finally, although we find that genetic reduction of mTOR postpones premature aging in Zmpste24 KO mice, frequent embryonic lethality occurs. Together, our findings show that over-activated mTOR contributes to premature aging in Zmpste24−/− mice, and suggest a potential strategy in treating HGPS patients with mTOR inhibitors.
CONFLICT OF INTEREST
The authors declare no competing interests.
Supporting Information
| Filename | Description |
|---|---|
| fsb220519-sup-0001-FigS1.tifTIFF image, 1.1 MB | Fig S1 |
| fsb220519-sup-0002-FigS2.tifTIFF image, 491.1 KB | Fig S2 |
| fsb220519-sup-0003-SupFigLegends.docWord document, 31.5 KB | Supplementary Material |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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