Short-term Low-Dose mTORC1 Inhibition in Aged Rats Counter-Regulates Age-Related Gene Changes and Blocks Age-Related Kidney Pathology
| Autor: | Reginald Valdez, Lin Fan, Yanqun Wang, Jiang Zhu, Sharon X. Wang, David J. Glass, Tea Shavlakadze, Joan Mannick, Weihua Zhou, Angelika Meyer, Oleg Iartchouk, Marc A. Egerman, Lloyd B. Klickstein, Bret Morin |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Aging medicine.medical_specialty Longevity Gene Expression mTORC1 Mechanistic Target of Rapamycin Complex 1 Kidney Drug Administration Schedule Rats Sprague-Dawley 03 medical and health sciences Internal medicine Gene expression medicine Chronic Progressive Nephropathy Animals Humans Everolimus Enzyme Inhibitors Renal Insufficiency Chronic Muscle Skeletal business.industry Gene Expression Profiling TOR Serine-Threonine Kinases HEK 293 cells Kidney metabolism Skeletal muscle Rats HEK293 Cells 030104 developmental biology Endocrinology medicine.anatomical_structure Liver Proteasome inhibitor Geriatrics and Gerontology business medicine.drug |
| Zdroj: | The Journals of Gerontology: Series A. 73:845-852 |
| ISSN: | 1758-535X 1079-5006 |
| DOI: | 10.1093/gerona/glx249 |
| Popis: | Rapalogs, inhibitors of mTORC1 (mammalian target of rapamycin complex 1), increase life span and delay age-related phenotypes in many species. However, the molecular mechanisms have not been fully elucidated. We determined gene expression changes comparing 6- and 24-month-old rats in the kidney, liver, and skeletal muscle, and asked which of these changes were counter-regulated by a clinically-translatable (short-term and low-concentration) treatment, with a rapalog (RAD001). Surprisingly, RAD001 had a more pronounced effect on the kidney under this regimen in comparison to the liver or skeletal muscle. Histologic evaluation of kidneys revealed that the severity of chronic progressive nephropathy lesions was lower in kidneys from 24-month-old rats treated with RAD001 compared with vehicle. In addition to other gene expression changes, c-Myc, which has been shown to regulate aging, was induced by aging in the kidney and counter-regulated by RAD001. RAD001 caused a decrease in c-Myc protein, which could be rescued by a proteasome inhibitor. These findings point to settings for use of mTORC1 inhibitors to treat age-related disorders, and highlight c-Myc regulation as one of the potential mechanisms by which mTORC1 inhibition is perturbing age-related phenotypes. |
| Databáze: | OpenAIRE |
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