Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice.
The chronic and systemic administration of rapamycin extends life span in mammals. Rapamycin is a pharmacological inhibitor of mTOR. Metformin also inhibits mTOR signaling but by activating the upstream kinase AMPK. Here we report the effects of chronic and systemic administration of the two mTOR inhibitors, rapamycin and metformin, on adult neural stem cells of the subventricular region and the dendate gyrus of the mouse hippocampus. While rapamycin decreased the number of neural progenitors, metformin-mediated inhibition of mTOR had no such effect. Adult-born neurons are considered important for cognitive and behavioral health, and may contribute to improved health span. Our results demonstrate that distinct approaches of inhibiting mTOR signaling can have significantly different effects on organ function. These results underscore the importance of screening individual mTOR inhibitors on different organs and physiological processes for potential adverse effects that may compromise health span.
Neuroscience Graduate Program, Arizona State University, Phoenix, AZ, 85287, USA.
Yael
Y
Kusne
Emily L
EL
Goldberg
Sara S
SS
Parker
Sophie M
SM
Hapak
Irina Y
IY
Maskaykina
Wade M
WM
Chew
Kirsten H
KH
Limesand
Heddwen L
HL
Brooks
Theodore J
TJ
Price
Nader
N
Sanai
Janko
J
Nikolich-Zugich
Sourav
S
Ghosh
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects*; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008136:Longevity / Q000187:drug effects*; D008687:Metformin / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D013234:Stem Cells / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D008687:Metformin; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus