Title | FOXO protects against age-progressive axonal degeneration. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Hwang I, Oh H, Santo E, Kim D-Y, Chen JW, Bronson RT, Locasale JW, Na Y, Lee J, Reed S, Toth M, Yu WH, Muller FL, Paik J |
Journal | Aging Cell |
Volume | 17 |
Issue | 1 |
Date Published | 2018 02 |
ISSN | 1474-9726 |
Keywords | Aging, Animals, Axons, Forkhead Transcription Factors, Gene Expression Regulation, Mechanistic Target of Rapamycin Complex 1, Mice, Knockout, Protective Agents, Signal Transduction |
Abstract | Neurodegeneration resulting in cognitive and motor impairment is an inevitable consequence of aging. Little is known about the genetic regulation of this process despite its overriding importance in normal aging. Here, we identify the Forkhead Box O (FOXO) transcription factor 1, 3, and 4 isoforms as a guardian of neuronal integrity by inhibiting age-progressive axonal degeneration in mammals. FOXO expression progressively increased in aging human and mouse brains. The nervous system-specific deletion of Foxo transcription factors in mice accelerates aging-related axonal tract degeneration, which is followed by motor dysfunction. This accelerated neurodegeneration is accompanied by levels of white matter astrogliosis and microgliosis in middle-aged Foxo knockout mice that are typically only observed in very old wild-type mice and other aged mammals, including humans. Mechanistically, axonal degeneration in nerve-specific Foxo knockout mice is associated with elevated mTORC1 activity and accompanying proteotoxic stress due to decreased Sestrin3 expression. Inhibition of mTORC1 by rapamycin treatment mimics FOXO action and prevented axonal degeneration in Foxo knockout mice with accelerated nervous system aging. Defining this central role for FOXO in neuroprotection during mammalian aging offers an invaluable window into the aging process itself. |
DOI | 10.1111/acel.12701 |
Alternate Journal | Aging Cell |
PubMed ID | 29178390 |
PubMed Central ID | PMC5771393 |
Grant List | R01 CA193256 / CA / NCI NIH HHS / United States R01 AG048284 / AG / NIA NIH HHS / United States R56 AG048284 / AG / NIA NIH HHS / United States R00 CA168997 / CA / NCI NIH HHS / United States P30 DK020541 / DK / NIDDK NIH HHS / United States S10 OD018164 / OD / NIH HHS / United States |
Related Faculty:
Ji-Hye Paik, Ph.D.