Cargando…

Age-Related Neuroprotection by Dietary Restriction Requires OXR1-Mediated Retromer Function

Dietary restriction (DR) is the most robust method to delay aging and the onset of neurogenerative disorders across multiple species, though the mechanisms behind this phenomenon remain unknown. To elucidate how DR mediates lifespan extension, we analyzed natural genetic variants that associate with...

Descripción completa

Detalles Bibliográficos
Autores principales: Wilson, Kenneth, Bar, Sudipta, Brownridge, George, Beck, Jennifer, Brem, Rachel, Bellen, Hugo, Ellerby, Lisa, Kapahi, Pankaj
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8680557/
http://dx.doi.org/10.1093/geroni/igab046.2151
_version_ 1784616773848399872
author Wilson, Kenneth
Bar, Sudipta
Brownridge, George
Beck, Jennifer
Brem, Rachel
Bellen, Hugo
Ellerby, Lisa
Kapahi, Pankaj
author_facet Wilson, Kenneth
Bar, Sudipta
Brownridge, George
Beck, Jennifer
Brem, Rachel
Bellen, Hugo
Ellerby, Lisa
Kapahi, Pankaj
author_sort Wilson, Kenneth
collection PubMed
description Dietary restriction (DR) is the most robust method to delay aging and the onset of neurogenerative disorders across multiple species, though the mechanisms behind this phenomenon remain unknown. To elucidate how DR mediates lifespan extension, we analyzed natural genetic variants that associate with increased longevity under DR conditions in the Drosophila Genetic Reference Panel. We found that neuronal expression of the fly homolog of human Oxidation Resistance 1 (OXR1) is necessary for DR-mediated lifespan extension. Neuronal knockdown of OXR1 also accelerated visual decline but not physical decline, arguing for a specific role of OXR1 in neuronal signaling. Further, we find that overexpression of the TLDc domain from human OXR1 is sufficient for lifespan extension in a diet-dependent manner. Studies from the Accelerating Medicines Partnership - Alzheimer's Disease network show that patients with reduced OXR1 protein levels are more prone to Alzheimer's disease diagnosis, and we find that overexpression of human OXR1 is protective in animal and cell Alzheimer's models. In seeking the mechanism by which OXR1 protects against age-related neuronal decline, we discovered that it provides a necessary function in regulating the neuronal retromer complex, which is essential for the recycling of transmembrane receptors and for maintenance of autophagy. We further discovered that OXR1 deficiency can be rescued by genetic or pharmacological enhancement of retromer function, and that this enhancement extends lifespan and healthspan. Understanding how OXR1 operates could help uncover novel mechanisms to slow neurodegeneration including Alzheimer's disease.
format Online
Article
Text
id pubmed-8680557
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-86805572021-12-17 Age-Related Neuroprotection by Dietary Restriction Requires OXR1-Mediated Retromer Function Wilson, Kenneth Bar, Sudipta Brownridge, George Beck, Jennifer Brem, Rachel Bellen, Hugo Ellerby, Lisa Kapahi, Pankaj Innov Aging Abstracts Dietary restriction (DR) is the most robust method to delay aging and the onset of neurogenerative disorders across multiple species, though the mechanisms behind this phenomenon remain unknown. To elucidate how DR mediates lifespan extension, we analyzed natural genetic variants that associate with increased longevity under DR conditions in the Drosophila Genetic Reference Panel. We found that neuronal expression of the fly homolog of human Oxidation Resistance 1 (OXR1) is necessary for DR-mediated lifespan extension. Neuronal knockdown of OXR1 also accelerated visual decline but not physical decline, arguing for a specific role of OXR1 in neuronal signaling. Further, we find that overexpression of the TLDc domain from human OXR1 is sufficient for lifespan extension in a diet-dependent manner. Studies from the Accelerating Medicines Partnership - Alzheimer's Disease network show that patients with reduced OXR1 protein levels are more prone to Alzheimer's disease diagnosis, and we find that overexpression of human OXR1 is protective in animal and cell Alzheimer's models. In seeking the mechanism by which OXR1 protects against age-related neuronal decline, we discovered that it provides a necessary function in regulating the neuronal retromer complex, which is essential for the recycling of transmembrane receptors and for maintenance of autophagy. We further discovered that OXR1 deficiency can be rescued by genetic or pharmacological enhancement of retromer function, and that this enhancement extends lifespan and healthspan. Understanding how OXR1 operates could help uncover novel mechanisms to slow neurodegeneration including Alzheimer's disease. Oxford University Press 2021-12-17 /pmc/articles/PMC8680557/ http://dx.doi.org/10.1093/geroni/igab046.2151 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Abstracts
Wilson, Kenneth
Bar, Sudipta
Brownridge, George
Beck, Jennifer
Brem, Rachel
Bellen, Hugo
Ellerby, Lisa
Kapahi, Pankaj
Age-Related Neuroprotection by Dietary Restriction Requires OXR1-Mediated Retromer Function
title Age-Related Neuroprotection by Dietary Restriction Requires OXR1-Mediated Retromer Function
title_full Age-Related Neuroprotection by Dietary Restriction Requires OXR1-Mediated Retromer Function
title_fullStr Age-Related Neuroprotection by Dietary Restriction Requires OXR1-Mediated Retromer Function
title_full_unstemmed Age-Related Neuroprotection by Dietary Restriction Requires OXR1-Mediated Retromer Function
title_short Age-Related Neuroprotection by Dietary Restriction Requires OXR1-Mediated Retromer Function
title_sort age-related neuroprotection by dietary restriction requires oxr1-mediated retromer function
topic Abstracts
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8680557/
http://dx.doi.org/10.1093/geroni/igab046.2151
work_keys_str_mv AT wilsonkenneth agerelatedneuroprotectionbydietaryrestrictionrequiresoxr1mediatedretromerfunction
AT barsudipta agerelatedneuroprotectionbydietaryrestrictionrequiresoxr1mediatedretromerfunction
AT brownridgegeorge agerelatedneuroprotectionbydietaryrestrictionrequiresoxr1mediatedretromerfunction
AT beckjennifer agerelatedneuroprotectionbydietaryrestrictionrequiresoxr1mediatedretromerfunction
AT bremrachel agerelatedneuroprotectionbydietaryrestrictionrequiresoxr1mediatedretromerfunction
AT bellenhugo agerelatedneuroprotectionbydietaryrestrictionrequiresoxr1mediatedretromerfunction
AT ellerbylisa agerelatedneuroprotectionbydietaryrestrictionrequiresoxr1mediatedretromerfunction
AT kapahipankaj agerelatedneuroprotectionbydietaryrestrictionrequiresoxr1mediatedretromerfunction