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Identification and evaluation of midbrain specific longevity-related genes in exceptionally long-lived but healthy mice

Brain aging is a complex biological process that is affected by both genetic background and environment. The transcriptomic analysis of aged human and rodent brains has been applied to identify age-associated molecular and cellular processes for which intervention could possibly restore declining br...

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Autores principales: Kim, Hyojung, Huh, Yu-Jin, Kim, Ji Hun, Jo, Minkyung, Shin, Joo-Heon, Park, Sang Chul, Ahn, Jee-Yin, Lee, Yun-Il, Lee, Yunjong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9874112/
https://www.ncbi.nlm.nih.gov/pubmed/36711211
http://dx.doi.org/10.3389/fnagi.2022.1030807
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author Kim, Hyojung
Huh, Yu-Jin
Kim, Ji Hun
Jo, Minkyung
Shin, Joo-Heon
Park, Sang Chul
Ahn, Jee-Yin
Lee, Yun-Il
Lee, Yunjong
author_facet Kim, Hyojung
Huh, Yu-Jin
Kim, Ji Hun
Jo, Minkyung
Shin, Joo-Heon
Park, Sang Chul
Ahn, Jee-Yin
Lee, Yun-Il
Lee, Yunjong
author_sort Kim, Hyojung
collection PubMed
description Brain aging is a complex biological process that is affected by both genetic background and environment. The transcriptomic analysis of aged human and rodent brains has been applied to identify age-associated molecular and cellular processes for which intervention could possibly restore declining brain functions induced by aging. However, whether these age-associated genetic alterations are indeed involved in the healthy aging of the brain remains unclear. We herein characterized a naturally occurring, extremely long-lived (34 months of age) but healthy mouse group retaining well-preserved motor functions. Strikingly, these long-lived mice maintained tyrosine hydroxylase expression and dopaminergic fiber densities, even in the presence of persistent neuroinflammation and expression of aging markers. Combined with Endeavor gene prioritization, we identified the following midbrain-specific longevity-associated genes in the midbrain of these mice: aimp2, hexb, cacybp, akt2, nrf1, axin1, wwp2, sp2, dnajb9, notch, traf7, and lrp1. A detailed biochemical analysis of the midbrain of these long-lived mice confirmed the increased expression of Nrf1 and the activation of Akt1 and 2. Interestingly, dopaminergic neuroprotective and age-associated E3 ubiquitin ligase parkin expression was retained at high levels in the aforementioned midbrains, possibly supporting the suppression of its toxic substrates AIMP2 and PARIS. In contrast, the 24-month-old mice with dopaminergic neurite deficits failed to maintain parkin expression in the midbrain. AIMP2-induced cytotoxicity, mitochondrial stress, and neurite toxicity can be prevented by overexpression of parkin, Akt1, and Nrf1 in SH-SY5Y and PC12 cells, and basal expression of parkin, Akt1, and Nrf1 is required for maintenance of mitochondrial function and neurite integrity in PC12 cells. Taken together, this longevity-associated pathway could be a potential target of intervention to maintain nigrostriatal dopaminergic fibers and motor ability to ensure healthy longevity.
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spelling pubmed-98741122023-01-26 Identification and evaluation of midbrain specific longevity-related genes in exceptionally long-lived but healthy mice Kim, Hyojung Huh, Yu-Jin Kim, Ji Hun Jo, Minkyung Shin, Joo-Heon Park, Sang Chul Ahn, Jee-Yin Lee, Yun-Il Lee, Yunjong Front Aging Neurosci Aging Neuroscience Brain aging is a complex biological process that is affected by both genetic background and environment. The transcriptomic analysis of aged human and rodent brains has been applied to identify age-associated molecular and cellular processes for which intervention could possibly restore declining brain functions induced by aging. However, whether these age-associated genetic alterations are indeed involved in the healthy aging of the brain remains unclear. We herein characterized a naturally occurring, extremely long-lived (34 months of age) but healthy mouse group retaining well-preserved motor functions. Strikingly, these long-lived mice maintained tyrosine hydroxylase expression and dopaminergic fiber densities, even in the presence of persistent neuroinflammation and expression of aging markers. Combined with Endeavor gene prioritization, we identified the following midbrain-specific longevity-associated genes in the midbrain of these mice: aimp2, hexb, cacybp, akt2, nrf1, axin1, wwp2, sp2, dnajb9, notch, traf7, and lrp1. A detailed biochemical analysis of the midbrain of these long-lived mice confirmed the increased expression of Nrf1 and the activation of Akt1 and 2. Interestingly, dopaminergic neuroprotective and age-associated E3 ubiquitin ligase parkin expression was retained at high levels in the aforementioned midbrains, possibly supporting the suppression of its toxic substrates AIMP2 and PARIS. In contrast, the 24-month-old mice with dopaminergic neurite deficits failed to maintain parkin expression in the midbrain. AIMP2-induced cytotoxicity, mitochondrial stress, and neurite toxicity can be prevented by overexpression of parkin, Akt1, and Nrf1 in SH-SY5Y and PC12 cells, and basal expression of parkin, Akt1, and Nrf1 is required for maintenance of mitochondrial function and neurite integrity in PC12 cells. Taken together, this longevity-associated pathway could be a potential target of intervention to maintain nigrostriatal dopaminergic fibers and motor ability to ensure healthy longevity. Frontiers Media S.A. 2023-01-11 /pmc/articles/PMC9874112/ /pubmed/36711211 http://dx.doi.org/10.3389/fnagi.2022.1030807 Text en Copyright © 2023 Kim, Huh, Kim, Jo, Shin, Park, Ahn, Lee and Lee. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Aging Neuroscience
Kim, Hyojung
Huh, Yu-Jin
Kim, Ji Hun
Jo, Minkyung
Shin, Joo-Heon
Park, Sang Chul
Ahn, Jee-Yin
Lee, Yun-Il
Lee, Yunjong
Identification and evaluation of midbrain specific longevity-related genes in exceptionally long-lived but healthy mice
title Identification and evaluation of midbrain specific longevity-related genes in exceptionally long-lived but healthy mice
title_full Identification and evaluation of midbrain specific longevity-related genes in exceptionally long-lived but healthy mice
title_fullStr Identification and evaluation of midbrain specific longevity-related genes in exceptionally long-lived but healthy mice
title_full_unstemmed Identification and evaluation of midbrain specific longevity-related genes in exceptionally long-lived but healthy mice
title_short Identification and evaluation of midbrain specific longevity-related genes in exceptionally long-lived but healthy mice
title_sort identification and evaluation of midbrain specific longevity-related genes in exceptionally long-lived but healthy mice
topic Aging Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9874112/
https://www.ncbi.nlm.nih.gov/pubmed/36711211
http://dx.doi.org/10.3389/fnagi.2022.1030807
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