Journal Home > Volume 11 , Issue 4

Exercise is recognized as an effective strategy to delay brain aging, which is related to the activation of autophagy. Trehalose is a natural compound that can activate autophagy and exert beneficial effects in delaying brain aging. In this study, we investigated whether trehalose may exert neuroprotection similar to those of exercise in delaying age-related cognitive decline. Fifteen-month-old male C57BL/6 mice underwent swim exercise and/or were treated with 2% trehalose for 12 weeks. Trehalose, exercise and the combination of exercise and trehalose intervention improved the learning and memory of aged mice. They also improved the ratio of LC3-II/LC3-I, the protein level of LC3-II, Bnip3L, and Parkin respectively. Additionally, both exercise and trehalose increased the phosphorylation of AMPK. Exercise decreased cortical phosphorylation of mTOR and S6k, whereas trehalose did not change these cortical levels. These data indicated that exercise and trehalose might modulate autophagy through mTOR-dependent or mTOR-independent pathways, respectively. However, a combination of exercise and trehalose did not play a synergistic role in improving cognitive function and modulation of autophagy. Taken together, our findings suggest that trehalose exerts similar effects to those of exercise in delaying age-related cognitive decline and that it may thus represent an exercise mimetic to delay brain aging.


menu
Abstract
Full text
Outline
About this article

Trehalose ameliorates autophagy dysregulation in aged cortex and acts as an exercise mimetic to delay brain aging in elderly mice

Show Author's information Shanyao Pana,1Shanshan Guoa,b,1Jiaru DaiaYanrong GuaGuoxiang WangaYulong WangcZhenghong QindLi Luoa( )
School of Physical Education and Sports Science, Soochow University, Suzhou 215021, China
School of Life Sciences, Fudan University, Shanghai 200032, China
Department of Rehabilitation, Shenzhen Second People's Hospital, The First Affiliated Hospital, Shenzhen University School of Medicine, Shenzhen 518035, China
Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China

1 The authors contributed equally to this work.Peer review under responsibility of KeAi Communications Co., Ltd.]]>

Abstract

Exercise is recognized as an effective strategy to delay brain aging, which is related to the activation of autophagy. Trehalose is a natural compound that can activate autophagy and exert beneficial effects in delaying brain aging. In this study, we investigated whether trehalose may exert neuroprotection similar to those of exercise in delaying age-related cognitive decline. Fifteen-month-old male C57BL/6 mice underwent swim exercise and/or were treated with 2% trehalose for 12 weeks. Trehalose, exercise and the combination of exercise and trehalose intervention improved the learning and memory of aged mice. They also improved the ratio of LC3-II/LC3-I, the protein level of LC3-II, Bnip3L, and Parkin respectively. Additionally, both exercise and trehalose increased the phosphorylation of AMPK. Exercise decreased cortical phosphorylation of mTOR and S6k, whereas trehalose did not change these cortical levels. These data indicated that exercise and trehalose might modulate autophagy through mTOR-dependent or mTOR-independent pathways, respectively. However, a combination of exercise and trehalose did not play a synergistic role in improving cognitive function and modulation of autophagy. Taken together, our findings suggest that trehalose exerts similar effects to those of exercise in delaying age-related cognitive decline and that it may thus represent an exercise mimetic to delay brain aging.

Keywords: Cognitive function, Autophagy, Trehalose, Exercise

References(59)

[1]

D.C. Rubinsztein, G. Mariño, G. Kroemer, Autophagy and aging, Cell 146 (2011) 682-695. https://doi.org/10.1016/j.cell.2011.07.030.

[2]

L. Luo, Z.H. Qin, Autophagy, aging, and longevity, Adv. Exp. Med. Biol. 1206 (2019) 509-525. https://doi.org/10.1007/978-981-15-0602-4_24.

[3]

T. Hara, K. Nakamura, M. Matsui, et al., Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice, Nature 441 (2006) 885-889. https://doi.org/10.1038/nature04724.

[4]

Y. Yu, L. Feng, J. Li, et al., The alteration of autophagy and apoptosis in the hippocampus of rats with natural aging-dependent cognitive deficits, Behav. Brain Res. 334 (2017) 155-162. https://doi.org/10.1016/j.bbr.2017.07.003.

[5]

M. Glatigny, S. Moriceau, M. Rivagorda, et al., Autophagy is required for memory formation and reverses age-related memory decline, Curr. Biol. 29 (2019) 435-448. https://doi.org/10.1016/j.cub.2018.12.021.

[6]

E. Luengo, I. Buendia, C. Fernández-Mendívil, et al., Pharmacological doses of melatonin impede cognitive decline in tau-related Alzheimer models, once tauopathy is initiated, by restoring the autophagic flux, J. Pineal Res. 67 (2019) e12578. https://doi.org/10.1111/jpi.12578.

[7]

Y. Li, L. Liu, Y. Tian, et al., Rapamycin improves sevoflurane-induced cognitive dysfunction in aged rats by mediating autophagy through the TLR4/MyD88/NF-κB signaling pathway, Mol. Med. Rep. 20 (2019) 3085-3094. https://doi.org/10.3892/mmr.2019.10541.

[8]

X. Kou, J. Li, X. Liu, et al., Swimming attenuates d-galactose-induced brain aging via suppressing miR-34a-mediated autophagy impairment and abnormal mitochondrial dynamics, J. Appl. Physiol. 122 (2017) 1462-1469. https://doi.org/10.1152/japplphysiol.00018.2017.

[9]

L. Luo, J.R. Dai, S.S. Guo, et al., Lysosomal proteolysis is associated with exercise-induced improvement of mitochondrial quality control in aged hippocampus, J. Gerontol. A Biol. Sci. Med. Sci. 72 (2017) 1342-1351. https://doi.org/10.1093/gerona/glw242.

[10]

W. Liu, Z. Wang, Y. Xia, et al., The balance of apoptosis and autophagy via regulation of the AMPK signal pathway in aging rat striatum during regular aerobic exercise, Exp. Gerontol. 124 (2019) 110647. https://doi.org/10.1016/j.exger.2019.110647.

[11]

J. Huang, X. Wang, Y. Zhu, et al., Exercise activates lysosomal function in the brain through AMPK-SIRT1-TFEB pathway, CNS Neurosci. Ther. 25 (2019) 796-807. https://doi.org/10.1111/cns.13114.

[12]

A.M. Gusdon, J. Callio, G. Distefano, et al., Exercise increases mitochondrial complex I activity and DRP1 expression in the brains of aged mice, Exp. Gerontol. 90 (2017) 1-13. https://doi.org/10.1016/j.exger.2017.01.013.

[13]

M.J. Casarejos, J. Perucho, J.L. López-Sendón, et al., Trehalose improves human fibroblast deficits in a new CHIP-mutation related ataxia, PLoS One 9 (2014) e106931. https://doi.org/10.1371/journal.pone.0106931.

[14]

Y.L. Kang, M.A. Saleem, K.W. Chan, et al., Trehalose, an mTOR independent autophagy inducer, alleviates human podocyte injury after puromycin aminonucleoside treatment, PLoS One 9 (2014) e113520. https://doi.org/10.1371/journal.pone.0113520.

[15]

X. Chen, M. Li, L. Li, et al., Trehalose, sucrose and raffinose are novel activators of autophagy in human keratinocytes through an mTOR-independent pathway, Sci. Rep. 6 (2016) 28423. https://doi.org/10.1038/srep28423.

[16]

P. Lotfi, D.Y. Tse, A. Di Ronza, et al., Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency, Autophagy 14 (2018) 1419-1434. https://doi.org/10.1080/15548627.2018.1474313.

[17]

S.D. Portbury, D.J. Hare, C. Sgambelloni, et al., Trehalose improves cognition in the transgenic tg2576 mouse model of Alzheimer's disease, J. Alzheimers Dis. 60 (2017) 549-560. https://doi.org/10.3233/jad-170322.

[18]

P.A. Howson, T.H. Johnston, P. Ravenscroft, et al., Beneficial effects of trehalose on striatal dopaminergic deficits in rodent and primate models of synucleinopathy in Parkinson's disease, J. Pharmacol. Exp. Ther. 369 (2019) 364-374. https://doi.org/10.1124/jpet.118.255695.

[19]

S. Sarkar, J.E. Davies, Z. Huang, et al., Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein, J. Biol. Chem. 282 (2007) 5641-5652. https://doi.org/10.1074/jbc.M609532200.

[20]

P. Rusmini, K. Cortese, V. Crippa, et al., Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration, Autophagy 15 (2019) 631-651. https://doi.org/10.1080/15548627.2018.1535292.

[21]

M. Palmieri, R. Pal, H.R. Nelvagal, et al., mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases, Nat. Commun. 8 (2017) 14338. https://doi.org/10.1038/ncomms14338.

[22]

A. Berry, M. Marconi, C. Musillo, et al., Trehalose administration in C57BL/6N old mice affects healthspan improving motor learning and brain anti-oxidant defences in a sex-dependent fashion: a pilot study, Exp. Gerontol. 129 (2020) 110755. https://doi.org/10.1016/j.exger.2019.110755.

[23]

L. Sun, Q. Zhao, Y. Xiao, et al., Trehalose targets Nrf2 signal to alleviate d-galactose induced aging and improve behavioral ability, Biochem. Biophys. Res. Commun. 521 (2020) 113-119. https://doi.org/10.1016/j.bbrc.2019.10.088.

[24]
D.J. Klionsky, K. Abdelmohsen, A. Abe, et al., Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition), Autophagy 12 (2016) 1-222. https://doi.org/10.1080/15548627.2015.1100356.
DOI
[25]

A. Di Rita, A. Peschiaroli, P.D. Acunzo, et al., HUWE1 E3 ligase promotes PINK1/PARKIN-independent mitophagy by regulating AMBRA1 activation via IKKα, Nat. Commun. 9 (2018) 3755. https://doi.org/10.1038/s41467-018-05722-3.

[26]

R.J. Youle, D.P. Narendra, Mechanisms of mitophagy, Nat. Rev. Mol. Cell Biol. 12 (2011) 9-14. https://doi.org/10.1038/nrm3028.

[27]

M. Zachari, I.G. Ganley, The mammalian ULK1 complex and autophagy initiation, Essays Biochem. 61 (2017) 585-596. https://doi.org/10.1042/ebc20170021.

[28]

L. Hang, J. Thundyil, K.L. Lim, Mitochondrial dysfunction and Parkinson disease: a Parkin-AMPK alliance in neuroprotection, Ann. N. Y. Acad. Sci. 1350 (2015) 37-47. https://doi.org/10.1111/nyas.12820.

[29]

Z.Q. Yao, X. Zhang, Y. Zhen, et al., A novel small-molecule activator of Sirtuin-1 induces autophagic cell death/mitophagy as a potential therapeutic strategy in glioblastoma, Cell Death Dis. 9 (2018) 767. https://doi.org/10.1038/s41419-018-0799-z.

[30]

J. Kim, M. Kundu, B. Viollet, et al., AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1, Nat. Cell Biol. 13 (2011) 132-141. https://doi.org/10.1038/ncb2152.

[31]

J.A. Morgan, G. Singhal, F. Corrigan, et al., The effects of aerobic exercise on depression-like, anxiety-like, and cognition-like behaviours over the healthy adult lifespan of C57BL/6 mice, Behav. Brain Res. 337 (2018) 193-203. https://doi.org/10.1016/j.bbr.2017.09.022.

[32]

M.W. Marlatt, M.C. Potter, P.J. Lucassen, et al., Running throughout middle-age improves memory function, hippocampal neurogenesis, and BDNF levels in female C57BL/6J mice, Dev. Neurobiol. 72 (2012) 943-952. https://doi.org/10.1002/dneu.22009.

[33]

U. Krüger, Y. Wang, S. Kumar, et al., Autophagic degradation of tau in primary neurons and its enhancement by trehalose, Neurobiol. Aging 33 (2012) 2291-2305. https://doi.org/10.1016/j.neurobiolaging.2011.11.009.

[34]

V. Schaeffer, I. Lavenir, S. Ozcelik, et al., Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy, Brain 135 (2012) 2169-2177. https://doi.org/10.1093/brain/aws143.

[35]

D.M. Lan, F.T. Liu, J. Zhao, et al., Effect of trehalose on PC12 cells overexpressing wild-type or A53T mutant α-synuclein, Neurochem. Res. 37 (2012) 2025-2032. https://doi.org/10.1007/s11064-012-0823-0.

[36]

K. Castillo, M. Nassif, V. Valenzuela, et al., Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons, Autophagy 9 (2013) 1308-1320. https://doi.org/10.4161/auto.25188.

[37]

X. Zhang, S. Chen, L. Song, et al., MTOR-independent, autophagic enhancer trehalose prolongs motor neuron survival and ameliorates the autophagic flux defect in a mouse model of amyotrophic lateral sclerosis, Autophagy 10 (2014) 588-602. https://doi.org/10.4161/auto.27710.

[38]

K. Liu, M.J. Jing, C. Liu, et al., Effect of trehalose on manganese-induced mitochondrial dysfunction and neuronal cell damage in mice, Basic Clin. Pharmacol. Toxicol. 125 (2019) 536-547. https://doi.org/10.1111/bcpt.13316.

[39]

T.J. LaRocca, C.M. Hearon, Jr., G.D. Henson, et al., Mitochondrial quality control and age-associated arterial stiffening, Exp. Gerontol. 58 (2014) 78-82. https://doi.org/10.1016/j.exger.2014.07.008.

[40]

M. Ulgherait, A. Rana, M. Rera, et al., AMPK modulates tissue and organismal aging in a non-cell-autonomous manner, Cell Rep. 8 (2014) 1767-1780. https://doi.org/10.1016/j.celrep.2014.08.006.

[41]

L.A. Lesniewski, D.R. Seals, A.E. Walker, et al., Dietary rapamycin supplementation reverses age-related vascular dysfunction and oxidative stress, while modulating nutrient-sensing, cell cycle, and senescence pathways, Aging Cell. 16 (2017) 17-26. https://doi.org/10.1111/acel.12524.

[42]

M.A. Samuel, P.E. Voinescu, B.N. Lilley, et al., LKB1 and AMPK regulate synaptic remodeling in old age, Nat. Neurosci. 17 (2014) 1190-1197. https://doi.org/10.1038/nn.3772.

[43]

C.J. Holler, G. Taylor, Z.T. McEachin, et al., Trehalose upregulates progranulin expression in human and mouse models of GRN haploinsufficiency: a novel therapeutic lead to treat frontotemporal dementia, Mol. Neurodegener. 11 (2016) 46. https://doi.org/10.1186/s13024-016-0114-3.

[44]

M. Parrini, D. Ghezzi, G. Deidda, et al., Aerobic exercise and a BDNF-mimetic therapy rescue learning and memory in a mouse model of down syndrome, Sci. Rep. 7 (2017) 16825. https://doi.org/10.1038/s41598-017-17201-8.

[45]

S.H. Choi, E. Bylykbashi, Z.K. Chatila, et al., Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer's mouse model, Science 361 (2018). https://doi.org/10.1126/science.aan8821.

[46]

D. Jiang, K. Chen, X. Lu, et al., Exercise ameliorates the detrimental effect of chloroquine on skeletal muscles in mice via restoring autophagy flux, Acta. Pharmacol. Sin. 35 (2014) 135-142. https://doi.org/10.1038/aps.2013.144.

[47]

M.C. Venables, F. Brouns, A.E. Jeukendrup, Oxidation of maltose and trehalose during prolonged moderate-intensity exercise, Med. Sci. Sports Exerc. 40 (2008) 1653-1659. https://doi.org/10.1249/MSS.0b013e318175716c.

[48]

T. Wadazumi, K. Watanabe, H. Watanabe, et al., Effects of a single ingestion of trehalose during prolonged exercise, Sports (Basel) 7 (2019). https://doi.org/10.3390/sports7050100.

[49]

A. Goyal, J. Miller, A.J. Watrous, et al., Electrical stimulation in hippocampus and entorhinal cortex impairs spatial and temporal memory, J. Neurosci. 38 (2018) 4471-4481. https://doi.org/10.1523/jneurosci.3049-17.2018.

[50]

X. Han, H. Tai, X. Wang, et al., AMPK activation protects cells from oxidative stress-induced senescence via autophagic flux restoration and intracellular NAD(+) elevation, Aging Cell. 15 (2016) 416-427. https://doi.org/10.1111/acel.12446.

[51]

G. Hewitt, B. Carroll, R. Sarallah, et al., SQSTM1/p62 mediates crosstalk between autophagy and the UPS in DNA repair, Autophagy 12 (2016) 1917-1930. https://doi.org/10.1080/15548627.2016.1210368.

[52]

R. Aparicio, A. Rana, D.W. Walker, Upregulation of the autophagy adaptor p62/SQSTM1 prolongs health and lifespan in middle-aged Drosophila, Cell Rep. 28 (2019) 1029-1040. https://doi.org/10.1016/j.celrep.2019.06.070.

[53]

M. Chen, Q. Meng, Y. Qin, et al., TRIM14 inhibits cGAS degradation mediated by selective autophagy receptor p62 to promote innate immune responses, Mol. Cell. 64 (2016) 105-119. https://doi.org/10.1016/j.molcel.2016.08.025.

[54]

A. Bitto, C.A. Lerner, T. Nacarelli, et al., P62/SQSTM1 at the interface of aging, autophagy, and disease, Age (Dordr) 36 (2014) 9626. https://doi.org/10.1007/s11357-014-9626-3.

[55]

S. Ning, L. Wang, The multifunctional protein p62 and its mechanistic roles in cancers, Curr. Cancer Drug Targets 19 (2019) 468-478. https://doi.org/10.2174/1568009618666181016164920.

[56]

G. Shimojo, B. Joseph, R. Shah, et al., Exercise activates vagal induction of dopamine and attenuates systemic inflammation, Brain Behav. Immun. 75 (2019) 181-191. https://doi.org/10.1016/j.bbi.2018.10.005.

[57]

Y. Lu, Y. Dong, D. Tucker, et al., Treadmill exercise exerts neuroprotection and regulates microglial polarization and oxidative stress in a streptozotocin-induced rat model of sporadic Alzheimer's disease, J. Alzheimers Dis. 56 (2017) 1469-1484. https://doi.org/10.3233/jad-160869.

[58]

K.K. Tang, X.Y. Liu, Z.Y. Wang, et al., Trehalose alleviates cadmium-induced brain damage by ameliorating oxidative stress, autophagy inhibition, and apoptosis, Metallomics 11 (2019) 2043-2051. https://doi.org/10.1039/c9mt00227h.

[59]

Q. He, Y. Wang, W. Lin, et al., Trehalose alleviates PC12 neuronal death mediated by lipopolysaccharide-stimulated BV-2 cells via inhibiting nuclear transcription factor NF-κB and AP-1 activation, Neurotox. Res. 26 (2014) 430-439. https://doi.org/10.1007/s12640-014-9487-7.

Publication history
Copyright
Acknowledgements
Rights and permissions

Publication history

Received: 28 December 2020
Revised: 10 March 2021
Accepted: 13 May 2021
Published: 28 April 2022
Issue date: July 2022

Copyright

© 2022 Beijing Academy of Food Sciences. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.

Acknowledgements

Acknowledgement

This work was supported by grants from the National Natural Science Foundation of China (81771500).

Rights and permissions

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Return