運動與疾病的關係/跑步對衰老大腦的好處

本頁是對 Dallagnol 等人 2017 年發表的題為“跑步 REST：身體活動減輕老年小鼠海馬體的神經炎症”的期刊文章的分析^[1]

這項研究的背景是什麼？

目前的醫學文獻支援這樣一種觀點，即運動對長期^[2]^[3]和短期^[4]^[5]的腦部健康都有積極的影響。運動對大腦的一個廣為人知的好處是它能夠抑制炎症，而炎症已被證明與阿爾茨海默病 (AD) 等多種神經疾病有關^[6]。炎症是導致衰老和與年齡相關的疾病的主要因素之一^[7]，它是由某些激素、維生素 D 和感染的減少而產生的^[8]。

以下研究主要關注運動對 RE1 靜默轉錄因子 (REST) 表達的作用，REST 是一種參與神經發生和神經保護的 RNA 調節因子，是炎症的反作用力^[9]。文獻表明，隨著大腦年齡的增長，REST 表達增加，從而提供神經保護，然而，患有神經退行性疾病的人 REST 表達下降^[9]。如果運動對大腦有神經保護作用，那麼它是否可以透過影響 REST 來實現呢？這項研究的其他重點是運動是否會改變腦源性神經營養因子 (BDNF)、IL-1β 和 IL-10 的水平。研究表明，BDNF 在神經可塑性和神經保護中起著關鍵作用^[10]，而 IL-1β 和 IL-10 已被證明是炎症標誌物^[1]。分析研究的目的，雖然作者沒有提到，但旨在為理解運動對衰老大腦的積極影響提供額外的有效性和範圍。

這項研究來自哪裡？

這項研究是由巴西聖卡塔琳娜聯邦大學的研究人員進行的，他們在腦生化研究方面擁有豐富的背景，這表明這篇論文經過了充分的研究。此外，幾位作者曾在同行評審期刊上發表的先前論文中合作過^[11]^[12]^[13]。研究人員表示，不存在個人或財務利益衝突，並引用了研究資金來源，表明在進行研究時不存在偏見^[1]。

這是一項什麼樣的研究？

這是一項使用 C57BL/6 雄性小鼠動物模型的定量實驗研究。作者沒有說明使用這種基因品系的原因，但它在文獻中被廣泛使用^[14]^[15]。對小鼠進行隨機分配到各自的組別，研究人員控制住屋環境（光照、食物、籠子型別、溫度）。由於研究中的變數的性質（運動和久坐），研究人員對這些變數沒有被矇蔽。透過控制大多數重要變數，研究人員在一定程度上最大限度地減少了資料中的誤差可能性。

這項研究包括什麼？

四組小鼠接觸了兩個變數，一個跑步輪 (RW) 和沒有 RW 的久坐環境 (SED)。在四組小鼠中，兩組為幼鼠（12-14 周），另外兩組為老鼠（19-21 個月）。總共四組分別為久坐幼鼠 (SED-young)、RW-young、久坐老年 (SED-aged) 和 RW-aged。每組在 8 周內接觸其特定的變數，並在這段時間內保持隔離，並控制光照，這些變數可能導致情緒變化^[16]。在 8 周後和動物在處死後收穫海馬體之前，測量了距離、速度、抬頭、開放區域探索和不動性。值得注意的是，開放區域測試和不動性在科學文獻中被廣泛用作抑鬱和焦慮的指標^[17]，或反映小鼠的情緒，因此，這些測量結果在其結果中具有有效性。對組織樣本進行分析，以確定 BDNF、REST、IL-1β 和 IL-10 的 mRNA 表達，從而表明它們在小鼠體內的變化作用。

基本結果是什麼？

結果可以分為兩部分：1）運動，即跑步，對小鼠情緒的影響；2）運動對炎症和神經保護機制的影響。關於運動對小鼠情緒的影響，SED-aged 小鼠表現出明顯更多的壁蹲行為，這是一種焦慮的跡象^[16]，而不是 RW-aged 小鼠和幼鼠，這表明運動對小鼠的情緒有積極的影響，而焦慮隨著年齡的增長可能會增加。這些結果支援了之前的證據，即抑鬱樣症狀隨著年齡的增長可能會增加^[18]^[19]，而運動可以減輕這些症狀^[20]。關於運動對神經保護機制和炎症的影響，與 SED-aged 對照組相比，RW-aged 小鼠的 BDNF 和 REST mRNA 表達顯著增加，表明運動能夠影響這兩個因素。這表明僅僅 8 周的 RW 運動後神經保護作用增強。此外，與 SED-aged 小鼠相比，RW-aged 小鼠的 IL-1β 和 IL-10 的測量值明顯更低，進一步支援了運動具有抗炎作用的證據^[21]。

我們可以從這項研究中得出什麼結論？

由於這項研究是首次研究運動對 REST 的直接影響，而且證據表明 REST 在健康的神經元衰老中至關重要，因此，我們可以從這項研究中得出的結論是，健康的大腦衰老可能需要運動。儘管這項研究是在小鼠身上進行的，但證據已經足夠有希望，可以進行人類臨床研究。由於這種特殊的動物模型在臨床前研究中被廣泛使用，因此預計這裡觀察到的生理變化也會發生在人類身上。進一步的研究還應確定這種變化是否與劑量有關，因為在這項研究中沒有控制特定的跑步劑量。

這項研究表明，運動可以減少炎症（神經元衰老的原因），並改善大腦中 REST 和 BDNF 的表達，這兩個都是已知的保護神經的因素。最終，運動似乎不僅能確保老年人健康的認知功能，還能減少神經退行性疾病的發生率。

實用建議

在澳大利亞，只有不到一半的 65 歲以上的人進行推薦量的運動^[22]，這可能與澳大利亞老齡人口中神經退行性疾病的增加有關^[23]。根據這項研究的理解，需要更加重視老年人運動的重要性，以提高生活質量和減少經濟疾病負擔。健康專業人員幫助老年人制定運動處方，以及老年人自己在這方面進行學習（參見“更多資訊/資源”），這一點至關重要。

參考文獻

↑ ^a ^b ^c Dallagnol, KMC, Remor, AP, da Silva, RA, Prediger, RD, Latini, A, Aguiar Jr, AS 2017, ‘Running for REST: Physical activity attenuates neuroinflammation in the hippocampus of aged mice’, Brain, Behaviour and Immunity, vol. 61, pp. 31-35
↑ Erikson, KI, Prakash, RS, Voss, MW, Chaddock, L, Hu, L, Morris, KS, et al. 2009, ‘Aerobic fitness is associated with hippocampal volume in elderly humans’, Hippocampus, vol. 19, no. 10, pp. 1030-1039
↑ Colcombe, SJ, Erickson, KI, Scalf, PE, Kim, JS, Prakash, R, McAuley, E, et al. 2006, ‘Aerobic exercise training increases brain volume in ageing humans’, The Journals of Gerontology: Series A, vol. 61, no. 11, pp. 1166-1170
↑ Vega, SR, Struder, HK, Wahrmann, BV, Schmidt, A, Bloch, W, Hollmann, W 2006, ‘Acute BDNF and cortisol response to low intensity exercise following ramp incremental exercise to exhaustion in humans’, Brain Research, vol. 1121, no. 1, pp. 59-65
↑ Nouchi, R, Taki, Y, Takeuchi, H, Sekiguchi, A, Hashizume, H, Nozawa, T, et al. 2014, ‘Four weeks of combination exercise improved executive functions, episodic memory and processing speed in healthy elderly people: evidence from a randomised controlled trial’, Age, vol. 36, no. 2, pp. 787-799
↑ Svensson, M, Lexell, J, Deierborg, T 2015, ‘Effects of physical exercise on neuroinflammation, neuroplasticity, neurodegeneration and behaviour: What we can learn from animal models in clinical settings’, Neurorehabilitation and Neural Repair, vol. 29, no. 6, pp. 577-589
↑ Chung, HY, Cesari, M, Anton, S, Marzetti, E, Giovannini, S, Seo, AY, et al. 2009, ‘Molecular inflammation: underpinnings of ageing and age-related diseases’, Ageing Research Reviews, vol. 8, no. 1, pp. 18-30
↑ Hubbard, RE, Woodhouse, KW 2010, ‘Frailty, inflammation and the elderly’, Biogerontology, vol. 11, no. 5, pp. 635-641
↑ ^a ^b Zhao, Y, Zhu, M, Yu, Y, Qiu, L, Zhang, Y, He, L, et al. 2017, ‘Brain REST/NRSF is not only a silent repressor but also an active protector’, Molecular Neurobiology, vol. 54, no. 1, pp. 541, 550
↑ Tapia-Arancibia, L, Aliga, E, Silhol, M, Arancibia, S 2008, ‘New insights into brain BDNF function in normal ageing and Alzheimer’s disease’, Brain Research Reviews, vol. 59, no. 1, pp. 201-220
↑ Aguiar, AS, Stragier, E, da Luz Scheffer, D, Remor, AP, Oliveira, PA, Prediger, RD, et al. 2014, ‘Effects of exercise on mitochondrial function, neuroplasticity and anxio-depressive behaviour of mice’, Neuroscience, vol. 271, pp. 56-63
↑ Aguiar, AS, Duzzioni, M, Remor, AP, Tristao, FSM, Matheus, FC, Raisman-Vozari, R, et al. 2016, ‘Moderate-intensity physical exercise protects against experimental 6-Hydroxydopamine-induced hemiparkinsonism through Nrf2-antioxidant response element pathway’, Neurochemical Research, vol. 41, no. 1-2, pp. 64-72
↑ Aguiar, AS, Moreira, ELG, Hoeller, AA, Oliveira, PA, Cordova, FM, Glaser, V, et al. 2013, ‘Exercise attenuates levodopa-induced dyskinesia in 6-hydroxydopamine-lesioned mice’, Neuroscience, vol. 243, pp. 46-53
↑ Mekad, K, Abe, K, Murakami, A, Nakamura, S, Nakata, H, Moriwaki, K, et al. 2009, ‘Genetic differences among C57BL/6 substrains’, Experimental Animals, vol. 58, no. 2, pp. 141-149
↑ Zurita, E, Chagoyen, M, Cantero, M, Alonso, R, Gonzalez-Neira, Lopez-Jimenez, A, et al. 2011, ‘Genetic polymorphisms among C57BL/6 mouse inbred strains’, Transgenic Research, vol. 20, no. 3, pp. 481-489
↑ ^a ^b Huang, Y, Zhou, W, Zhang, Y 2012, ‘Bright lighting conditions during testing increase thigmotaxis and impair water maze performance in BALB/c mice’, Behavioural Brain Research, vol. 226, no. 1, pp. 26-31
↑ Cryan, JF, Holmes, A 2005, ‘The ascent of mouse: Advances in modelling human depression and anxiety’, Nature Reviews. Drug Discovery, vol. 4, no. 9, pp. 775-790
↑ Stordal, E, Mykletun, A, Dahl, AA 2003, ‘The association between age and depression in the general population: a multivariate examination’, Act Psychiatrica Scandinavica, vol. 107, no. 2, pp. 132-141
↑ Alexopoulas, GS 2005, ‘Depression in the elderly’, The Lancet, vol. 365, no. 9475, pp. 1961-1970
↑ Arent, SM, Lnders, DM, Etnier, JL 2000, ‘The effects of exercise on mood in older adults: A meta-analytic review’, Journal of Ageing and Physical Activity, vol. 8, pp. 407-430
↑ Petersen, AMW, Pedersen, BK 2005, ‘The anti-inflammatory effect of exercise’, Journal of Applied Physiology, vol. 98, no. 4, pp. 1154-1162
↑ Sims, J, Hill, K, Hunt, S, Haralambous, B 2010, ‘Physical activity recommendations for older Australians’, Australasian Journal on Ageing, vol. 29, no. 2, pp. 81-87
↑ Begg, Stephen, Vos, Theo, Barker, Bridget, Stevenson, Chris, Stanley, Lucy and Lopez, Alan D. 2007, The burden of disease and injury in Australia 2003, Australian Institute of Health and Welfare, [Canberra, A. C. T.]

[Dallagnol-1] Dallagnol, KMC, Remor, AP, da Silva, RA, Prediger, RD, Latini, A, Aguiar Jr, AS 2017, ‘Running for REST: Physical activity attenuates neuroinflammation in the hippocampus of aged mice’, Brain, Behaviour and Immunity, vol. 61, pp. 31-35

[2] Erikson, KI, Prakash, RS, Voss, MW, Chaddock, L, Hu, L, Morris, KS, et al. 2009, ‘Aerobic fitness is associated with hippocampal volume in elderly humans’, Hippocampus, vol. 19, no. 10, pp. 1030-1039

[3] Colcombe, SJ, Erickson, KI, Scalf, PE, Kim, JS, Prakash, R, McAuley, E, et al. 2006, ‘Aerobic exercise training increases brain volume in ageing humans’, The Journals of Gerontology: Series A, vol. 61, no. 11, pp. 1166-1170

[4] Vega, SR, Struder, HK, Wahrmann, BV, Schmidt, A, Bloch, W, Hollmann, W 2006, ‘Acute BDNF and cortisol response to low intensity exercise following ramp incremental exercise to exhaustion in humans’, Brain Research, vol. 1121, no. 1, pp. 59-65

[5] Nouchi, R, Taki, Y, Takeuchi, H, Sekiguchi, A, Hashizume, H, Nozawa, T, et al. 2014, ‘Four weeks of combination exercise improved executive functions, episodic memory and processing speed in healthy elderly people: evidence from a randomised controlled trial’, Age, vol. 36, no. 2, pp. 787-799

[6] Svensson, M, Lexell, J, Deierborg, T 2015, ‘Effects of physical exercise on neuroinflammation, neuroplasticity, neurodegeneration and behaviour: What we can learn from animal models in clinical settings’, Neurorehabilitation and Neural Repair, vol. 29, no. 6, pp. 577-589

[7] Chung, HY, Cesari, M, Anton, S, Marzetti, E, Giovannini, S, Seo, AY, et al. 2009, ‘Molecular inflammation: underpinnings of ageing and age-related diseases’, Ageing Research Reviews, vol. 8, no. 1, pp. 18-30

[8] Hubbard, RE, Woodhouse, KW 2010, ‘Frailty, inflammation and the elderly’, Biogerontology, vol. 11, no. 5, pp. 635-641

[Zhao-9] Zhao, Y, Zhu, M, Yu, Y, Qiu, L, Zhang, Y, He, L, et al. 2017, ‘Brain REST/NRSF is not only a silent repressor but also an active protector’, Molecular Neurobiology, vol. 54, no. 1, pp. 541, 550

[10] Tapia-Arancibia, L, Aliga, E, Silhol, M, Arancibia, S 2008, ‘New insights into brain BDNF function in normal ageing and Alzheimer’s disease’, Brain Research Reviews, vol. 59, no. 1, pp. 201-220

[11] Aguiar, AS, Stragier, E, da Luz Scheffer, D, Remor, AP, Oliveira, PA, Prediger, RD, et al. 2014, ‘Effects of exercise on mitochondrial function, neuroplasticity and anxio-depressive behaviour of mice’, Neuroscience, vol. 271, pp. 56-63

[12] Aguiar, AS, Duzzioni, M, Remor, AP, Tristao, FSM, Matheus, FC, Raisman-Vozari, R, et al. 2016, ‘Moderate-intensity physical exercise protects against experimental 6-Hydroxydopamine-induced hemiparkinsonism through Nrf2-antioxidant response element pathway’, Neurochemical Research, vol. 41, no. 1-2, pp. 64-72

[13] Aguiar, AS, Moreira, ELG, Hoeller, AA, Oliveira, PA, Cordova, FM, Glaser, V, et al. 2013, ‘Exercise attenuates levodopa-induced dyskinesia in 6-hydroxydopamine-lesioned mice’, Neuroscience, vol. 243, pp. 46-53

[14] Mekad, K, Abe, K, Murakami, A, Nakamura, S, Nakata, H, Moriwaki, K, et al. 2009, ‘Genetic differences among C57BL/6 substrains’, Experimental Animals, vol. 58, no. 2, pp. 141-149

[15] Zurita, E, Chagoyen, M, Cantero, M, Alonso, R, Gonzalez-Neira, Lopez-Jimenez, A, et al. 2011, ‘Genetic polymorphisms among C57BL/6 mouse inbred strains’, Transgenic Research, vol. 20, no. 3, pp. 481-489

[Huang-16] Huang, Y, Zhou, W, Zhang, Y 2012, ‘Bright lighting conditions during testing increase thigmotaxis and impair water maze performance in BALB/c mice’, Behavioural Brain Research, vol. 226, no. 1, pp. 26-31

[17] Cryan, JF, Holmes, A 2005, ‘The ascent of mouse: Advances in modelling human depression and anxiety’, Nature Reviews. Drug Discovery, vol. 4, no. 9, pp. 775-790

[18] Stordal, E, Mykletun, A, Dahl, AA 2003, ‘The association between age and depression in the general population: a multivariate examination’, Act Psychiatrica Scandinavica, vol. 107, no. 2, pp. 132-141

[19] Alexopoulas, GS 2005, ‘Depression in the elderly’, The Lancet, vol. 365, no. 9475, pp. 1961-1970

[20] Arent, SM, Lnders, DM, Etnier, JL 2000, ‘The effects of exercise on mood in older adults: A meta-analytic review’, Journal of Ageing and Physical Activity, vol. 8, pp. 407-430

[21] Petersen, AMW, Pedersen, BK 2005, ‘The anti-inflammatory effect of exercise’, Journal of Applied Physiology, vol. 98, no. 4, pp. 1154-1162

[22] Sims, J, Hill, K, Hunt, S, Haralambous, B 2010, ‘Physical activity recommendations for older Australians’, Australasian Journal on Ageing, vol. 29, no. 2, pp. 81-87

[23] Begg, Stephen, Vos, Theo, Barker, Bridget, Stevenson, Chris, Stanley, Lucy and Lopez, Alan D. 2007, The burden of disease and injury in Australia 2003, Australian Institute of Health and Welfare, [Canberra, A. C. T.]

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