衰老過程中行為和認(rèn)知功能退化的調(diào)控機(jī)制研究

袁潔，蔡時青

衰老過程中行為和認(rèn)知功能退化的調(diào)控機(jī)制研究

袁潔1,2，蔡時青1,2

1. 中國科學(xué)院神經(jīng)科學(xué)研究所，神經(jīng)科學(xué)國家重點(diǎn)實(shí)驗(yàn)室，上海 2000312. 中國科學(xué)院腦科學(xué)與智能技術(shù)卓越創(chuàng)新中心，上海 200031

隨著人類預(yù)期壽命延長，人口老齡化問題越來越嚴(yán)重。過去幾十年關(guān)于衰老的研究使人們對長壽的生物學(xué)機(jī)理有了一定的認(rèn)識，然而延長壽命應(yīng)以保持老年個體健康的行為和認(rèn)知功能為前提，近期研究顯示延長壽命不一定延緩衰老過程中的行為和認(rèn)知功能退化。衰老相關(guān)行為退化的調(diào)控機(jī)制目前知道的還很少，如何實(shí)現(xiàn)老年人口健康的衰老是現(xiàn)代社會極具挑戰(zhàn)也是迫切需要解決的問題。衰老過程伴隨著明顯的認(rèn)知等行為功能的退化，過去的研究對這些功能的退化進(jìn)行了比較詳細(xì)的描述，包括情節(jié)記憶、工作記憶、信息處理速度等認(rèn)知功能的衰退，運(yùn)動能力降低，節(jié)律紊亂等。隨著神經(jīng)科學(xué)與技術(shù)的發(fā)展，越來越多的研究集中到大腦的結(jié)構(gòu)和功能隨衰老的改變。本文在簡單描述衰老過程中行為功能退化現(xiàn)象的基礎(chǔ)上，主要對大腦結(jié)構(gòu)和網(wǎng)絡(luò)連接、神經(jīng)元形態(tài)和功能、大腦基因表達(dá)以及一些保守的生物學(xué)信號通路等方面在衰老過程中的改變的研究進(jìn)展展開綜述性介紹，重點(diǎn)關(guān)注這些變化與行為和認(rèn)知功能退化之間的聯(lián)系。目前大部分的研究結(jié)果還只建立了這些變化與行為和認(rèn)知功能退化的相關(guān)關(guān)系，因果關(guān)系的確立還有待進(jìn)一步的研究。相信更多對衰老過程中行為和認(rèn)知功能退化的調(diào)控機(jī)制的研究將對改善老年人的生活質(zhì)量有極大幫助，同時對尋找預(yù)防神經(jīng)退行性疾病發(fā)生的方法也有指示作用。

衰老；認(rèn)知功能；行為退化；突觸；神經(jīng)遞質(zhì)；線粒體；氧化壓力；表觀遺傳

隨著年齡增加，人們的各項(xiàng)生理功能逐漸退化，其中認(rèn)知等各種行為功能的降低是衰老最為明顯的特征之一[1,2]?，F(xiàn)代社會，人們的平均壽命大幅度提高，人口老齡化也日益嚴(yán)重。根據(jù)國家統(tǒng)計(jì)局?jǐn)?shù)據(jù)，到2019年末，我國60歲及以上老年人口已有2.54億，占總?cè)丝诘?8.1%；預(yù)計(jì)到2050年，我國社會將進(jìn)入深度老齡化階段，60歲及以上人口占總?cè)丝诒壤龑⒊^30%。除此之外，我國失能老人的總數(shù)和比例也在不斷增加。失能老人是指失智或行動不便，喪失生活自理能力的老人。據(jù)國家統(tǒng)計(jì)局?jǐn)?shù)據(jù)，到2020年我國大約有4190萬失能老人，到2050年這個數(shù)字將增加一倍到9700萬。這將嚴(yán)重影響著老年人的生活質(zhì)量，給家庭和社會帶來巨大壓力。衰老是阿爾茲海默病(Alzheimer’s disease, AD)等神經(jīng)退行性疾病的最主要風(fēng)險(xiǎn)因素。因此，如何實(shí)現(xiàn)老齡人口健康地老去，減少失能老人的數(shù)量，預(yù)防老年性疾病的發(fā)生是現(xiàn)代社會極具挑戰(zhàn)，也是迫切需要解決的問題。

科學(xué)意義上的衰老研究歷史始于1935年，科學(xué)家發(fā)現(xiàn)節(jié)食可以延長大鼠()壽命[3]，這說明衰老是一個可調(diào)節(jié)的過程。隨著實(shí)驗(yàn)方法的發(fā)展，人們對于衰老的理解逐漸豐富，科學(xué)家相繼提出了很多理論試圖解釋衰老。20世紀(jì)50年代提出的衰老進(jìn)化理論認(rèn)為進(jìn)化會選擇對生命早期發(fā)育和生長繁殖有利的基因突變，然而這些突變在生命晚期則會加速衰老[4]。1961年，美國科學(xué)家Hayflick博士發(fā)現(xiàn)細(xì)胞老化現(xiàn)象即細(xì)胞的分裂能力是有限的，經(jīng)過有限次數(shù)的分裂之后細(xì)胞就進(jìn)入老化時期，這種現(xiàn)象也稱為“海弗利克極限”[5]。人們進(jìn)一步發(fā)現(xiàn)正常細(xì)胞每經(jīng)過一次有絲分裂，位于染色體末端的端粒會隨之逐漸縮短，當(dāng)端粒長度縮短到臨界水平的時候細(xì)胞便停止分裂進(jìn)入老化階段[6]。20世紀(jì)50年代之后，現(xiàn)代生物學(xué)理論對衰老的解釋主要?dú)w為兩類：程序性和損傷/錯誤累積理論。程序性理論認(rèn)為衰老就像發(fā)育過程一樣遵從一個程序性的生物學(xué)時間表，這個過程依賴于時序性的開啟或者關(guān)閉特定基因的表達(dá)來控制衰老。損傷/錯誤累積理論則認(rèn)為衰老是隨機(jī)的，不可控的過程，環(huán)境因素對細(xì)胞和分子逐漸侵蝕破壞，導(dǎo)致?lián)p傷累積，進(jìn)而引起衰老。盡管科學(xué)家們提出了上百個理論來解釋衰老，還沒有一個單獨(dú)的理論可以全面的解釋衰老過程[7]。隨著分子生物學(xué)的發(fā)展，從20世紀(jì)90年代開始衰老研究進(jìn)入基因時代，1983年美國科學(xué)家Klass首先在模式動物秀麗隱桿線蟲(，簡稱線蟲)中發(fā)現(xiàn)有些基因突變的線蟲相對野生型線蟲存活時間更長[8]。后來美國科學(xué)家Kenyon教授發(fā)現(xiàn)單個基因突變可以使線蟲壽命延長一倍[9]。接下來的30年，科學(xué)家發(fā)現(xiàn)了上百個長壽基因，大部分這些基因從酵母到哺乳動物中都是保守的，它們參與到不同的信號通路[10]。人們對于壽命的調(diào)控機(jī)制有了一定的認(rèn)識。

值得注意的是，衰老不僅僅包括壽命，還伴隨著行為和認(rèn)知功能的退化。最近的一些研究表明并不是所有長壽途徑都能改善衰老的行為退化[11,12]，這暗示機(jī)體對行為退化和壽命的調(diào)節(jié)可能存在不一樣的調(diào)控機(jī)制。然而，對于認(rèn)知和行為退化的分子機(jī)制目前人們知道的還很少，是衰老研究領(lǐng)域的重點(diǎn)和難點(diǎn)。本文將綜合介紹行為和認(rèn)知功能的不同方面在衰老過程中發(fā)生了怎樣的變化；這些變化與大腦中的結(jié)構(gòu)和神經(jīng)元的功能之間有著怎樣的聯(lián)系；哪些分子細(xì)胞調(diào)控機(jī)制可以解釋這些變化；目前的研究發(fā)現(xiàn)了哪些可以延緩行為和認(rèn)知功能退化的方法等研究進(jìn)展。

1 衰老過程中行為和認(rèn)知功能的退化

正常衰老過程中人類()的行為衰退包括認(rèn)知能力退化，運(yùn)動能力降低，睡眠和節(jié)律紊亂等等(圖1)。認(rèn)知是通過感覺、經(jīng)驗(yàn)以及思考獲得知識并指導(dǎo)日?；顒拥倪^程，包涵很多方面，比如學(xué)習(xí)、記憶、決策、注意和執(zhí)行能力等[2]。當(dāng)人們老的時候可能會變得更有智慧，但也會經(jīng)歷記憶力變差，反應(yīng)變慢的情況。這也反映了衰老過程中認(rèn)知功能的不同方面隨衰老的變化并不是統(tǒng)一的，認(rèn)知能力在衰老過程中的變化主要分為兩種類型：一類如情節(jié)記憶、短期工作記憶、信息處理速度以及注意力等在衰老過程中顯著降低，另一類以知識和經(jīng)驗(yàn)為代表的語義記憶和內(nèi)隱記憶在衰老中相對保持不變[2,13,14]。情節(jié)記憶可以使個體記錄、存儲并檢索關(guān)于自身經(jīng)歷的情景。不同的研究均表明情節(jié)記憶在衰老過程中是下降的[15]，而且被認(rèn)為是正常衰老過程中下降最為明顯的一類長期記憶[16]。在獼猴()、大鼠和小鼠()中也一致發(fā)現(xiàn)情節(jié)記憶的下降[17]。工作記憶是暫時性存儲和處理信息用于后續(xù)復(fù)雜決策等的認(rèn)知行為過程，是一類易受衰老影響的認(rèn)知行為[2,14]。在獼猴中的工作也表明工作記憶在衰老過程中會顯著降低，而且主要是由于前額葉皮層的一類延遲神經(jīng)元發(fā)放減弱導(dǎo)致[18]。工作記憶主要依賴于前額葉皮層，這個腦區(qū)相對于其他腦區(qū)對衰老更為敏感，人們認(rèn)為這個腦區(qū)在老年個體的缺陷導(dǎo)致了工作記憶能力在衰老時下降。此外，很多研究認(rèn)為工作記憶的缺陷對衰老相關(guān)長期記憶、解決問題能力以及決策能力的退化有重要影響[19]。執(zhí)行能力是一系列認(rèn)知過程的組合，支持個體為新的情境或目標(biāo)組織資源，調(diào)整策略，作出適應(yīng)性的行為調(diào)整。復(fù)雜的認(rèn)知功能依賴于一系列的執(zhí)行能力，大量研究表明執(zhí)行能力在衰老過程中的退化是很多認(rèn)知功能退化的重要原因[20]。額葉紋狀體回路在衰老時候的變化，可能是執(zhí)行能力退化的主要原因[21]。信息處理速度反映的是刺激引起運(yùn)動反應(yīng)的過程，大量研究表明信息處理速度在30歲左右開始下降，并在后續(xù)的生命過程中持續(xù)降低[13]?？v向分析個體從20歲到60歲之間認(rèn)知能力變化，發(fā)現(xiàn)信息處理速度是受衰老影響最大的一個模塊[22]。信息處理速度的降低或許可以解釋為什么老年人需要花更多的時間來學(xué)習(xí)新的知識。注意力的退化表現(xiàn)為老年人對于一項(xiàng)任務(wù)中令其分心的信息更加難以忽略。老年人同時處理兩項(xiàng)或多項(xiàng)信息，或者同時完成多項(xiàng)任務(wù)的能力隨年齡增加而明顯降低，尤其是當(dāng)任務(wù)復(fù)雜度增加的時候這種能力下降顯得更加明顯，這也反應(yīng)大腦處理資源的能力在正常衰老過程中是下降的[23]。

圖1 衰老過程中認(rèn)知和運(yùn)動等行為功能的退化

正常衰老過程中人類的行為衰退包括認(rèn)知能力退化，運(yùn)動能力降低和節(jié)律紊亂等。認(rèn)知功能的衰退主要包括工作記憶、情節(jié)記憶、信息處理速度以及注意力等在衰老過程中顯著退化。運(yùn)動能力減退主要是運(yùn)動速度減緩和運(yùn)動協(xié)調(diào)性變差。節(jié)律紊亂主要表現(xiàn)為節(jié)律行為的幅度和周期長度的擾亂。大腦是行為和認(rèn)知功能的控制中心，大腦衰老導(dǎo)致了這些行為功能的退化。

有一些認(rèn)知能力在衰老過程中并不表現(xiàn)出隨衰老而退化的現(xiàn)象，而是能夠得到很好的維持，甚至隨年齡增長還有所增加。語義記憶主要是關(guān)于一般事實(shí)和知識的記憶，研究發(fā)現(xiàn)語義記憶在衰老過程中不會下降，甚至在55歲以后會有略微增加[24]。內(nèi)隱性記憶包括程序記憶，它的形成和使用是無意識的，內(nèi)隱記憶受衰老的影響也很小[13]。此外，情感調(diào)節(jié)的能力在衰老過程中反而會得到加強(qiáng)，老年人情感穩(wěn)定性明顯提高，這可能與內(nèi)側(cè)前額葉系統(tǒng)的可塑性有關(guān)[25～27]。

運(yùn)動功能在衰老過程中也易受影響。運(yùn)動功能的下降在各個物種中都是保守的[17]。相對于年輕個體，老年個體的運(yùn)動速度和協(xié)調(diào)控制能力會降低。研究表明衰老時運(yùn)動速度會有大約15%～30%的下降，這可能與大腦信息處理速度在衰老時的衰退有關(guān)[28,29]。老年個體運(yùn)動的協(xié)調(diào)性變差，如平衡能力和步態(tài)出現(xiàn)問題，這是老年人跌倒并導(dǎo)致疾病和損傷的主要風(fēng)險(xiǎn)因素之一[30]。并且老年人很難同時處理多個動作，這種現(xiàn)象與小腦缺陷的病人相似，說明衰老過程中小腦的退化可能對運(yùn)動失調(diào)有貢獻(xiàn)[29]。當(dāng)然衰老過程中運(yùn)動能力的退化除了與大腦內(nèi)中樞神經(jīng)系統(tǒng)的失調(diào)相關(guān)以外，周圍神經(jīng)系統(tǒng)和肌肉系統(tǒng)的退化也有貢獻(xiàn)。

衰老過程中節(jié)律紊亂主要表現(xiàn)為節(jié)律行為的幅度和周期長度的擾亂。動物的節(jié)律行為主要受大腦的視交叉上核(Suprachiasmatic nucleus, SCN)腦區(qū)控制。有報(bào)道顯示在大鼠中，隨年齡增加SCN腦區(qū)的神經(jīng)元會減少[31]；而獼猴中的研究則發(fā)現(xiàn)該腦區(qū)的神經(jīng)元數(shù)目并沒有減少[32]。在哺乳動物中節(jié)律行為受一系列節(jié)律基因的控制，如正向轉(zhuǎn)錄調(diào)節(jié)基因、，負(fù)向轉(zhuǎn)錄調(diào)節(jié)基因和[33]。近期的研究發(fā)現(xiàn)在小鼠的SCN腦區(qū)中，SIRT1參與調(diào)控了中樞節(jié)律控制行為，大腦中和節(jié)律基因的表達(dá)隨衰老顯著降低[34]。在大腦中特異性敲除使小鼠表現(xiàn)出衰老相似的節(jié)律紊亂行為，而在小鼠大腦中過表達(dá)則可以保護(hù)衰老相關(guān)的節(jié)律失調(diào)；其作用機(jī)制是SIRT1可以直接結(jié)合并調(diào)控節(jié)律基因的表達(dá)[34]。

2 行為和認(rèn)知功能退化的調(diào)控機(jī)制

2.1 大腦結(jié)構(gòu)和網(wǎng)絡(luò)在衰老過程中的變化

早在20世紀(jì)30年代開始就有研究描述衰老過程中的認(rèn)知功能退化，而直到近50年隨著技術(shù)和神經(jīng)學(xué)科的發(fā)展，人們對行為和認(rèn)知退化的研究集中到了神經(jīng)科學(xué)的機(jī)制方面[35]。大腦是行為和認(rèn)知功能的控制中心，大腦衰老導(dǎo)致了這些行為功能的退化，衰老過程中大腦的結(jié)構(gòu)，神經(jīng)元之間的連接和功能也發(fā)生了明顯的變化。

腦成像技術(shù)如正電子發(fā)射計(jì)算機(jī)斷層顯像(positron emission tomography, PET)和功能性核磁共振成像技術(shù)(functional magnetic resonance imaging, fMRI)的發(fā)展，一方面促進(jìn)了對大腦結(jié)構(gòu)的理解，另一方面對正在執(zhí)行認(rèn)知測試任務(wù)的個體進(jìn)行大腦成像可以幫助人們了解哪些腦區(qū)參與了這種行為，在衰老過程中參與這一行為的腦區(qū)和神經(jīng)元的活動有哪些變化。從整體上看，大腦不同腦區(qū)的活動以及互相之間的功能連接在衰老過程中出現(xiàn)擾亂，主要表現(xiàn)為在某些任務(wù)中，老年人的大腦活動在局部腦區(qū)相對于年輕人有減弱；另一方面，面對同一任務(wù)，老年人所調(diào)用的腦區(qū)和年輕人相比有很大區(qū)別，這些可能與行為退化有關(guān)。比如完成執(zhí)行能力相關(guān)的任務(wù)過程中，年輕個體的前額葉皮層左側(cè)區(qū)域會出現(xiàn)很強(qiáng)的活動，而在老年個體中該區(qū)域的活動很低[36,37]。另外在完成策略編碼的任務(wù)過程中，表現(xiàn)較好的老年人的雙側(cè)前額葉皮層都會激活，而年輕人以及任務(wù)中表現(xiàn)較差的老年人，則只有左側(cè)的前額葉皮層會激活[38]。這暗示老年大腦運(yùn)用一種補(bǔ)償機(jī)制以更好地完成認(rèn)知活動。正常衰老過程中，前額葉皮層結(jié)構(gòu)和網(wǎng)絡(luò)上的改變看起來對衰老相關(guān)的多種記憶功能的降低有重要貢獻(xiàn)。這種大腦高級系統(tǒng)活動的變化可能與很多因素有關(guān)，如突觸密度、神經(jīng)元活動、興奮性和抑制性連接強(qiáng)度、神經(jīng)遞質(zhì)的結(jié)合強(qiáng)弱隨衰老的改變，以及包裹在神經(jīng)元軸突周圍的髓鞘在衰老過程中出現(xiàn)損傷[13,39]。對大腦結(jié)構(gòu)的研究表明衰老過程中大腦體積的減少并不是均勻地發(fā)生在全腦，人們發(fā)現(xiàn)最先在衰老過程中看到變化的腦區(qū)是前額葉皮層，其次是內(nèi)側(cè)顳葉，頂葉皮層和小腦[20]。枕葉皮層的體積在衰老過程中沒有明顯變化。額葉皮層體積的減少與執(zhí)行功能的減弱、情節(jié)記憶和工作記憶的退化等密切聯(lián)系[19,40]。

2.2 神經(jīng)元形態(tài)和功能在衰老過程中的變化

近期的研究發(fā)現(xiàn)，大腦體積在衰老時減少的主要原因并不是神經(jīng)元死亡，而可能是樹突分枝和突觸形態(tài)以及密度的改變[41]。海馬以及旁邊的內(nèi)側(cè)顳葉在情節(jié)記憶等長期記憶中作用非常重要，研究顯

示正常衰老過程中在人[42,43]、非人靈長類[44,45]、以及大鼠[46,47]的海馬和新皮層并沒有明顯的細(xì)胞死亡，而海馬區(qū)的神經(jīng)元丟失是阿爾茲海默病的一個顯著特征。衰老過程中前額葉皮層的神經(jīng)元似乎更容易受衰老的影響。有報(bào)道顯示在年老的非人靈長類中，雖然背外側(cè)前額葉皮層沒有明顯的神經(jīng)元丟失[48]，前額葉皮層的8A區(qū)則有明顯的神經(jīng)元減少(～30%)，這種減少還與工作記憶的缺陷有非常顯著的相關(guān)性，而前額葉皮層的46區(qū)神經(jīng)元數(shù)目則保持不變[49]。在人[50～52]、非人靈長類[53]和大鼠[54]的前額葉皮層檢測到錐體神經(jīng)元的樹突分枝減少，而海馬一些亞區(qū)的神經(jīng)元樹突分枝在衰老過程中并沒有出現(xiàn)明顯的變化[41]。在人[55,56]、非人靈長類[57]和嚙齒類[58～60]中的研究一致的發(fā)現(xiàn)小腦浦肯野細(xì)胞在衰老過程中會減少，浦肯野細(xì)胞的樹突分枝會出現(xiàn)回縮[61,62]，這些可能與年老個體運(yùn)動功能變差等有關(guān)。

大量研究發(fā)現(xiàn)，人和其他哺乳動物大腦中神經(jīng)元的突觸密度隨衰老減少，然而并非所有腦區(qū)突觸對衰老的敏感程度都是一樣的，前額葉皮層以及海馬區(qū)的突觸變化相對其他腦區(qū)要更加明顯，這也能解釋為什么這兩個腦區(qū)所調(diào)控的行為在正常衰老過程中退化更為明顯[41]。前額葉皮層突觸密度的改變主要表現(xiàn)為大量的軸棘突觸減少，尤其是瘦小型的樹突棘組成的突觸，靈長類第三層神經(jīng)元軸棘突觸丟失的程度與認(rèn)知缺陷的程度顯著相關(guān)[63,64]。由于瘦小型樹突棘是易于動態(tài)變化的，衰老過程中這種類型突觸的減少可能對工作記憶和執(zhí)行能力等這些靈活度要求高的認(rèn)知行為影響較大。比如在獼猴中在體記錄前額葉皮層的神經(jīng)元活動，發(fā)現(xiàn)有一類在工作記憶中延遲發(fā)放的神經(jīng)元的發(fā)放頻率從中年時期開始減弱，到老年時期減弱更為嚴(yán)重，這種延遲神經(jīng)元的發(fā)放減弱可以通過抑制cAMP信號，或者抑制某些亞型的鉀離子通道而得到部分恢復(fù)[18]。電鏡結(jié)果顯示參與抑制這一信號通路的基本蛋白復(fù)合物組分都出現(xiàn)在瘦小型樹突棘[65]，暗示衰老相關(guān)瘦小型樹突棘的丟失在工作記憶的退化中起重要作用。研究顯示衰老過程中海馬的很多亞區(qū)突觸形態(tài)和密度有明顯改變，如獼猴海馬下托區(qū)的突觸密度減少明顯[66]；大鼠CA3區(qū)分子層的突觸密度明顯減少[67]，CA1區(qū)的突觸數(shù)目雖沒有隨年齡增加而減少[68]，但該區(qū)域突觸后致密區(qū)的大小的減少與空間學(xué)習(xí)記憶的缺陷有很好的相關(guān)性[69]。與正常衰老不同，CA1區(qū)突觸數(shù)目的減少是早期AD的一個顯著特征[41,70]。海馬區(qū)主要與形成長期記憶有關(guān)，因此突觸也從簡單的軸棘突觸轉(zhuǎn)變?yōu)閺?fù)雜的穿孔突觸和多突觸軸突棒頭。與前額葉皮層不同，在海馬中是復(fù)雜型的突觸更容易受衰老影響。大鼠齒狀回的穿孔突觸減少以及獼猴齒狀回的多突觸軸突棒頭減少與海馬相關(guān)的認(rèn)知行為退化有關(guān)[66,71,72]。觀察小鼠小腦浦肯野細(xì)胞的突觸結(jié)構(gòu)在衰老過程中的變化也發(fā)現(xiàn)樹突棘和突觸密度都有減少[73]。在人、貓和大鼠中一致發(fā)現(xiàn)，紋狀體的突觸數(shù)目隨年齡增加而減少，其形狀相對于年輕個體也會有所改變[74～76]。對大鼠杏仁核的研究顯示，這個腦區(qū)的突觸密度并不會隨年齡增加出現(xiàn)變化[77,78]，這可能與老年個體情感功能的維持有密切關(guān)系。

衰老過程中除了突觸形態(tài)和密度會發(fā)生改變，突觸功能也有明顯的變化，包括突觸連接強(qiáng)度、可塑性和神經(jīng)遞質(zhì)信號的減少等。與海馬區(qū)形態(tài)學(xué)觀察到的結(jié)果一致，老年大鼠齒狀回記錄到的興奮性突觸后膜電位減少[79,80]。研究恒河猴的前額葉皮層第二、三層椎體神經(jīng)元的突觸電生理特性發(fā)現(xiàn)，興奮性突觸后電流的頻率在老年猴中顯著降低，而抑制性突觸后電流頻率顯著增加[81]，說明突觸功能的衰退導(dǎo)致了大腦興奮性和抑制性環(huán)路的失衡。線蟲中的研究顯示，突觸傳遞過程在衰老時出現(xiàn)明顯衰退，通過化合物刺激來提高突觸傳遞的功能可以提高年老線蟲的運(yùn)動能力[82]。這些結(jié)果都表明突觸功能在衰老過程中出現(xiàn)缺陷。神經(jīng)元形態(tài)、生理特性以及突觸間連接強(qiáng)度的改變對衰老神經(jīng)元可塑性的影響可以通過記錄長時程增強(qiáng)(long-term potentia-tion, LTP)和長時程抑制(long-term depression, LTD)來反映，這方面的研究在大鼠的海馬區(qū)開展得比較多。突觸可塑性的變化主要表現(xiàn)為LTP的誘導(dǎo)和維持出現(xiàn)問題，老年大鼠的LTP的誘導(dǎo)閾值變高，而且LTP在維持階段更快地衰減[80,83]，LTP的衰減速度與空間記憶行為的表現(xiàn)相關(guān)。長時程抑制的結(jié)果與長時程增強(qiáng)是相反的，老年大鼠神經(jīng)元對LTD 更為敏感，表現(xiàn)為LTD的誘導(dǎo)閾值降低[84]。這些結(jié)果提示老年個體更難形成新的記憶，也更容易忘記新形成的記憶[85]。LTP的形成和維持過程都依賴于鈣信號，衰老大腦中鈣穩(wěn)態(tài)的失衡對神經(jīng)元可塑性的缺陷有重要貢獻(xiàn)[86]。如在中老年小鼠中，可以通過抑制L型鈣通道或者鈣依賴的鈣釋放來恢復(fù)由于LTP功能缺陷而引起的記憶行為衰退[87]。

神經(jīng)遞質(zhì)是介導(dǎo)神經(jīng)元之間信號傳遞的化學(xué)物質(zhì)，神經(jīng)遞質(zhì)系統(tǒng)在衰老過程會發(fā)生變化，這種變化與衰老過程中的行為和認(rèn)知功能退化密切相關(guān)。比如衰老過程中多巴胺的水平在人和其他動物大腦中都是下降的[13,88]，使用多巴胺的前體物L(fēng)-DOPA提高老年人多巴胺的水平，可以提高獎賞相關(guān)的學(xué)習(xí)行為的效率，并改變紋狀體區(qū)域的腦活動狀態(tài)[89]，說明多巴胺水平的下降是行為衰退的重要原因，提高多巴胺水平可能可以改善老年人認(rèn)知行為表現(xiàn)。老年人大腦多巴胺的受體和轉(zhuǎn)運(yùn)體在前皮層和紋狀體中表達(dá)都下降[90]，衰老時人紋狀體中D2受體的降低比較明顯，用正電子斷層成像的方法發(fā)現(xiàn)D2受體的可用量與注意力等行為表現(xiàn)有關(guān)[91]。給老年獼猴服用D2受體激動劑，可以緩解延遲記憶行為能力降低[92]。5-羥色胺功能的下降和年老的時候認(rèn)知、情感和睡眠等行為失常(如睡眠質(zhì)量下降[93]、性行為衰退以及老年抑郁行為[94])有密切關(guān)聯(lián)。有關(guān)在正常衰老過程中5-羥色胺水平的變化情況目前存在一些爭議：在人的多個腦區(qū)沒有檢測到5-羥色胺水平的明顯變化[95]，在小鼠中則有所增加[96]；而在大鼠中，5-羥色胺水平在很多腦區(qū)如前皮層、紋狀體和下丘腦等都是下降的，且老年大鼠前皮層和枕葉皮層5-羥色胺水平的降低與記憶行為的缺陷密切相關(guān)[97～102]。這種差異可能與不同研究中研究對象的年齡、性別、所檢測的腦區(qū)及所用的檢測方法不同有關(guān)[103]。運(yùn)用PET方法發(fā)現(xiàn)，人腦中的5-羥色胺轉(zhuǎn)運(yùn)體在衰老過程中是下降的[104,105]；5-羥色胺的受體亞型較多，通過PET方法在體研究，發(fā)現(xiàn)人5-羥色胺受體1A和2A在人的前皮層和海馬是減少的[94]，5-羥色胺2A受體在尾狀核和殼核也是減少的[106]。我們實(shí)驗(yàn)室在線蟲中的研究發(fā)現(xiàn)，衰老過程中線蟲的多巴胺和5-羥色胺水平都有明顯下降，這兩種遞質(zhì)的降低導(dǎo)致了咽喉肌肉跳動行為、雄蟲交配行為以及線蟲對食物響應(yīng)行為的衰退，外加多巴胺和5-羥色胺可以提高老年線蟲的這些行為表現(xiàn)[11]，表明這兩種神經(jīng)遞質(zhì)在衰老時候的下降是相關(guān)行為退化的原因。

在哺乳動物的中樞神經(jīng)系統(tǒng)中，谷氨酸是介導(dǎo)大部分興奮性突觸的神經(jīng)遞質(zhì)[107,108]。大量研究顯示，谷氨酸參與的很多行為如學(xué)習(xí)記憶、動機(jī)和運(yùn)動功能在衰老過程中有明顯退化。老年人運(yùn)動皮層的谷氨酸水平較年輕人的低[109]。人紋狀體區(qū)域的谷氨酸含量隨衰老也有明顯減少，且與一些復(fù)雜的認(rèn)知和運(yùn)動行為功能退化相關(guān)[110]。研究大鼠大腦中谷氨酸含量在衰老過程中的變化，發(fā)現(xiàn)谷氨酸水平在前皮層和海馬中有顯著的降低，而在顳葉和枕葉皮層中沒有明顯變化，在紋狀體的一些亞區(qū)中則是增加的[111]。此外，大鼠中谷氨酸能神經(jīng)末梢處的高親和性谷氨酸轉(zhuǎn)運(yùn)體的表達(dá)水平隨衰老而減少[112,113]。在嚙齒類中的研究發(fā)現(xiàn)，谷氨酸受體N-甲基-D-天冬氨酸(N-methyl-D-aspartate, NMDA)受體在多個腦區(qū)如海馬、前皮層和紋狀體中隨衰老明顯降低[114,115]，α-氨基-3羥基-5甲基-4異惡唑(α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid, AMPA)受體在海馬的一些亞區(qū)域也出現(xiàn)減少[116]。NMDA受體的激活對LTP的誘導(dǎo)具有重要作用，而AMPA受體則參與LTP的維持，這兩個受體在衰老過程中的改變對老年大腦的突觸可塑性有重要影響。海馬區(qū)細(xì)胞表面AMPA受體GluR1的下降程度與大鼠空間記憶行為表現(xiàn)變差的程度呈相關(guān)關(guān)系[117]，另外NMDA和AMPA受體在海馬區(qū)的減少與小鼠衰老時空間記憶功能缺陷呈正相關(guān)[118]。這些研究表明谷氨酸介導(dǎo)的突觸傳遞在大腦衰老過程中降低，且與認(rèn)知功能的退化密切關(guān)聯(lián)。γ-氨基丁酸(γ-aminobutyric acid, GABA)是大腦中主要的抑制性神經(jīng)遞質(zhì)，與觀察、注意等行為有密切關(guān)系[119]。利用磁共振波譜分析發(fā)現(xiàn)人前皮層的GABA水平在老年時期持續(xù)降低，且與運(yùn)動和認(rèn)知功能的缺陷密切相關(guān)[120,121]。其他研究結(jié)果也發(fā)現(xiàn)正常衰老個體中前皮層的GABA水平較年輕時期有減少[122]。GABA遞質(zhì)系統(tǒng)的變化可能改變了大腦中抑制性和興奮性神經(jīng)遞質(zhì)之間的平衡，腦成像研究中觀察到的老年人前額葉皮層的腦活動增加也可能是由于抑制性神經(jīng)遞質(zhì)減少導(dǎo)致的，從而導(dǎo)致老年個體傾向于神經(jīng)興奮毒性[1]。

近幾十年來成像技術(shù)的發(fā)展促進(jìn)了對大腦結(jié)構(gòu)和網(wǎng)絡(luò)連接的理解。衰老過程中大腦體積減少主要發(fā)生在前額葉和海馬區(qū)域[123]，大腦中神經(jīng)元的形態(tài)和功能在衰老過程中發(fā)生了一系列的變化，包括突觸密度減少和突觸可塑性降低[124]，還有神經(jīng)遞質(zhì)系統(tǒng)的減少(圖2)。這些方面的變化在前額葉皮層和海馬腦區(qū)更為明顯，對應(yīng)這兩個腦區(qū)調(diào)控的認(rèn)知功能也是衰老過程中退化最為明顯的。這些變化是由什么機(jī)制調(diào)控的，又是如何導(dǎo)致行為功能衰退的，還需要進(jìn)一步的研究來闡明。

2.3 衰老過程中大腦基因表達(dá)的變化

通過全基因組基因芯片分析人大腦前額葉皮層的基因表達(dá)水平在衰老過程中的變化，發(fā)現(xiàn)突觸功能相關(guān)基因的表達(dá)變化最為明顯[125]，其中參與學(xué)習(xí)記憶和突觸可塑性的相關(guān)基因，如AMPA受體的亞基GluR1 (glutamate receptor 1, GluR1)及NMDA受體，還有GABAA受體亞型都在中年以后表達(dá)顯著降低。另外，突觸鈣信號系統(tǒng)和囊跑運(yùn)輸相關(guān)基因的表達(dá)水平也有明顯降低。其他一些重要生物學(xué)過程相關(guān)的基因也隨衰老發(fā)生明顯改變，如線粒體功能相關(guān)的基因表達(dá)下調(diào)，免疫調(diào)節(jié)和壓力應(yīng)答相關(guān)的基因表達(dá)上調(diào)，而且這些信號通路的基因在衰老過程中的表達(dá)變化在不同物種中都是相似的[1,126]。表達(dá)下調(diào)的基因啟動子區(qū)域的DNA損傷可能是導(dǎo)致這些基因在衰老中表達(dá)下降的原因[125]。另外有研究薈萃分析多個人前額葉皮層基因表達(dá)數(shù)據(jù)庫，也一致地發(fā)現(xiàn)突觸傳遞相關(guān)基因的表達(dá)下調(diào)是該腦區(qū)衰老時最顯著的特征，神經(jīng)再生相關(guān)基因的表達(dá)降低，炎癥和免疫相關(guān)過程的基因表達(dá)上調(diào)也是普遍現(xiàn)象[127]。不同數(shù)據(jù)庫對人海馬等腦區(qū)的研究結(jié)果也顯示，突觸傳遞和可塑性相關(guān)的基因在衰老過程中表達(dá)下調(diào)，炎癥和免疫應(yīng)答相關(guān)的基因表達(dá)上調(diào)[128]。此外，在非人靈長類[129]、大鼠[130]和小鼠[131,132]的衰老大腦中這幾個生物學(xué)信號通路相關(guān)基因的變化與人大腦基因表達(dá)變化趨勢基本上是一致的(表1)。蛋白組學(xué)分析的結(jié)果與轉(zhuǎn)錄組學(xué)的結(jié)果相似，衰老過程中獼猴海馬腦區(qū)蛋白水平明顯降低的主要有電子呼吸傳遞鏈的蛋白和胞質(zhì)核糖體蛋白，而抗氧化蛋白的表達(dá)則增加[133]；小鼠海馬和皮層中蛋白表達(dá)量受衰老影響最為明顯的是線粒體功能、氧化壓力、突觸、核糖體功能等相關(guān)通路上的蛋白[134,135]。

圖2 衰老過程中行為和認(rèn)知功能退化的可能機(jī)制

衰老大腦內(nèi)細(xì)胞、分子和功能發(fā)生明顯改變，是行為和認(rèn)知功能退化的可能機(jī)制。神經(jīng)元之間的連接改變，主要是突觸的密度減少、功能減弱、突觸可塑性降低，神經(jīng)遞質(zhì)系統(tǒng)的功能降低；神經(jīng)元內(nèi)線粒體功能降低，氧化應(yīng)激增加，蛋白穩(wěn)態(tài)失衡導(dǎo)致聚集的蛋白斑塊堆積，DNA甲基化和組蛋白表觀遺傳修飾等隨衰老發(fā)生改變；膠質(zhì)細(xì)胞激活導(dǎo)致大腦神經(jīng)元的持續(xù)慢性炎癥。

總體看來，不同物種大腦中的基因表達(dá)水平和蛋白水平受衰老的影響類似：響應(yīng)氧應(yīng)激的基因以及免疫炎癥相關(guān)基因的表達(dá)顯著增加，線粒體功能和突觸傳遞相關(guān)基因的表達(dá)則顯著降低。這暗示不同物種的大腦衰老可能具有非常保守的分子調(diào)控機(jī)制。其中突觸功能相關(guān)的蛋白減少很可能導(dǎo)致了衰老動物中神經(jīng)元之間的連接減弱，高級認(rèn)知功功能的缺陷。免疫應(yīng)答和炎癥相關(guān)的基因上調(diào)則暗示大腦可能處于長期的慢性炎癥狀態(tài)，盡管適度的免疫激活有神經(jīng)保護(hù)的作用，但持續(xù)的慢性免疫炎癥將

增加大腦的認(rèn)知退化和神經(jīng)退行性疾病發(fā)生的風(fēng)險(xiǎn)[136]。線粒體是細(xì)胞的能量工廠，對神經(jīng)元發(fā)揮正常功能至關(guān)重要，線粒體能量代謝相關(guān)基因的表達(dá)降低在認(rèn)知功能障礙和AD病人中表現(xiàn)得更為明顯[137,138]。

2.4 保守的生物學(xué)信號通路在調(diào)節(jié)衰老相關(guān)行為和認(rèn)知功能退化中的作用

2.4.1 線粒體功能和氧化應(yīng)激

大腦是非常耗能的器官，成年人的大腦大約只占身體總重量的2%，卻消耗了大約20%的總耗氧量。線粒體產(chǎn)生的ATP對神經(jīng)元的存活、興奮性形成和突觸信號傳遞等功能至關(guān)重要。神經(jīng)元中的線粒體還可以調(diào)節(jié)鈣信號穩(wěn)態(tài)、突觸可塑性、細(xì)胞存活和死亡[139]。線粒體功能降低是衰老的一個顯著特征[140]，線粒體在衰老過程中的變化包括形態(tài)和功能的改變。近期的研究發(fā)現(xiàn)老年獼猴前額葉皮層神經(jīng)元突觸前末梢的線粒體形態(tài)由長管狀轉(zhuǎn)變?yōu)榄h(huán)狀或者圈狀，且環(huán)狀線粒體的數(shù)目與工作記憶的表現(xiàn)有負(fù)相關(guān)關(guān)系[141]。研究顯示衰老過程中大鼠大腦中線粒體的總量沒有明顯變化，而線粒體的電子傳遞的效率有降低。線粒體電子呼吸傳遞鏈上不同的復(fù)合物對衰老的敏感程度是不一樣的，復(fù)合物I和復(fù)合物IV的活性隨衰老而降低[142,143]，而復(fù)合物II的活性在衰老過程中維持較好[144]。電子呼吸傳遞鏈上的復(fù)合物I和復(fù)合物IV的活性降低與認(rèn)知功能的衰退呈線性相關(guān)[142]。線粒體氧化磷酸化的過程是產(chǎn)生氧自由基(reactive oxygen species, ROS)的主要來源，大量研究表明衰老過程中線粒體電子呼吸傳遞鏈的效率降低，線粒體功能減弱，導(dǎo)致副產(chǎn)物ROS的量增加[145]；另外，衰老大腦中抗氧化蛋白過氧化物歧化酶(superoxide dismutase, SOD)、過氧化氫酶和谷胱甘肽的活性降低，導(dǎo)致清理ROS的能力在衰老中逐漸降低[142,146]，累積的ROS會進(jìn)一步導(dǎo)致線粒體呼吸鏈上的蛋白復(fù)合物和線粒體DNA氧化損傷，進(jìn)而導(dǎo)致線粒體功能繼續(xù)失調(diào)[142,147,148]。這樣一個有害的反饋環(huán)路使得大腦中神經(jīng)元這樣耗能高的細(xì)胞對衰老特別敏感。提高線粒體功能可以改善年老動物的行為表現(xiàn)并能延長壽命，如在線蟲中提高氧化磷酸化的輔酶NAD+水平可以阻止衰老相關(guān)的線粒體功能衰退，并提高線蟲的運(yùn)動能力，延長線蟲的壽命[149]。最新的研究發(fā)現(xiàn)，通過給老年小鼠注射從年輕小鼠分離的線粒體增加了大腦和骨骼肌組織的ATP水平、降低了ROS水平，并且老年小鼠的認(rèn)知和運(yùn)動行為得到明顯改善[150]。

表1 衰老大腦中基因表達(dá)變化的主要特征

其中人、非人靈長類和嚙齒類為大腦的基因表達(dá)變化，果蠅和線蟲為整個生物體的基因表達(dá)變化。

大量研究認(rèn)為衰老過程中線粒體功能降低主要由于線粒體DNA突變累積所致[151～153]，在人類大腦衰老過程中線粒體DNA的突變確實(shí)是增加的[154～156]。為了研究線粒體DNA突變是不是衰老的一個重要原因，科學(xué)家構(gòu)建了表達(dá)突變形式的線粒體 DNA 聚合酶(該酶只保留了DNA聚合的功能，失去了校對修復(fù)功能)的轉(zhuǎn)基因小鼠模型，該轉(zhuǎn)基因小鼠表現(xiàn)出明顯的早衰表型，如毛發(fā)減少、駝背、生育力下降并且壽命顯著縮短，其線粒體 DNA 突變累積明顯增加，但有意思的是ROS水平和氧化損傷水平并沒有增加[152,157]。值得注意的是這種轉(zhuǎn)基因小鼠線粒體DNA突變累積的頻率要比正常衰老過程中線粒體DNA突變累積的頻率高得多[148]，另外衰老大腦是伴隨有ROS水平增加、氧化損傷累積的，因此正常衰老過程中線粒體DNA突變所起的作用還有待進(jìn)一步研究。我們實(shí)驗(yàn)室的工作發(fā)現(xiàn)表觀遺傳因子BAZ2B和EHMT1可通過抑制線粒體功能相關(guān)基因的表達(dá)，從而抑制線粒體功能[158]。在衰老的大腦中這兩個因子表達(dá)量增加，暗示衰老大腦中表觀遺傳的變化對線粒體功能缺陷有重要貢獻(xiàn)。

衰老過程氧化應(yīng)激和抗氧化之間的平衡對神經(jīng)元維持正常結(jié)構(gòu)以及發(fā)揮正常功能是必需的。衰老過程中氧化應(yīng)激增加使神經(jīng)元累積損傷和聚集的蛋白、損傷的線粒體、超氧化的磷脂、損傷的核和線粒體DNA等，導(dǎo)致細(xì)胞膜特性改變、酶和受體蛋白的功能受損、鈣信號失衡和突觸功能降低[159,160]。研究表明L型鈣通道，以及NMDA受體氧化還原狀態(tài)的改變可以影響細(xì)胞內(nèi)鈣穩(wěn)態(tài)，從而影響海馬區(qū)神經(jīng)元的興奮性[161,162]，并影響突觸的可塑性[163]。另有一些研究表明，抗氧化能力減弱，清理氧化損傷能力降低將導(dǎo)致行為等功能的加速退化。如在果蠅和小鼠中降低過氧化物歧化酶SOD2的水平會加速運(yùn)動行為退化、損傷神經(jīng)元DNA并誘導(dǎo)神經(jīng)退行性疾病的發(fā)生[164,165]。小鼠過表達(dá)細(xì)胞外SOD1可以增加海馬神經(jīng)元的可塑性，提高運(yùn)動行為和空間學(xué)習(xí)行為的能力[166]。另外大鼠海馬中過表達(dá)SOD1也可以延緩認(rèn)知功能的降低，然而氧化損傷的降低與認(rèn)知行為的表現(xiàn)并沒有很好的相關(guān)性[167]，暗示氧化損傷本身可能并不是導(dǎo)致行為和認(rèn)知功能退化的主要原因，而與氧化還原信號相關(guān)的信號通路可能更為重要。近期有很多其他研究也對氧自由基的衰老理論提出了挑戰(zhàn)。在線蟲中的研究顯示低水平的氧化脅迫反而可以延長壽命，如受抗霉素 A或低濃度百草枯處理的線蟲以及一些線粒體功能降低的突變線蟲中，雖然ROS水平增加了，但其壽命卻延長了[168～170]。因此，雖然氧化水平增加，氧化損傷累積是大腦衰老的一個重要特征，但是氧化脅迫是如何影響行為和認(rèn)知功能退化的，是衰老過程ROS 水平增加導(dǎo)致了大腦功能受損，還是ROS 作為細(xì)胞內(nèi)信號分子參與的信號通路出現(xiàn)問題從而導(dǎo)致了大腦功能衰退，還有待更多的研究。

2.4.2 蛋白穩(wěn)態(tài)

正常衰老過程中，蛋白質(zhì)量控制系統(tǒng)如自噬和蛋白酶體系統(tǒng)功能降低[171,172]，大腦中聚集的蛋白斑塊累積增加。在模式動物果蠅()和小鼠中，抑制自噬會引起神經(jīng)退行性病變并縮短壽命，這種神經(jīng)退行性病變同時伴隨著泛素化的蛋白聚集[173～175]。果蠅中提高基礎(chǔ)的自噬功能可延長壽命[176]，而且研究發(fā)現(xiàn)一些長壽突變體通常都激活了自噬功能，自噬對這些長壽突變體的壽命延長是必需的[177,178]。另外有研究表明影響線粒體自噬通路的基因PINK1和PARKIN的突變將引起神經(jīng)退行性病變，如家族性帕金森病以及晚發(fā)性阿爾茲海默病[179]。在小鼠模型中降低大腦蛋白酶體的功能，會增加一些蛋白的堆積，其中有些是之前報(bào)道在AD疾病中表達(dá)發(fā)生變化的蛋白，并且小鼠的空間記憶功能受損[180]。這些結(jié)果說明衰老過程中蛋白穩(wěn)態(tài)失衡對認(rèn)知和行為功能退化有重要貢獻(xiàn)，而且可能是阿爾茲海默病、帕金森病等其他蛋白毒性的神經(jīng)退行性疾病中蛋白出現(xiàn)折疊異常和聚集的重要機(jī)制[181,182]。

2.4.3 慢性炎癥

炎癥相關(guān)的基因表達(dá)增加是不同物種大腦衰老過程中基因表達(dá)變化的一個共有特征，膠質(zhì)細(xì)胞介導(dǎo)了大腦中的神經(jīng)炎癥反應(yīng)[183]，衰老過程中星形膠質(zhì)細(xì)胞和小膠質(zhì)細(xì)胞激活的標(biāo)志基因表達(dá)都明顯增加[184,185]，如小鼠星形膠質(zhì)細(xì)胞的標(biāo)志性蛋白GFAP[186,187]。降低小鼠星形膠質(zhì)細(xì)胞的GFAP的水平可以提高 LTP 和神經(jīng)元存活[188,189]。小膠質(zhì)細(xì)胞是大腦中的免疫細(xì)胞，老年大腦中激活的小膠質(zhì)細(xì)胞數(shù)目增加，具有更高的炎癥標(biāo)志水平，處于持續(xù)的慢性炎癥狀態(tài)[190]。大腦中炎癥因子變化的特點(diǎn)主要有白細(xì)胞介素(IL)1β、IL-6以及腫瘤壞死因子等炎癥因子增加，而IL-10和IL-4抗炎癥因子減少[190]。長期的過多的神經(jīng)性炎癥可以導(dǎo)致神經(jīng)元突觸損傷[191]、功能缺陷[192,193]以及一些神經(jīng)推行性疾病的發(fā)生[194,195]。

2.5 行為和認(rèn)知退化的遺傳和表觀遺傳因素

雖然在動物模型中發(fā)現(xiàn)了上百個長壽基因，但科學(xué)家對人類的長壽機(jī)理了解并不多，目前主要發(fā)現(xiàn)了和的遺傳變異可能與人類長壽相關(guān)[196,197]。關(guān)于認(rèn)知和行為功能退化的遺傳因素，近年有些研究將一些基因，如腦源性神經(jīng)營養(yǎng)因子(brain-derived neurotrophic factor,)、載脂蛋白E(apolipoprotein E,)和兒茶酚-O-甲基轉(zhuǎn)移酶(catechol-O-methyltransferase,)與老年人的認(rèn)知功能退化聯(lián)系起來[198,199]。參與海馬依賴的學(xué)習(xí)和記憶行為，它的表達(dá)水平在正常衰老過程中逐漸降低[200]，可導(dǎo)致衰老大鼠認(rèn)知功能下降[201]。基因位點(diǎn)的變異不僅與晚發(fā)型阿爾茲海默病有關(guān)，還與正常衰老的認(rèn)知退化有關(guān)[202]。COMT是降解多巴胺、腎上腺素和去甲腎上腺素的關(guān)鍵酶，上的一個遺傳變異會影響該酶的活性并與前額葉依賴的執(zhí)行能力的退化有關(guān)[198]。這些單個基因?qū)τ谒ダ舷嚓P(guān)認(rèn)知和行為功能的影響很小，由于認(rèn)知和行為功能的退化是一個非常復(fù)雜的表型，可能有大量基因參與調(diào)控同一行為表型，而且很多認(rèn)知行為是互相關(guān)聯(lián)的，可能需要一個精細(xì)的基因網(wǎng)絡(luò)的調(diào)控?，F(xiàn)代測序技術(shù)的發(fā)展對尋找新的影響認(rèn)知等行為功能退化的基因?qū)泻艽髱椭?/p>

基于雙胞胎的研究表明遺傳物質(zhì)的不同可能只能解釋個體之間壽命差異的20%～30%，至少有70%的壽命差異是受環(huán)境因素影響的[203～205]。越來越多研究表明個人所處的環(huán)境和生活狀態(tài)，飲食習(xí)慣等對維持老年時候良好的行為功能，以及預(yù)防退行性疾病的發(fā)生有很重要的影響[206,207]。環(huán)境因素明顯影響著正常和疾病狀態(tài)下的大腦衰老，表觀遺傳調(diào)控因子是聯(lián)系環(huán)境因素和細(xì)胞信號的重要分子。雖然大部分衰老相關(guān)的表觀遺傳的研究結(jié)果主要是在外周組織獲得的，大腦中表觀遺傳的特征也發(fā)生與衰老相關(guān)的變化。由于大腦中絕大部分的神經(jīng)元在產(chǎn)前發(fā)育時期就已經(jīng)脫離細(xì)胞周期，成為不再分裂的細(xì)胞，因此DNA甲基化、組蛋白修飾以及表觀遺傳組的其他分子對于維持整個生命過程中神經(jīng)元的健康和功能非常重要[208]。

衰老大腦中DNA甲基化和組蛋白修飾都發(fā)生了明顯改變。DNA甲基化主要發(fā)生在CpG雙核甘酸位點(diǎn)。近年來隨著DNA甲基化芯片和二代測序技術(shù)的發(fā)展，人們對不同組織和細(xì)胞DNA甲基化水平在生命過程中的變化有了比較全面的了解，發(fā)現(xiàn)特定位點(diǎn)的DNA甲基化水平與衰老有很大相關(guān)性，可以比較準(zhǔn)確的預(yù)測個體的出生年代，還可以指示個體的生物學(xué)年齡以及衰老相關(guān)的風(fēng)險(xiǎn)因素[209,210]。研究人大腦皮層DNA甲基化在衰老過程中的變化，發(fā)現(xiàn)DNA胞嘧啶甲基化水平在一些特定基因的啟動子區(qū)域是增加的，這種增加會抑制突觸信號相關(guān)基因的表達(dá)以及其他一些大腦功能[211,212]。組蛋白乙?；揎検腔蚧罨臉?biāo)志，乙?；揎椀慕档蜁种票恍揎椈虻谋磉_(dá)。老年人前額葉皮層中一些與GABA能神經(jīng)信號傳遞、5-羥色胺信號以及線粒體功能相關(guān)基因的啟動子遠(yuǎn)端區(qū)域，組蛋白乙?；浇档蚚213]。嚙齒類動物的研究中也有類似的發(fā)現(xiàn)，海馬區(qū)域與記憶形成和穩(wěn)定相關(guān)的基因的H4K12乙?；皆诶夏晷∈笾忻黠@降低[214]。這些基因上的組蛋白修飾的變化將影響基因的表達(dá)水平，進(jìn)而影響神經(jīng)元的功能以及信號傳遞。提高年老小鼠H4K12乙?；娇梢曰謴?fù)年老小鼠衰老相關(guān)基因的表達(dá)水平和學(xué)習(xí)能力[215]。另有研究表明，使用組蛋白去乙?；?histone deacetylase, HDAC)抑制劑處理小鼠可以改善小鼠的長期記憶行為并增加海馬的神經(jīng)再生能力[216,217]。目前已發(fā)現(xiàn)HDAC 抑制劑對AD等多種神經(jīng)退行性疾病的動物模型有神經(jīng)保護(hù)和促進(jìn)神經(jīng)再生的作用[218～222]。在早衰模型小鼠的大腦中，H4K20me1和H3K36me3的水平在衰老的時候顯著降低，并伴隨有抑制性的表觀遺傳標(biāo)志H3K27me3增加[223]。在果蠅的整體組織中 H3K9me3和HP1蛋白是降低的，但在頭部組織中H3K9me3是增加的，說明衰老過程中不同組織中的組蛋白修飾的變化是不一樣的[224]。

我們實(shí)驗(yàn)室的研究發(fā)現(xiàn)人大腦前額葉皮層H3K9甲基轉(zhuǎn)移酶EHMT1和表觀遺傳識別因子BAZ2B的表達(dá)水平隨衰老逐漸增加，在AD病人的大腦中有進(jìn)一步增加，并且與疾病進(jìn)程正相關(guān)。它們的線蟲同源蛋白，分別是SET-6和BAZ-2，可以結(jié)合到線粒體功能相關(guān)基因的啟動子區(qū)域，調(diào)控這些基因的H3K9me3甲基化修飾，抑制線粒體功能相關(guān)基因的表達(dá)。敲除和可以延緩線蟲行為功能退化，這是通過提高線粒體功能實(shí)現(xiàn)的。這種調(diào)控機(jī)制在小鼠中也是保守的，敲除小鼠中的同源基因Baz2b可以阻止小鼠認(rèn)知行為隨衰老的退化[158]。此外，有其他研究支持這一發(fā)現(xiàn)，在AD病人和AD模型小鼠的大腦中，EHMT1的表達(dá)水平增加，利用小分子藥物抑制EHMT1蛋白功能可以改善AD模型小鼠的突觸功能和學(xué)習(xí)記憶行為[225,226]。

總的來看在衰老大腦中在神經(jīng)元存活、突觸傳遞以及學(xué)習(xí)記憶相關(guān)基因的啟動子區(qū)域，主要是促進(jìn)基因表達(dá)的表觀遺傳修飾如組蛋白乙?；?、H3K36me3、H4K20me1水平降低，而抑制基因表達(dá)的表觀遺傳修飾如DNA甲基化、H3K9me2/3和H3K27me3水平增加，從而導(dǎo)致這些目標(biāo)基因表達(dá)隨衰老下降。目前關(guān)于大腦衰老的表觀遺傳組學(xué)圖譜還不完整，衰老中表觀遺傳的變化是如何調(diào)控行為衰退的仍很不清楚，需要更多進(jìn)一步的研究。由于表觀遺傳修飾的可逆性，是否可以通過藥物干預(yù)表觀遺傳狀態(tài)來改善老年人的認(rèn)知行為是值得關(guān)注的。

3 延緩衰老相關(guān)行為和認(rèn)知功能退化的方法

3.1 節(jié)食

自1935年首次報(bào)道節(jié)食可以延長壽命以來，已有大量文獻(xiàn)報(bào)道節(jié)食對衰老的調(diào)控作用，在不同物種中節(jié)食都有延長壽命的作用[227]。此外，研究發(fā)現(xiàn)節(jié)食可以改善多種衰老相關(guān)認(rèn)知功能的退化，比如學(xué)習(xí)記憶行為。在人的研究中發(fā)現(xiàn)，持續(xù)兩年的輕度節(jié)食可以略微提高健康老年人的工作記憶[228]；另外，三個月的節(jié)食提高了老年人的語言記憶，但并沒有明顯改善其他方面與衰老相關(guān)的記憶退化[229]。在靈長類中，節(jié)食減輕了衰老過程中的大腦萎縮，降低發(fā)病率[230]，長期慢性節(jié)食提高了老年猴的工作記憶[231]。在嚙齒類中的研究發(fā)現(xiàn)大鼠經(jīng)長期節(jié)食飼養(yǎng)可以改善年老時期的迷宮行為表現(xiàn)[232]，此外給小鼠間歇性的節(jié)食飼養(yǎng)也可以增強(qiáng)中年小鼠的學(xué)習(xí)記憶，促進(jìn)突觸可塑性，增加某些腦區(qū)NMDA受體的表達(dá)[233]。節(jié)食還可以抑制AD模型小鼠大腦中Aβ的聚集[234]，改善糖尿病病人衰老相關(guān)的認(rèn)知退化[235]。盡管大部分的研究都顯示節(jié)食可改善老年個體的認(rèn)知和行為功能，但有些研究發(fā)現(xiàn)長期的節(jié)食對大鼠記憶并無改善作用[236]，這暗示節(jié)食的起始時間、持續(xù)時間、程度、方式等對衰老相關(guān)行為功能退化的作用還是值得細(xì)究的[237]。節(jié)食改善衰老時的行為能力的機(jī)制還不是很清楚。目前認(rèn)為節(jié)食改善大腦功能的可能機(jī)制涉及保護(hù)線粒體功能[238,239]、減少氧自由基釋放、增加抗氧化能力、減少神經(jīng)元氧化壓力[240,241]、促進(jìn)突觸可塑性[242,243]、誘導(dǎo)壓力應(yīng)答基因以及神經(jīng)營養(yǎng)因子的表達(dá)[244]和增加神經(jīng)再生等[245,246]。

3.2 Sirtuins和NAD+

Sirtuins屬于一個進(jìn)化上保守的蛋白家族，是一類以煙酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide, NAD+)作為輔助底物的去乙酰化酶。研究發(fā)現(xiàn)過表達(dá)Sirtuin的成員在多個物種中都有延長壽命的作用[247]，且有研究發(fā)現(xiàn)Sirt1介導(dǎo)了節(jié)食引起的長壽信號通路[248]。近期的研究還發(fā)現(xiàn)SIRT1在小鼠海馬神經(jīng)元中表達(dá)，參與了學(xué)習(xí)記憶以及突觸可塑性調(diào)控[249,250]，過表達(dá)SIRT1可以促進(jìn)健康衰老[251]，并有預(yù)防神經(jīng)退行性疾病的作用[252]。NAD+是能量代謝中的輔酶，也是Sirtuin去乙酰化酶的限速底物，研究表明NAD+水平和Sirtuin的活性在衰老過程中降低[253,254]。通過藥物或遺傳方法提高NAD+水平可以延長線蟲壽命，并提高年老線蟲的運(yùn)動行為[149]。通過在小鼠海馬CA1區(qū)域特異性敲低NAD+合成酶降低大腦NAD+水平致使小鼠表現(xiàn)出衰老類似的認(rèn)知缺陷的表型[255]。給小鼠長期服用NAD+前體物質(zhì)煙酰胺單核苷酸，可減輕小鼠與衰老相關(guān)的各種生理功能的衰退，包括運(yùn)動和視力退化[256]。此外，NAD+處理 AD 模型的小鼠可以部分阻止記憶丟失[257]。進(jìn)一步研究Sirtuin激動劑和增加NAD+水平對人類衰老相關(guān)行為和認(rèn)知功能是否有改善，對多種疾病是否有緩解作用值得期待。

3.3 運(yùn)動和腦力訓(xùn)練

雖然很多研究都關(guān)注開發(fā)藥物來實(shí)現(xiàn)健康衰老，事實(shí)上很多的研究顯示運(yùn)動以及智力訓(xùn)練可以保護(hù)大腦功能，甚至可以改善神經(jīng)退行性疾病引起的行為缺陷。大量研究表明，持續(xù)適度的鍛煉對認(rèn)知、運(yùn)動等各項(xiàng)生理功能具有積極的作用[258,259]，另外還可以減少癡呆和AD等疾病的發(fā)病率[260]。其可能的機(jī)制包括，增強(qiáng)線粒體功能、增加大腦自噬水平[261]、降低炎癥水平[262]、增加神經(jīng)營養(yǎng)因子水平、增強(qiáng)突觸可塑性及刺激神經(jīng)再生[263]。運(yùn)動能增加人血清中的BDNF水平[264]，小鼠中的研究表明運(yùn)動引起的BDNF增加可以促進(jìn)神經(jīng)元的可塑性和大腦健康[265,266]，抑制BDNF信號通路會消除運(yùn)動對認(rèn)知的改善[267]。另外近期研究顯示跑步可增加小鼠，猴子和人血漿中肌肉細(xì)胞分泌的因子組織蛋白酶B。在人的血漿中組織蛋白酶B的水平與記憶力是正相關(guān)的，小鼠中組織蛋白酶 B介導(dǎo)了運(yùn)動促進(jìn)老年動物神經(jīng)再生和改善記憶行為的作用[268]。除了運(yùn)動，腦力訓(xùn)練也是有助于延緩衰老相關(guān)認(rèn)知退化的一種方式。有研究表明教育可以降低認(rèn)知行為的下降速率[269～271]。老年人如果更多地參與到社會活動及要求腦力的活動中，則可以推測他們的認(rèn)知能力在后續(xù)衰老過程中退化更緩慢，發(fā)生癡呆和阿爾茲海默病的可能性更低[272,273]。而且更重要的是老年時期而不是年輕時期的腦力活動，更影響衰老相關(guān)認(rèn)知功能的退化[274]，法國生物學(xué)家拉馬克提出的“用進(jìn)廢退”可以很好地概括這種腦力訓(xùn)練對認(rèn)知衰老的保護(hù)作用。這種改善大腦認(rèn)知衰退的機(jī)制目前還不清楚，可能與大腦本身的可塑性有關(guān)[275,276]，還可能與神經(jīng)再生有關(guān)，如在豐富環(huán)境中飼養(yǎng)的小鼠突觸密度更高，海馬的神經(jīng)再生能力更強(qiáng)[277]。

3.4 改善認(rèn)知和行為功能的化合物

模式動物中的研究表明，一些延長壽命的信號通路也可延緩行為和認(rèn)知退化。雷帕霉素通過抑制mTOR信號通路，可以延長多種模式動物包括酵母、果蠅和小鼠的壽命[278～280]。在早衰模型的大鼠中，雷帕霉素減少了焦慮行為，并提高了運(yùn)動和探索行為，同時抑制了大腦萎縮[281]。大量研究顯示雷帕霉素對衰老大腦的各項(xiàng)功能有保護(hù)作用。長期低劑量的雷帕霉素處理提高了老年小鼠的認(rèn)知功能，其作用機(jī)制是通過降低大腦的炎癥水平，并增加海馬的NMDA信號[282]。其他研究也發(fā)現(xiàn)長期給小鼠服用雷帕霉素，小鼠的多巴胺和5-羥色胺等單胺類神經(jīng)遞質(zhì)水平都有顯著提高，并阻止了衰老相關(guān)的認(rèn)知退化，還可以改善衰老相關(guān)的焦慮和抑郁行為[283]。給大鼠服用雷帕霉素也得到了類似的發(fā)現(xiàn)[284]。雷帕霉素還可以減少AD模型小鼠Aβ的堆積，并提高認(rèn)知功能[285,286]。mTOR對調(diào)節(jié)蛋白穩(wěn)態(tài)是非常關(guān)鍵的信號通路，同時控制著蛋白合成和降解。服用雷帕霉素的量、起始時間、持續(xù)時間對衰老相關(guān)行為退化的改善作用很關(guān)鍵，這是為什么有些研究發(fā)現(xiàn)給老年小鼠服用雷帕霉素并沒有改善認(rèn)知功能的原因[287]。

近幾年來異時異種共生的方法(即將年輕和年老小鼠通過手術(shù)聯(lián)合在一起，使小鼠共享血液循環(huán)系統(tǒng))在衰老研究中的應(yīng)用，發(fā)現(xiàn)血液中有影響衰老的因子。年輕小鼠的血液使年老小鼠的多個組織，包括肌肉、大腦、骨骼的功能都顯得年輕化[288,289]。科學(xué)家進(jìn)一步發(fā)現(xiàn)給老年小鼠注射年輕小鼠的血漿就足以改善海馬相關(guān)的學(xué)習(xí)記憶行為，增加神經(jīng)再生的能力；反過來老年小鼠血漿注射到年輕小鼠使得年輕小鼠的神經(jīng)再生能力降低，學(xué)習(xí)記憶能力也變差[290,291]。進(jìn)一步研究血漿中到底哪種蛋白或生化因子可以調(diào)控大腦衰老，科學(xué)家發(fā)現(xiàn)了CCL11、GDF11、TIMP2等因子可以調(diào)控衰老相關(guān)行為退化。在衰老過程中趨化因子CCL11在血液中是增加的，而且其水平與學(xué)習(xí)記憶表現(xiàn)負(fù)相關(guān)，增加年輕小鼠血液中CCL11水平會降低小鼠的神經(jīng)再生和學(xué)習(xí)記憶功能[290]。GDF11可以增加大腦神經(jīng)再生和血管完整性[291]。此外，近期研究發(fā)現(xiàn)人臍帶血中含有的蛋白 TIMP2可以增加老年小鼠海馬神經(jīng)再生功能和神經(jīng)元的可塑性，并且提高老年小鼠的空間記憶以及認(rèn)知行為[292]。這些結(jié)果說明血液中具有調(diào)節(jié)行為退化的因子，有些檢測年輕血液對神經(jīng)退行性疾病的作用的臨床試驗(yàn)正在進(jìn)行中。

4 結(jié)語與展望

過去幾十年對不同動物中衰老相關(guān)認(rèn)知和行為退化以及大腦衰老的研究已經(jīng)積累了大量進(jìn)展，在人類和其他模式動物中一致地發(fā)現(xiàn)一些認(rèn)知行為如情節(jié)記憶、空間記憶、工作記憶、信息處理速度等，運(yùn)動能力和節(jié)律行為在衰老過程中有明顯退化。大腦結(jié)構(gòu)，網(wǎng)絡(luò)連接，以及神經(jīng)元形態(tài)和功能，神經(jīng)遞質(zhì)水平等在不同的腦區(qū)會呈現(xiàn)不同程度的變化，其中前額葉皮層和海馬是受衰老影響比較大的兩個腦區(qū)。這些變化與衰老過程中認(rèn)知和行為退化之間有著密切的聯(lián)系。隨著高通量測序、蛋白組學(xué)等分析方法的發(fā)展，行為退化的分子細(xì)胞機(jī)制也逐漸展現(xiàn)。目前的研究已發(fā)現(xiàn)有一些策略是可以延緩衰老相關(guān)行為衰退的，比如節(jié)食、運(yùn)動和腦力訓(xùn)練還有應(yīng)用一些化學(xué)因子等，表明衰老相關(guān)行為退化是一個可塑的過程，找到合適的方法可以延緩行為和認(rèn)知功能衰退，提高老年人的生活質(zhì)量。

除了目前已取得的研究進(jìn)展，關(guān)于衰老過程中認(rèn)知和行為退化的分子的分子機(jī)制還有很多問題有待解答，如為什么老年人行為退化的程度存在很大的個體之間差異？盡管大多數(shù)的老年人都出現(xiàn)明顯的行為和認(rèn)知功能的退化，有一些老年人卻能維持很好的行為功能。研究這些老年人之間的個體差異有助于我們理解衰老如何影響認(rèn)知能力，哪些因素可以阻止行為退化。部分研究表明遺傳變異對這種個體差異可能有一定貢獻(xiàn)[293]，通過構(gòu)建動物模型(如不同地區(qū)野生型的線蟲、雜交品系的小鼠或者大鼠)模擬人類的遺傳變異來研究老年動物行為的個體差異可能是很好的突破點(diǎn)。另外，衰老過程中大腦結(jié)構(gòu)、神經(jīng)元形態(tài)以及互相之間連接的變化是如何產(chǎn)生的，又是如何導(dǎo)致行為衰退的？目前還是相關(guān)性的研究為主，很難得到因果關(guān)系的證據(jù)。新發(fā)展起來的CRISPR/Cas9基因編輯技術(shù)在哺乳動物上的應(yīng)用，以及克隆猴的成功為研究這些問題提供了新的策略。大腦衰老過程中基因表達(dá)變化在不同的物種都有比較保守的特征，那么這些保守的生物學(xué)信號通路的變化是如何協(xié)同調(diào)控的？很可能表觀遺傳調(diào)控在其中起了重要的作用。越來越多的研究關(guān)注到除了延長壽命，延緩行為和認(rèn)知功能的退化也是延緩衰老的重要目標(biāo)。相信未來對衰老相關(guān)行為退化調(diào)控機(jī)制的進(jìn)一步研究，可以找到更多更有效的延緩認(rèn)知和行為退化的方法，為實(shí)現(xiàn)健康衰老，預(yù)防退行性疾病的發(fā)生奠定基礎(chǔ)。

[1] Bishop NA, Lu T, Yankner BA. Neural mechanisms of ageing and cognitive decline., 2010, 464(7288): 529–535.

[2] Harada CN, Natelson Love MC, Triebel KL. Normal cognitive aging., 2013, 29(4): 737– 752.

[3] McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935., 1989, 5(3): 155–171; discussion 172.

[4] Gavrilov LA, Gavrilova NS. Evolutionary theories of aging and longevity., 2002, 2: 339–356.

[5] Shay JW, Wright WE. Hayflick, his limit, and cellular ageing., 2000, 1(1): 72–76.

[6] Jiang H, Ju Z, Rudolph KL. Telomere shortening and ageing., 2007, 40(5): 314–324.

[7] Jin K. Modern biological theories of aging., 2010, 1(2): 72–74.

[8] Klass MR. A method for the isolation of longevity mutants in the nematode caenorhabditis elegans and initial results., 1983, 22(3–4): 279–286.

[9] Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R. A c. Elegans mutant that lives twice as long as wild type., 1993, 366(6454): 461–464.

[10] Kenyon CJ. The genetics of ageing., 2010, 464(7288): 504–512.

[11] Yin JA, Liu XJ, Yuan J, Jiang J, Cai SQ. Longevity manipulations differentially affect serotonin/dopamine level and behavioral deterioration in aging caenorhabditis elegans., 2014, 34(11): 3947–3958.

[12] Bansal A, Zhu LJ, Yen K, Tissenbaum HA. Uncoupling lifespan and healthspan in caenorhabditis elegans longevity mutants., 2015, 112(3): E277–286.

[13] Hedden T, Gabrieli JD. Insights into the ageing mind: A view from cognitive neuroscience., 2004, 5(2): 87–96.

[14] Riddle DR. Brain aging: Models, methods, and mechanisms. CRC Press, 2007.

[15] Spencer WD, Raz N. Differential effects of aging on memory for content and context: A meta-analysis., 1995, 10(4): 527–539.

[16] Nyberg L, L?vden M, Riklund K, Lindenberger U, B?ckman L. Memory aging and brain maintenance., 2012, 16(5): 292–305.

[17] Yeoman M, Scutt G, Faragher R. Insights into cns ageing from animal models of senescence., 2012, 13(6): 435–445.

[18] Wang M, Gamo NJ, Yang Y, Jin LE, Wang XJ, Laubach M, Mazer JA, Lee D, Arnsten AF. Neuronal basis of age-related working memory decline., 2011, 476(7359): 210–213.

[19] West RL. An application of prefrontal cortex function theory to cognitive aging., 1996, 120(2): 272–292.

[20] Buckner RL. Memory and executive function in aging and ad: Multiple factors that cause decline and reserve factors that compensate., 2004, 44(1): 195–208.

[21] Kirova AM, Bays RB, Lagalwar S. Working memory and executive function decline across normal aging, mild cognitive impairment, and alzheimer's disease., 2015, 2015: 748212.

[22] Zelinski EM, Burnight KP. Sixteen-year longitudinal and time lag changes in memory and cognition in older adults., 1997, 12(3): 503–513.

[23] Commodari E, Guarnera M. Attention and aging., 2008, 20(6): 578–584.

[24] R?nnlund M, Nyberg L, B?ckman L, Nilsson LG. Stability, growth, and decline in adult life span development of declarative memory: Cross-sectional and longitudinal data from a population-based study., 2005, 20(1): 3–18.

[25] Carstensen LL, Lockenhoff CE. Aging, emotion, and evolution: The bigger picture., 2003, 1000: 152–179.

[26] Williams LM, Brown KJ, Palmer D, Liddell BJ, Kemp AH, Olivieri G, Peduto A, Gordon E. The mellow years?: Neural basis of improving emotional stability over age., 2006, 26(24): 6422–6430.

[27] Carstensen LL, Fung HH, Charles ST. Socioemotional selectivity theory and the regulation of emotion in the second half of life., 2003, 27(2): 103– 123.

[28] Mattay VS, Fera F, Tessitore A, Hariri AR, Das S, Callicott JH, Weinberger DR. Neurophysiological correlates of age-related changes in human motor function., 2002, 58(4): 630–635.

[29] Seidler RD, Bernard JA, Burutolu TB, Fling BW, Gordon MT, Gwin JT, Kwak Y, Lipps DB. Motor control and aging: Links to age-related brain structural, functional, and biochemical effects., 2010, 34(5): 721–733.

[30] Faulkner JA, Larkin LM, Claflin DR, Brooks SV. Age-related changes in the structure and function of skeletal muscles., 2007, 34(11): 1091–1096.

[31] Tsukahara S, Tanaka S, Ishida K, Hoshi N, Kitagawa H. Age-related change and its sex differences in histoarchitecture of the hypothalamic suprachiasmatic nucleus of f344/n rats., 2005, 40(3): 147–155.

[32] Roberts DE, Killiany RJ, Rosene DL. Neuron numbers in the hypothalamus of the normal aging rhesus monkey: Stability across the adult lifespan and between the sexes., 2012, 520(6): 1181–1197.

[33] Satoh A, Imai SI, Guarente L. The brain, sirtuins, and ageing., 2017, 18(6): 362–374.

[34] Chang HC, Guarente L. Sirt1 mediates central circadian control in the scn by a mechanism that decays with aging., 2013, 153(7): 1448–1460.

[35] Anderson ND, Craik FI. 50 years of cognitive aging theory., 2017, 72(1): 1–6.

[36] Persson J, Sylvester CY, Nelson JK, Welsh KM, Jonides J, Reuter-Lorenz PA. Selection requirements during verb generation: Differential recruitment in older and younger adults., 2004, 23(4): 1382–1390.

[37] Logan JM, Sanders AL, Snyder AZ, Morris JC, Buckner RL. Under-recruitment and nonselective recruitment: Dissociable neural mechanisms associated with aging., 2002, 33(5): 827–840.

[38] Rosen AC, Prull MW, O'Hara R, Race EA, Desmond JE, Glover GH, Yesavage JA, Gabrieli JDE. Variable effects of aging on frontal lobe contributions to memory., 2002, 13(18): 2425–2428.

[39] Andrews-Hanna JR, Snyder AZ, Vincent JL, Lustig C, Head D, Raichle ME, Buckner RL. Disruption of large-scale brain systems in advanced aging., 2007, 56(5): 924–935.

[40] Resnick SM, Pham DL, Kraut MA, Zonderman AB, Davatzikos C. Longitudinal magnetic resonance imaging studies of older adults: A shrinking brain., 2003, 23(8): 3295–3301.

[41] Burke SN, Barnes CA. Neural plasticity in the ageing brain., 2006, 7(1): 30–40.

[42] Pakkenberg B, Gundersen HJ. Neocortical neuron number in humans: Effect of sex and age., 1997, 384(2): 312–320.

[43] West MJ, Coleman PD, Flood DG, Troncoso JC. Differences in the pattern of hippocampal neuronal loss in normal ageing and alzheimer's disease., 1994, 344(8925): 769–772.

[44] Merrill DA, Roberts JA, Tuszynski MH. Conservation of neuron number and size in entorhinal cortex layers ii, iii, and v/vi of aged primates., 2000, 422(3): 396–401.

[45] Keuker JI, Luiten PG, Fuchs E. Preservation of hippocampal neuron numbers in aged rhesus monkeys., 2003, 24(1): 157–165.

[46] Merrill DA, Chiba AA, Tuszynski MH. Conservation of neuronal number and size in the entorhinal cortex of behaviorally characterized aged rats., 2001, 438(4): 445–456.

[47] Rapp PR, Gallagher M. Preserved neuron number in the hippocampus of aged rats with spatial learning deficits., 1996, 93(18): 9926–9930.

[48] Peters A, Morrison JH, Rosene DL, Hyman BT. Feature article: Are neurons lost from the primate cerebral cortex during normal aging?, 1998, 8(4): 295–300.

[49] Smith DE, Rapp PR, McKay HM, Roberts JA, Tuszynski MH. Memory impairment in aged primates is associated with focal death of cortical neurons and atrophy of subcortical neurons., 2004, 24(18): 4373–4381.

[50] Scheibel ME, Lindsay RD, Tomiyasu U, Scheibel AB. Progressive dendritic changes in aging human cortex., 1975, 47(3): 392–403.

[51] Nakamura S, Akiguchi I, Kameyama M, Mizuno N. Age-related changes of pyramidal cell basal dendrites in layers iii and v of human motor cortex: A quantitative golgi study., 1985, 65(3–4): 281–284.

[52] de Brabander JM, Kramers RJ, Uylings HB. Layer- specific dendritic regression of pyramidal cells with ageing in the human prefrontal cortex., 1998, 10(4): 1261–1269.

[53] Peters A, Sethares C, Moss MB. The effects of aging on layer 1 in area 46 of prefrontal cortex in the rhesus monkey., 1998, 8(8): 671–684.

[54] Markham JA, Juraska JM. Aging and sex influence the anatomy of the rat anterior cingulate cortex., 2002, 23(4): 579–588.

[55] Hall TC, Miller AKH, Corsellis JAN. Variations in human purkinje-cell population according to age and sex., 1975, 1(3): 267–292.

[56] Andersen BB, Gundersen HJ, Pakkenberg B. Aging of the human cerebellum: A stereological study., 2003, 466(3): 356–365.

[57] Nandy K. Morphological changes in the cerebellar cortex of aging macaca nemestrina., 1981, 2(1): 61–64.

[58] Rogers J, Zornetzer SF, Bloom FE, Mervis RE. Senescent microstructural changes in rat cerebellum., 1984, 292(1): 23–32.

[59] Sturrock RR. Changes in neuron number in the cerebellar cortex of the ageing mouse., 1989, 30(4): 499–503.

[60] Woodruff-Pak DS, Foy MR, Akopian GG, Lee KH, Zach J, Nguyen KP, Comalli DM, Kennard JA, Agelan A, Thompson RF. Differential effects and rates of normal aging in cerebellum and hippocampus., 2010, 107(4): 1624–1629.

[61] Zhang C, Hua T, Zhu Z, Luo X. Age-related changes of structures in cerebellar cortex of cat., 2006, 31(1): 55–60.

[62] Quackenbush LJ, Ngo H, Pentney RJ. Evidence for nonrandom regression of dendrites of purkinje neurons during aging., 1990, 11(2): 111–115.

[63] Peters A, Sethares C, Luebke JI. Synapses are lost during aging in the primate prefrontal cortex., 2008, 152(4): 970–981.

[64] Dumitriu D, Hao J, Hara Y, Kaufmann J, Janssen WG, Lou W, Rapp PR, Morrison JH. Selective changes in thin spine density and morphology in monkey prefrontal cortex correlate with aging-related cognitive impairment., 2010, 30(22): 7507–7515.

[65] Arnsten AF, Paspalas CD, Gamo NJ, Yang Y, Wang M. Dynamic network connectivity: A new form of neuroplasticity., 2010, 14(8): 365–375.

[66] Uemura E. Age-related changes in the subiculum of macaca mulatta: Synaptic density., 1985, 87(3): 403–411.

[67] Adams MM, Donohue HS, Linville MC, Iversen EA, Newton IG, Brunso-Bechtold JK. Age-related synapse loss in hippocampal ca3 is not reversed by caloric restriction., 2010, 171(2): 373–382.

[68] Geinisman Y, Ganeshina O, Yoshida R, Berry RW, Disterhoft JF, Gallagher M. Aging, spatial learning, and total synapse number in the rat ca1 stratum radiatum., 2004, 25(3): 407–416.

[69] Nicholson DA, Yoshida R, Berry RW, Gallagher M, Geinisman Y. Reduction in size of perforated postsynaptic densities in hippocampal axospinous synapses and age-related spatial learning impairments., 2004, 24(35): 7648–7653.

[70] Morrison JH, Baxter MG. The ageing cortical synapse: Hallmarks and implications for cognitive decline., 2012, 13(4): 240–250.

[71] Bondareff W, Geinisman Y. Loss of synapses in the dentate gyrus of the senescent rat., 1976, 145(1): 129–136.

[72] Geinisman Y, Bondareff W, Dodge JT. Partial deafferentation of neurons in the dentate gyrus of the senescent rat., 1977, 134(3): 541–545.

[73] Fan WJ, Yan MC, Wang L, Sun YZ, Deng JB, Deng JX. Synaptic aging disrupts synaptic morphology and function in cerebellar purkinje cells., 2018, 13(6): 1019–1025.

[74] Cruz-Sánchez FF, Cardozo A, Tolosa E. Neuronal changes in the substantia nigra with aging: A golgi study., 1995, 54(1): 74–81.

[75] Itzev D, Lolova I, Lolov S, Usunoff KG. Age-related changes in the synapses of the rat's neostriatum., 2001, 109(1): 80–89.

[76] Levine MS, Adinolfi AM, Fisher RS, Hull CD, Buchwald NA, McAllister JP. Quantitative morphology of medium-sized caudate spiny neurons in aged cats., 1986, 7(4): 277–286.

[77] Marcuzzo S, Dall'oglio A, Ribeiro MF, Achaval M, Rasia-Filho AA. Dendritic spines in the posterodorsal medial amygdala after restraint stress and ageing in rats., 2007, 424(1): 16–21.

[78] Rubinow MJ, Drogos LL, Juraska JM. Age-related dendritic hypertrophy and sexual dimorphism in rat basolateral amygdala., 2009, 30(1): 137–146.

[79] Barnes CA. Memory deficits associated with senescence: A neurophysiological and behavioral study in the rat., 1979, 93(1): 74–104.

[80] Barnes CA, McNaughton BL. Physiological compensation for loss of afferent synapses in rat hippocampal granule cells during senescence., 1980, 309: 473–485.

[81] Luebke JI, Chang YM, Moore TL, Rosene DL. Normal aging results in decreased synaptic excitation and increased synaptic inhibition of layer 2/3 pyramidal cells in the monkey prefrontal cortex., 2004, 125(1): 277–288.

[82] Liu J, Zhang B, Lei H, Feng Z, Hsu AL, Xu XZ. Functional aging in the nervous system contributes to age-dependent motor activity decline in c. Elegans., 2013, 18(3): 392–402.

[83] Moore CI, Browning MD, Rose GM. Hippocampal plasticity induced by primed burst, but not long-term potentiation, stimulation is impaired in area ca1 of aged fischer 344 rats., 1993, 3(1): 57–66.

[84] Norris CM, Korol DL, Foster TC. Increased susceptibility to induction of long-term depression and long-term potentiation reversal during aging., 1996, 16(17): 5382–5392.

[85] Lister JP, Barnes CA. Neurobiological changes in the hippocampus during normative aging., 2009, 66(7): 829–833.

[86] Foster TC, Sharrow KM, Masse JR, Norris CM, Kumar A. Calcineurin links ca2+ dysregulation with brain aging., 2001, 21(11): 4066–4073.

[87] Ris L, Godaux E. Synapse specificity of long-term potentiation breaks down with aging., 2007, 14(3): 185–189.

[88] Backman L, Nyberg L, Lindenberger U, Li SC, Farde L. The correlative triad among aging, dopamine, and cognition: Current status and future prospects., 2006, 30(6): 791–807.

[89] Chowdhury R, Guitart-Masip M, Lambert C, Dayan P, Huys Q, Düzel E, Dolan RJ. Dopamine restores reward prediction errors in old age., 2013, 16(5): 648–653.

[90] Karrer TM, Josef AK, Mata R, Morris ED, Samanez- Larkin GR. Reduced dopamine receptors and transporters but not synthesis capacity in normal aging adults: A meta-analysis., 2017, 57: 36–46.

[91] Reeves S, Bench C, Howard R. Ageing and the nigrostriatal dopaminergic system., 2002, 17(4): 359–370.

[92] Arnsten AF, Cai JX, Steere JC, Goldman-Rakic PS. Dopamine d2 receptor mechanisms contribute to age-related cognitive decline: The effects of quinpirole on memory and motor performance in monkeys., 1995, 15(5 Pt 1): 3429–3439.

[93] Melancon MO, Lorrain D, Dionne IJ. Exercise and sleep in aging: Emphasis on serotonin., 2014, 62(5): 276–283.

[94] Meltzer CC, Smith G, DeKosky ST, Pollock BG, Mathis CA, Moore RY, Kupfer DJ, Reynolds CF, 3rd. Serotonin in aging, late-life depression, and alzheimer's disease: The emerging role of functional imaging., 1998, 18(6): 407–430.

[95] Wester P, Hardy JA, Marcusson J, Nyberg P, Winblad B. Serotonin concentrations in normal aging human brains: Relation to serotonin receptors., 1984, 5(3): 199–203.

[96] McEntee WJ, Crook TH. Serotonin, memory, and the aging brain., 1991, 103(2): 143–149.

[97] Miguez JM, Aldegunde M, Paz-Valinas L, Recio J, Sanchez-Barcelo E. Selective changes in the contents of noradrenaline, dopamine and serotonin in rat brain areas during aging., 1999, 106(11–12): 1089–1098.

[98] Petkov VD, Stancheva SL, Petkov VV, Alova LG. Age-related changes in brain biogenic monoamines and monoamine oxidase., 1987, 18(4): 397–401.

[99] Bhaskaran D, Radha E. Monoamine levels and monoamine oxidase activity in different regions of rat brain as a function of age., 1983, 23(2): 151–160.

[100] Herrera AJ, Machado A, Cano J. The influence of age on neurotransmitter turnover in the rat's superior colliculus., 1991, 12(4): 289–294.

[101] Stemmelin J, Lazarus C, Cassel S, Kelche C, Cassel JC. Immunohistochemical and neurochemical correlates of learning deficits in aged rats., 2000, 96(2): 275–289.

[102] Rodriguez JJ, Noristani HN, Verkhratsky A. The serotonergic system in ageing and alzheimer's disease., 2012, 99(1): 15–41.

[103] Karrer TM, McLaughlin CL, Guaglianone CP, Samanez-Larkin GR. Reduced serotonin receptors and transporters in normal aging adults: A meta-analysis of pet and spect imaging studies., 2019, 80: 1–10.

[104] Fazio P, Schain M, Varnas K, Halldin C, Farde L, Varrone A. Mapping the distribution of serotonin transporter in the human brainstem with high-resolution pet: Validation using postmortem autoradiography data., 2016, 133: 313–320.

[105] Yamamoto M, Suhara T, Okubo Y, Ichimiya T, Sudo Y, Inoue M, Takano A, Yasuno F, Yoshikawa K, Tanada S. Age-related decline of serotonin transporters in living human brain of healthy males., 2002, 71(7): 751–757.

[106] Wong DF, Wagner Jr HN, Dannals RF, Links JM, Frost JJ, Ravert HT, Wilson AA, Rosenbaum AE, Gjedde A, Douglass KH. Effects of age on dopamine and serotonin receptors measured by positron tomography in the living human brain., 1984, 226(4681): 1393– 1396.

[107] Fonnum F. Glutamate: A neurotransmitter in mammalian brain., 1984, 42(1): 1–11.

[108] Orrego F, Villanueva S. The chemical nature of the main central excitatory transmitter: A critical appraisal based upon release studies and synaptic vesicle localization., 1993, 56(3): 539–555.

[109] Kaiser LG, Schuff N, Cashdollar N, Weiner MW. Age-related glutamate and glutamine concentration changes in normal human brain: 1h mr spectroscopy study at 4 t., 2005, 26(5): 665–672.

[110] Zahr NM, Mayer D, Rohlfing T, Chanraud S, Gu M, Sullivan EV, Pfefferbaum A. In vivo glutamate measured with magnetic resonance spectroscopy: Behavioral correlates in aging., 2013, 34(4): 1265–1276.

[111] Segovia G, Porras A, Del Arco A, Mora F. Glutamatergic neurotransmission in aging: A critical perspective., 2001, 122(1): 1–29.

[112] Saransaari P, Oja SS. Age-related changes in the uptake and release of glutamate and aspartate in the mouse brain., 1995, 81(2–3): 61–71.

[113] Najlerahim A, Francis PT, Bowen DM. Age-related alteration in excitatory amino acid neurotransmission in rat brain., 1990, 11(2): 155–158.

[114] Clayton DA, Grosshans DR, Browning MD. Aging and surface expression of hippocampal nmda receptors., 2002, 277(17): 14367–14369.

[115] Magnusson KR, Brim BL, Das SR. Selective vulnerabilities of n-methyl-d-aspartate (nmda) receptors during brain aging., 2010, 2: 11.

[116] Magnusson KR, Cotman CW. Age-related changes in excitatory amino acid receptors in two mouse strains., 1993, 14(3): 197–206.

[117] Yang YJ, Chen HB, Wei B, Wang W, Zhou PL, Zhan JQ, Hu MR, Yan K, Hu B, Yu B. Cognitive decline is associated with reduced surface glur1 expression in the hippocampus of aged rats., 2015, 591: 176–181.

[118] Magnusson KR. Aging of glutamate receptors: Correlations between binding and spatial memory performance in mice., 1998, 104(3): 227–248.

[119] Paredes RG, Agmo A. Gaba and behavior: The role of receptor subtypes., 1992, 16(2): 145–170.

[120] Cuypers K, Maes C, Swinnen SP. Aging and gaba., 2018, 10(6): 1186–1187.

[121] Porges EC, Woods AJ, Edden RA, Puts NA, Harris AD, Chen H, Garcia AM, Seider TR, Lamb DG, Williamson JB, Cohen RA. Frontal gamma-aminobutyric acid concentrations are associated with cognitive performance in older adults., 2017, 2(1): 38–44.

[122] Gao F, Edden RA, Li M, Puts NA, Wang G, Liu C, Zhao B, Wang H, Bai X, Zhao C, Wang X, Barker PB. Edited magnetic resonance spectroscopy detects an age-related decline in brain gaba levels., 2013, 78: 75–82.

[123] Peters A. Structural changes that occur during normal aging of primate cerebral hemispheres., 2002, 26(7): 733–741.

[124] Petralia RS, Mattson MP, Yao PJ. Communication breakdown: The impact of ageing on synapse structure., 2014, 14: 31–42.

[125] Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J, Yankner BA. Gene regulation and DNA damage in the ageing human brain., 2004, 429(6994): 883–891.

[126] McCarroll SA, Murphy CT, Zou S, Pletcher SD, Chin CS, Jan YN, Kenyon C, Bargmann CI, Li H. Comparing genomic expression patterns across species identifies shared transcriptional profile in aging., 2004, 36(2): 197–204.

[127] Wruck W, Adjaye J. Meta-analysis of human prefrontal cortex reveals activation of gfap and decline of synaptic transmission in the aging brain., 2020, 8(1): 26.

[128] Ham S, Lee SV. Advances in transcriptome analysis of human brain aging., 2020, 52(11): 1787–1797.

[129] Fraser HB, Khaitovich P, Plotkin JB, P??bo S, Eisen MB. Aging and gene expression in the primate brain., 2005, 3(9): e274.

[130] Blalock EM, Chen KC, Sharrow K, Herman JP, Porter NM, Foster TC, Landfield PW. Gene microarrays in hippocampal aging: Statistical profiling identifies novel processes correlated with cognitive impairment., 2003, 23(9): 3807–3819.

[131] Lee CK, Weindruch R, Prolla TA. Gene-expression profile of the ageing brain in mice., 2000, 25(3): 294–297.

[132] Jiang CH, Tsien JZ, Schultz PG, Hu Y. The effects of aging on gene expression in the hypothalamus and cortex of mice., 2001, 98(4): 1930–1934.

[133] Meng S, Xia WC, Pan M, Jia YJ, He ZL, Ge W. Proteomics profiling and pathway analysis of hippocampal aging in rhesus monkeys., 2020, 21(1): 2.

[134] Li YC, Yu HT, Chen CY, Li SP, Zhang ZJ, Xu H, Zhu FQ, Liu JJ, Spencer PS, Dai ZL, Yang XF. Proteomic profile of mouse brain aging contributions to mitochondrial dysfunction, DNA oxidative damage, loss of neurotrophic factor, and synaptic and ribosomal proteins., 2020, 2020: 5408452.

[135] Vanguilder HD, Freeman WM. The hippocampal neuroproteome with aging and cognitive decline: Past progress and future directions., 2011, 3: 8.

[136] Cribbs DH, Berchtold NC, Perreau V, Coleman PD, Rogers J, Tenner AJ, Cotman CW. Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neuro-degeneration: A microarray study., 2012, 9: 179.

[137] Liang WS, Reiman EM, Valla J, Dunckley T, Beach TG, Grover A, Niedzielko TL, Schneider LE, Mastroeni D, Caselli R, Kukull W, Morris JC, Hulette CM, Schmechel D, Rogers J, Stephan DA. Alzheimer's disease is associated with reduced expression of energy metabolism genes neurons., 2008, 105(11): 4441–4446.

[138] Miller JA, Oldham MC, Geschwind DH. A systems level analysis of transcriptional changes in alzheimer's disease and normal aging., 2008, 28(6): 1410–1420.

[139] Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders., 2008, 60(5): 748–766.

[140] López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging., 2013, 153(6): 1194–1217.

[141] Hara Y, Yuk F, Puri R, Janssen WGM, Rapp PR, Morrison JH. Presynaptic mitochondrial morphology in monkey prefrontal cortex correlates with working memory and is improved with estrogen treatment., 2014, 111(1): 486–491.

[142] Navarro A, Boveris A. The mitochondrial energy transduction system and the aging process., 2007, 292(2): C670–686.

[143] Navarro A, Boveris A. Rat brain and liver mitochondria develop oxidative stress and lose enzymatic activities on aging., 2004, 287(5): R1244–1249.

[144] Swerdlow RH. Brain aging, alzheimer's disease, and mitochondria., 2011, 1812(12): 1630–1639.

[145] Shigenaga MK, Hagen TM, Ames BN. Oxidative damage and mitochondrial decay in aging., 1994, 91(23): 10771–10778.

[146] Venkateshappa C, Harish G, Mahadevan A, Srinivas Bharath MM, Shankar SK. Elevated oxidative stress and decreased antioxidant function in the human hippocampus and frontal cortex with increasing age: Implications for neurodegeneration in alzheimer's disease., 2012, 37(8): 1601–1614.

[147] Paradies G, Petrosillo G, Pistolese M, Ruggiero FM. The effect of reactive oxygen species generated from the mitochondrial electron transport chain on the cytochrome c oxidase activity and on the cardiolipin content in bovine heart submitochondrial particles., 2000, 466(2–3): 323–326.

[148] Sun N, Youle RJ, Finkel T. The mitochondrial basis of aging., 2016, 61(5): 654–666.

[149] Mouchiroud L, Houtkooper RH, Moullan N, Katsyuba E, Ryu D, CantóC, Mottis A, Jo YS, Viswanathan M, Schoonjans K, Guarente L, Auwerx J. The nad(+)/ sirtuin pathway modulates longevity through activation of mitochondrial upr and foxo signaling., 2013, 154(2): 430–441.

[150] Zhao ZZ, Yu ZY, Hou YX, Zhang L, Fu AL. Improvement of cognitive and motor performance with mitotherapy in aged mice., 2020, 16(5): 849–858.

[151] Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases., 2006, 443(7113): 787–795.

[152] Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, Hofer T, Seo AY, Sullivan R, Jobling WA, Morrow JD, Van Remmen H, Sedivy JM, Yamasoba T, Tanokura M, Weindruch R, Leeuwenburgh C, Prolla TA. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging., 2005, 309(5733): 481–484.

[153] Kauppila TES, Kauppila JHK, Larsson NG. Mammalian mitochondria and aging: An update., 2017, 25(1): 57–71.

[154] Richter C, Park JW, Ames BN. Normal oxidative damage to mitochondrial and nuclear-DNA is extensive., 1988, 85(17): 6465–6467.

[155] Corral-Debrinski M, Horton T, Lott MT, Shoffner JM, Beal MF, Wallace DC. Mitochondrial DNA deletions in human brain: Regional variability and increase with advanced age., 1992, 2(4): 324–329.

[156] Lin MT, Simon DK, Ahn CH, Kim LM, Beal MF. High aggregate burden of somatic mtdna point mutations in aging and alzheimer's disease brain., 2002, 11(2): 133–145.

[157] Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly YM, Gidlof S, Oldfors A, Wibom R, Tornell J, Jacobs HT, Larsson NG. Premature ageing in mice expressing defective mito-chondrial DNA polymerase., 2004, 429(6990): 417–423.

[158] Yuan J, Chang SY, Yin SG, Liu ZY, Cheng X, Liu XJ, Jiang Q, Gao G, Lin DY, Kang XL, Ye SW, Chen Z, Yin JA, Hao P, Jiang L, Cai SQ. Two conserved epigenetic regulators prevent healthy ageing., 2020, 579(7797): 118–122.

[159] Stefanatos R, Sanz A. The role of mitochondrial ros in the aging brain., 2018, 592(5): 743–758.

[160] Chakrabarti S, Munshi S, Banerjee K, Thakurta IG, Sinha M, Bagh MB. Mitochondrial dysfunction during brain aging: Role of oxidative stress and modulation by antioxidant supplementation., 2011, 2(3): 242–256.

[161] Foster TC. Calcium homeostasis and modulation of synaptic plasticity in the aged brain., 2007, 6(3): 319–325.

[162] Bodhinathan K, Kumar A, Foster TC. Redox sensitive calcium stores underlie enhanced after hyperpolarization of aged neurons: Role for ryanodine receptor mediated calcium signaling., 2010, 104(5): 2586– 2593.

[163] Serrano F, Klann E. Reactive oxygen species and synaptic plasticity in the aging hippocampus., 2004, 3(4): 431–443.

[164] Melov S, Schneider JA, Day BJ, Hinerfeld D, Coskun P, Mirra SS, Crapo JD, Wallace DC. A novel neurological phenotype in mice lacking mitochondrial manganese superoxide dismutase., 1998, 18(2): 159–163.

[165] Paul A, Belton A, Nag S, Martin I, Grotewiel MS, Duttaroy A. Reduced mitochondrial sod displays mortality characteristics reminiscent of natural aging., 2007, 128(11–12): 706–716.

[166] Hu D, Serrano F, Oury TD, Klann E. Aging-dependent alterations in synaptic plasticity and memory in mice that overexpress extracellular superoxide dismutase., 2006, 26(15): 3933–3941.

[167] Lee WH, Kumar A, Rani A, Herrera J, Xu J, Someya S, Foster TC. Influence of viral vector-mediated delivery of superoxide dismutase and catalase to the hippocampus on spatial learning and memory during aging., 2012, 16(4): 339–350.

[168] Schaar CE, Dues DJ, Spielbauer KK, Machiela E, Cooper JF, Senchuk M, Hekimi S, Van Raamsdonk JM. Mitochondrial and cytoplasmic ros have opposing effects on lifespan., 2015, 11(2): e1004972.

[169] Back P, Braeckman BP, Matthijssens F. Ros in aging caenorhabditis elegans: Damage or signaling?, 2012, 2012: 608478.

[170] Sena LA, Chandel NS. Physiological roles of mitochondrial reactive oxygen species., 2012, 48(2): 158–167.

[171] Rubinsztein DC, Mari?o G, Kroemer G. Autophagy and aging., 2011, 146(5): 682–695.

[172] Tomaru U, Takahashi S, Ishizu A, Miyatake Y, Gohda A, Suzuki S, Ono A, Ohara J, Baba T, Murata S, Tanaka K, Kasahara M. Decreased proteasomal activity causes age-related phenotypes and promotes the development of metabolic abnormalities., 2012, 180(3): 963–972.

[173] Juhász G, Erdi B, Sass M, Neufeld TP. Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in drosophila., 2007, 21(23): 3061–3066.

[174] Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice., 2006, 441(7095): 885–889.

[175] Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K. Loss of autophagy in the central nervous system causes neurodegeneration in mice., 2006, 441(7095): 880–884.

[176] Simonsen A, Cumming RC, Brech A, Isakson P, Schubert DR, Finley KD. Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult drosophila., 2008, 4(2): 176–184.

[177] Melendez A, Talloczy Z, Seaman M, Eskelinen EL, Hall DH, Levine B. Autophagy genes are essential for dauer development and life-span extension in c. Elegans., 2003, 301(5638): 1387–1391.

[178] Hansen M, Chandra A, Mitic LL, Onken B, Driscoll M, Kenyon C. A role for autophagy in the extension of lifespan by dietary restriction in c. Elegans., 2008, 4(2): e24.

[179] Nixon RA. The role of autophagy in neurodegenerative disease., 2013, 19(8): 983–997.

[180] Fischer DF, van Dijk R, van Tijn P, Hobo B, Verhage MC, van der Schors RC, Li KW, van Minnen J, Hol EM, van Leeuwen FW. Long-term proteasome dysfunction in the mouse brain by expression of aberrant ubiquitin., 2009, 30(6): 847–863.

[181] Klaips CL, Jayaraj GG, Hartl FU. Pathways of cellular proteostasis in aging and disease., 2018, 217(1): 51–63.

[182] Mattson MP, Magnus T. Ageing and neuronal vulnerability., 2006, 7(4): 278–294.

[183] Walsh JG, Muruve DA, Power C. Inflammasomes in the cns., 2014, 15(2): 84–97.

[184] Conde JR, Streit WJ. Microglia in the aging brain., 2006, 65(3): 199–203.

[185] Goss JR, Finch CE, Morgan DG. Age-related changes in glial fibrillary acidic protein mrna in the mouse brain., 1991, 12(2): 165–170.

[186] Hayakawa N, Kato H, Araki T. Age-related changes of astorocytes, oligodendrocytes and microglia in the mouse hippocampal ca1 sector., 2007, 128(4): 311–316.

[187] Cotrina ML, Nedergaard M. Astrocytes in the aging brain., 2002, 67(1): 1–10.

[188] McCall MA, Gregg RG, Behringer RR, Brenner M, Delaney CL, Galbreath EJ, Zhang CL, Pearce RA, Chiu SY, Messing A. Targeted deletion in astrocyte intermediate filament (gfap) alters neuronal physiology., 1996, 93(13): 6361–6366.

[189] Menet V, Gimenez YRM, Sandillon F, Privat A. Gfap null astrocytes are a favorable substrate for neuronal survival and neurite growth., 2000, 31(3): 267– 272.

[190] Satoh A, Imai S, Guarente L. The brain, sirtuins, and ageing., 2017, 18(6): 362–374.

[191] Hefendehl JK, Neher JJ, Sühs RB, Kohsaka S, Skodras A, Jucker M. Homeostatic and injury-induced microglia behavior in the aging brain., 2014, 13(1): 60–69.

[192] Wong WT. Microglial aging in the healthy cns: Phenotypes, drivers, and rejuvenation., 2013, 7: 22.

[193] Peters A, Josephson K, Vincent SL. Effects of aging on the neuroglial cells and pericytes within area 17 of the rhesusmonkey cerebral cortex., 1991, 229(3): 384–398.

[194] Loane DJ, Deighan BF, Clarke RM, Griffin RJ, Lynch AM, Lynch MA. Interleukin-4 mediates the neuroprotective effects of rosiglitazone in the aged brain., 2009, 30(6): 920–931.

[195] Downer EJ, Cowley TR, Lyons A, Mills KH, Berezin V, Bock E, Lynch MA. A novel anti-inflammatory role of ncam-derived mimetic peptide, fgl., 2010, 31(1): 118–128.

[196] Christensen K, Johnson TE, Vaupel JW. The quest for genetic determinants of human longevity: Challenges and insights., 2006, 7(6): 436–448.

[197] Brooks-Wilson AR. Genetics of healthy aging and longevity., 2013, 132(12): 1323–1338.

[198] Goldberg TE, Weinberger DR. Genes and the parsing of cognitive processes., 2004, 8(7): 325–335.

[199] Harris SE, Deary IJ. The genetics of cognitive ability and cognitive ageing in healthy older people., 2011, 15(9): 388–394.

[200] Tapia-Arancibia L, Aliaga E, Silhol M, Arancibia S. New insights into brain bdnf function in normal aging and alzheimer disease., 2008, 59(1): 201–220.

[201] Gooney M, Messaoudi E, Maher FO, Bramham CR, Lynch MA. Bdnf-induced ltp in dentate gyrus is impaired with age: Analysis of changes in cell signaling events., 2004, 25(10): 1323–1331.

[202] Wisdom NM, Callahan JL, Hawkins KA. The effects of apolipoprotein e on non-impaired cognitive functioning: A meta-analysis., 2011, 32(1): 63–74.

[203] Herskind AM, McGue M, Holm NV, Sorensen TI, Harvald B, Vaupel JW. The heritability of human longevity: A population-based study of 2872 danish twin pairs born 1870–1900., 1996, 97(3): 319–323.

[204] v BHJ, Iachine I, Skytthe A, Vaupel JW, McGue M, Koskenvuo M, Kaprio J, Pedersen NL, Christensen K. Genetic influence on human lifespan and longevity., 2006, 119(3): 312–321.

[205] Shadyab AH, LaCroix AZ. Genetic factors associated with longevity: A review of recent findings., 2015, 19: 1–7.

[206] Newman AB, Murabito JM. The epidemiology of longevity and exceptional survival., 2013, 35: 181–197.

[207] Gurland BJ, Page WF, Plassman BL. A twin study of the genetic contribution to age-related functional impairment., 2004, 59(8): 859–863.

[208] Akbarian S, Beeri MS, Haroutunian V. Epigenetic determinants of healthy and diseased brain aging and cognition., 2013, 70(6): 711–718.

[209] Horvath S, Raj K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing., 2018, 19(6): 371–384.

[210] Jones MJ, Goodman SJ, Kobor MS. DNA methylation and healthy human aging., 2015, 14(6): 924–932.

[211] Hernandez DG, Nalls MA, Gibbs JR, Arepalli S, van der Brug M, Chong S, Moore M, Longo DL, Cookson MR, Traynor BJ, Singleton AB. Distinct DNA methylation changes highly correlated with chronological age in the human brain., 2011, 20(6): 1164–1172.

[212] Numata S, Ye T, Hyde TM, Guitart-Navarro X, Tao R, Wininger M, Colantuoni C, Weinberger DR, Kleinman JE, Lipska BK. DNA methylation signatures in development and aging of the human prefrontal cortex., 2012, 90(2): 260–272.

[213] Tang B, Dean B, Thomas EA. Disease- and age-related changes in histone acetylation at gene promoters in psychiatric disorders., 2011, 1: e64.

[214] Akbarian S, Beeri MS, Haroutunian V. Epigenetic determinants of healthy and diseased brain aging and cognition., 2013, 70(6): 711–718.

[215] Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S, Agis-Balboa RC, Cota P, Wittnam JL, Gogol-Doering A, Opitz L, Salinas-Riester G, Dettenhofer M, Kang H, Farinelli L, Chen W, Fischer A. Altered histone acetylation is associated with age-dependent memory impairment in mice., 2010, 328(5979): 753–756.

[216] Haettig J, Stefanko DP, Multani ML, Figueroa DX, McQuown SC, Wood MA. Hdac inhibition modulates hippocampus-dependent long-term memory for object location in a cbp-dependent manner., 2011, 18(2): 71–79.

[217] Reolon GK, Maurmann N, Werenicz A, Garcia VA, Schroder N, Wood MA, Roesler R. Posttraining systemic administration of the histone deacetylase inhibitor sodium butyrate ameliorates aging-related memory decline in rats., 2011, 221(1): 329–332.

[218] Fischer A, Sananbenesi F, Mungenast A, Tsai LH. Targeting the correct hdac(s) to treat cognitive disorders., 2010, 31(12): 605–617.

[219] Chuang DM, Leng Y, Marinova Z, Kim HJ, Chiu CT. Multiple roles of hdac inhibition in neurodegenerative conditions., 2009, 32(11): 591–601.

[220] Baltan S, Murphy SP, Danilov CA, Bachleda A, Morrison RS. Histone deacetylase inhibitors preserve white matter structure and function during ischemia by conserving atp and reducing excitotoxicity., 2011, 31(11): 3990–3999.

[221] Tsou AY, Friedman LS, Wilson RB, Lynch DR. Pharmacotherapy for friedreich ataxia., 2009, 23(3): 213–223.

[222] Covington HE, 3rd, Maze I, LaPlant QC, Vialou VF, Ohnishi YN, Berton O, Fass DM, Renthal W, Rush AJ, 3rd, Wu EY, Ghose S, Krishnan V, Russo SJ, Tamminga C, Haggarty SJ, Nestler EJ. Antidepressant actions of histone deacetylase inhibitors., 2009, 29(37): 11451–11460.

[223] Wang CM, Tsai SN, Yew TW, Kwan YW, Ngai SM. Identification of histone methylation multiplicities patterns in the brain of senescence-accelerated prone mouse 8., 2010, 11(1): 87–102.

[224] Wood JG, Hillenmeyer S, Lawrence C, Chang CY, Hosier S, Lightfoot W, Mukherjee E, Jiang N, Schorl C, Brodsky AS, Neretti N, Helfand SL. Chromatin remodeling in the aging genome of drosophila., 2010, 9(6): 971–978.

[225] Lin L, Liu A, Li HQ, Feng J, Yan Z. Inhibition of histone methyltransferases ehmt1/2 reverses amyloid- beta-induced loss of ampar currents in human stem cell-derived cortical neurons., 2019, 70(4): 1175–1185.

[226] Zheng Y, Liu AY, Wang ZJ, Cao Q, Wang W, Lin L, Ma KJ, Zhang F, Wei J, Matas E, Cheng J, Chen GJ, Wang X, Yan Z. Inhibition of ehmt1/2 rescues synaptic and cognitive functions for alzheimer's disease., 2019, 142(3): 787–807.

[227] Anderson RM, Weindruch R. The caloric restriction paradigm: Implications for healthy human aging., 2012, 24(2): 101–106.

[228] Leclerc E, Trevizol AP, Grigolon RB, Subramaniapillai M, McIntyre RS, Brietzke E, Mansur RB. The effect of caloric restriction on working memory in healthy non-obese adults., 2020, 25(1): 2–8.

[229] Witte AV, Fobker M, Gellner R, Knecht S, Fl?el A. Caloric restriction improves memory in elderly humans., 2009, 106(4): 1255–1260.

[230] Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R. Caloric restriction delays disease onset and mortality in rhesus monkeys., 2009, 325(5937): 201–204.

[231] Dal-Pan A, Pifferi F, Marchal J, Picq JL, Aujard F. Cognitive performances are selectively enhanced during chronic caloric restriction or resveratrol supplementation in a primate., 2011, 6(1): e16581.

[232] Goodrick CL. Effects of lifelong restricted feeding on complex maze performance in rats., 1984, 7(1): 1–2.

[233] Fontán-Lozano A, Sáez-Cassanelli JL, Inda MC, de los Santos-Arteaga M, Sierra-Domínguez SA, López-Lluch G, Delgado-García JM, Carrión AM. Caloric restriction increases learning consolidation and facilitates synaptic plasticity through mechanisms dependent on nr2b subunits of the nmda receptor., 2007, 27(38): 10185–10195.

[234] Patel NV, Gordon MN, Connor KE, Good RA, Engelman RW, Mason J, Morgan DG, Morgan TE, Finch CE. Caloric restriction attenuates abeta-deposition in alzheimer transgenic models., 2005, 26(7): 995– 1000.

[235] Yu Q, Zou LY, Kong ZW, Yang L. Cognitive impact of calorie restriction: A narrative review., 2020, 21(10): 1394–1401.

[236] Yanai S, Okaichi Y, Okaichi H. Long-term dietary restriction causes negative effects on cognitive functions in rats., 2004, 25(3): 325–332.

[237] Dias IR, Santos CS, Magalhaes C, de Oliveira LRS, Peixoto MFD, De Sousa RAL, Cassilhas RC. Does calorie restriction improve cognition?, 2020, 9: 37–45.

[238] Guarente L. Mitochondria—a nexus for aging, calorie restriction, and sirtuins?, 2008, 132(2): 171–176.

[239] Zid BM, Rogers AN, Katewa SD, Vargas MA, Kolipinski MC, Lu TA, Benzer S, Kapahi P. 4e-bp extends lifespan upon dietary restriction by enhancing mitochondrial activity in drosophila., 2009, 139(1): 149–160.

[240] Lanza IR, Zabielski P, Klaus KA, Morse DM, Heppelmann CJ, Bergen HR, Dasari S, Walrand S, Short KR, Johnson ML, Robinson MM, Schimke JM, Jakaitis DR, Asmann YW, Sun ZF, Nair KS. Chronic caloric restriction preserves mitochondrial function in senescence without increasing mitochondrial biogenesis., 2012, 16(6): 777–788.

[241] Hyun DH, Emerson SS, Jo DG, Mattson MP, de Cabo R. Calorie restriction up-regulates the plasma membrane redox system in brain cells and suppresses oxidative stress during aging., 2006, 103(52): 19908–19912.

[242] Adams MM, Shi L, Linville MC, Forbes ME, Long AB, Bennett C, Newton IG, Carter CS, Sonntag WE, Riddle DR, Brunso-Bechtold JK. Caloric restriction and age affect synaptic proteins in hippocampal ca3 and spatial learning ability., 2008, 211(1): 141–149.

[243] Mattson MP. The impact of dietary energy intake on cognitive aging., 2010, 2: 5.

[244] Prolla TA, Mattson MP. Molecular mechanisms of brain aging and neurodegenerative disorders: Lessons from dietary restriction., 2001, 24(11 Suppl): S21–31.

[245] Eriksson PS, Perfilieva E, Bj?rk-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH. Neurogenesis in the adult human hippocampus., 1998, 4(11): 1313–1317.

[246] Lee J, Duan W, Mattson MP. Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice., 2002, 82(6): 1367–1375.

[247] Longo VD, Kennedy BK. Sirtuins in aging and age-related disease., 2006, 126(2): 257–268.

[248] Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA. Calorie restriction promotes mammalian cell survival by inducing the sirt1 deacetylase., 2004, 305(5682): 390–392.

[249] Michán S, Li Y, Chou MM, Parrella E, Ge H, Long JM, Allard JS, Lewis K, Miller M, Xu W, Mervis RF, Chen J, Guerin KI, Smith LE, McBurney MW, Sinclair DA, Baudry M, de Cabo R, Longo VD. Sirt1 is essential for normal cognitive function and synaptic plasticity., 2010, 30(29): 9695–9707.

[250] Gao J, Wang WY, Mao YW, Gr?ff J, Guan JS, Pan L, Mak G, Kim D, Su SC, Tsai LH. A novel pathway regulates memory and plasticity via sirt1 and mir-134., 2010, 466(7310): 1105–1109.

[251] Herranz D, Mu?oz-Martin M, Ca?amero M, Mulero F, Martinez-Pastor B, Fernandez-Capetillo O, Serrano M. Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer., 2010, 1: 3.

[252] Ng F, Wijaya L, Tang BL. Sirt1 in the brain-connections with aging-associated disorders and lifespan., 2015, 9: 64.

[253] Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP, Mercken EM, Palmeira CM, de Cabo R, Rolo AP, Turner N, Bell EL, Sinclair DA. Declining nad(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging., 2013, 155(7): 1624–1638.

[254] Yoshino J, Mills KF, Yoon MJ, Imai S. Nicotinamide mononucleotide, a key nad(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice., 2011, 14(4): 528–536.

[255] Johnson S, Wozniak DF, Imai S. Ca1 nampt knockdown recapitulates hippocampal cognitive phenotypes in old mice which nicotinamide mononucleotide improves., 2018, 4: 10.

[256] Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, Yoshino J, Imai S. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice., 2016, 24(6): 795–806.

[257] Gong B, Pan Y, Vempati P, Zhao W, Knable L, Ho L, Wang J, Sastre M, Ono K, Sauve AA, Pasinetti GM. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in alzheimer's mouse models., 2013, 34(6): 1581–1588.

[258] Busse AL, Gil G, Santarem JM, Jacob Filho W. Physical activity and cognition in the elderly: A review., 2009, 3(3): 204–208.

[259] Kramer AF, Erickson KI, Colcombe SJ. Exercise, cognition, and the aging brain., 2006, 101(4): 1237–1242.

[260] Chakravarty EF, Hubert HB, Lingala VB, Fries JF. Reduced disability and mortality among aging runners: A 21-year longitudinal study., 2008, 168(15): 1638–1646.

[261] He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou Z, An Z, Loh J, Fisher J, Sun Q, Korsmeyer S, Packer M, May HI, Hill JA, Virgin HW, Gilpin C, Xiao G, Bassel-Duby R, Scherer PE, Levine B. Exercise-induced bcl2-regulated autophagy is required for muscle glucose homeostasis., 2012, 481(7382): 511–515.

[262] Nascimento CM, Pereira JR, de Andrade LP, Garuffi M, Talib LL, Forlenza OV, Cancela JM, Cominetti MR, Stella F. Physical exercise in mci elderly promotes reduction of pro-inflammatory cytokines and improve-ments on cognition and bdnf peripheral levels., 2014, 11(8): 799–805.

[263] Stranahan AM, Mattson MP. Recruiting adaptive cellular stress responses for successful brain ageing., 2012, 13(3): 209–216.

[264] Ferris LT, Williams JS, Shen CL. The effect of acute exercise on serum brain-derived neurotrophic factor levels and cognitive function., 2007, 39(4): 728–734.

[265] Cotman CW, Berchtold NC. Exercise: A behavioral intervention to enhance brain health and plasticity., 2002, 25(6): 295–301.

[266] Gómez-Pinilla F, Ying Z, Roy RR, Molteni R, Edgerton VR. Voluntary exercise induces a bdnf-mediated me-chanism that promotes neuroplasticity., 2002, 88(5): 2187–2195.

[267] Vaynman S, Ying Z, Gomez-Pinilla F. Hippocampal bdnf mediates the efficacy of exercise on synaptic plasticity and cognition., 2004, 20(10): 2580–2590.

[268] Moon HY, Becke A, Berron D, Becker B, Sah N, Benoni G, Janke E, Lubejko ST, Greig NH, Mattison JA, Duzel E, van Praag H. Running-induced systemic cathepsin b secretion is associated with memory function., 2016, 24(2): 332–340.

[269] Gross AL, Mungas DM, Crane PK, Gibbons LE, MacKay-Brandt A, Manly JJ, Mukherjee S, Romero H, Sachs B, Thomas M, Potter GG, Jones RN. Effects of education and race on cognitive decline: An integrative study of generalizability versus study-specific results., 2015, 30(4): 863–880.

[270] Valenzuela MJ, Sachdev P. Brain reserve and dementia: A systematic review., 2006, 36(4): 441– 454.

[271] Farmer ME, Kittner SJ, Rae DS, Bartko JJ, Regier DA. Education and change in cognitive function. The epidemiologic catchment area study., 1995, 5(1): 1–7.

[272] Fratiglioni L, Paillard-Borg S, Winblad B. An active and socially integrated lifestyle in late life might protect against dementia., 2004, 3(6): 343–353.

[273] Small BJ, Dixon RA, McArdle JJ, Grimm KJ. Do changes in lifestyle engagement moderate cognitive decline in normal aging? Evidence from the victoria longitudinal study., 2012, 26(2): 144–155.

[274] L?vdén M, B?ckman L, Lindenberger U, Schaefer S, Schmiedek F. A theoretical framework for the study of adult cognitive plasticity., 2010, 136(4): 659–676.

[275] May A. Experience-dependent structural plasticity in the adult human brain., 2011, 15(10): 475–482.

[276] Draganski B, Gaser C, Busch V, Schuierer G, Bogdahn U, May A. Neuroplasticity: Changes in grey matter induced by training., 2004, 427(6972): 311–312.

[277] Kempermann G, Kuhn HG, Gage FH. Experience- induced neurogenesis in the senescent dentate gyrus., 1998, 18(9): 3206–3212.

[278] Lamming DW, Ye L, Sabatini DM, Baur JA. Rapalogs and mtor inhibitors as anti-aging therapeutics., 2013, 123(3): 980–989.

[279] Bitto A, Ito TK, Pineda VV, LeTexier NJ, Huang HZ, Sutlief E, Tung H, Vizzini N, Chen B, Smith K, Meza D, Yajima M, Beyer RP, Kerr KF, Davis DJ, Gillespie CH, Snyder JM, Treuting PM, Kaeberlein M. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice., 2016, 5: e16351.

[280] Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice., 2009, 460(7253): 392–395.

[281] Kolosova NG, Vitovtov AO, Muraleva NA, Akulov AE, Stefanova NA, Blagosklonny MV. Rapamycin suppresses brain aging in senescence-accelerated oxys rats., 2013, 5(6): 474–484.

[282] Majumder S, Caccamo A, Medina DX, Benavides AD, Javors MA, Kraig E, Strong R, Richardson A, Oddo S. Lifelong rapamycin administration ameliorates age- dependent cognitive deficits by reducing il-1beta and enhancing nmda signaling., 2012, 11(2): 326–335.

[283] Halloran J, Hussong SA, Burbank R, Podlutskaya N, Fischer KE, Sloane LB, Austad SN, Strong R, Richardson A, Hart MJ, Galvan V. Chronic inhibition of mammalian target of rapamycin by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice., 2012, 223: 102–113.

[284] Van Skike CE, Lin AL, Roberts Burbank R, Halloran JJ, Hernandez SF, Cuvillier J, Soto VY, Hussong SA, Jahrling JB, Javors MA, Hart MJ, Fischer KE, Austad SN, Galvan V. Mtor drives cerebrovascular, synaptic, and cognitive dysfunction in normative aging., 2020, 19(1): e13057.

[285] Caccamo A, Majumder S, Richardson A, Strong R, Oddo S. Molecular interplay between mammalian target of rapamycin (mtor), amyloid-beta, and tau: Effects on cognitive impairments., 2010, 285(17): 13107–13120.

[286] Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Richardson A, Strong R, Galvan V. Inhibition of mtor by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of alzheimer's disease., 2010, 5(4): e9979.

[287] Talboom JS, Velazquez R, Oddo S. The mammalian target of rapamycin at the crossroad between cognitive aging and alzheimer's disease., 2015, 1: 15008.

[288] Castellano JM, Kirby ED, Wyss-Coray T. Blood-borne revitalization of the aged brain., 2015, 72(10): 1191–1194.

[289] Wyss-Coray T. Ageing, neurodegeneration and brain rejuvenation., 2016, 539(7628): 180–186.

[290] Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding ZQ, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Després S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA, Wyss-Coray T. The ageing systemic milieu negatively regulates neurogenesis and cognitive function., 2011, 477(7362): 90–94.

[291] Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, Chen JW, Lee RT, Wagers AJ, Rubin LL. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors., 2014, 344(6184): 630–634.

[292] Castellano JM, Mosher KI, Abbey RJ, McBride AA, James ML, Berdnik D, Shen JC, Zou B, Xie XS, Tingle M, Hinkson IV, Angst MS, Wyss-Coray T. Human umbilical cord plasma proteins revitalize hippocampal function in aged mice., 2017, 544(7651): 488– 492.

[293] Yin JA, Gao G, Liu XJ, Hao ZQ, Li K, Kang XL, Li H, Shan YH, Hu WL, Li HP, Cai SQ. Genetic variation in glia-neuron signalling modulates ageing rate., 2017, 551(7679): 198–203.

The regulatory mechanisms of behavioral and cognitive aging

Jie Yuan1,2, Shiqing Cai1,2

,,,,,,

With the increase of life expectancy, the world’s population is aging rapidly. Previous work in the field of aging greatly increases our understanding of biological mechanisms underlying longevity. Researchers have unraveled a number of longevity pathways conserved from yeast to mammals. However, recent evidence shows that mechanisms regulating the life span and those regulating age-related behavioral decline could be dissociated. The regulatory mechanisms underlying behavioral and cognitive aging is largely unknown. Previous work has described a significant age-related decline in cognitive behaviors including episodic memory, working memory, processing speed, as well as motor function deterioration and circadian dysfunction. With the advance of neuroscience and technology, more and more studies have focused on the age-related changes in structure and function of the brain. In this review， we briefly describe the deterioration of cognitive function and other behaviors in the aging process, and survey the role of age-related changes in brain structure and network, neuron morphology and function, transcriptome in brain and some conserved biological pathways on age-related cognitive and behavioral decline. Further studies on the mechanisms underpinning age-related cognitive and behavioral decline may provide clues not only for improving the quality of life for the ageing population, but also for developing intervention approaches for neurodegenerative diseases.

aging; cognitive function; behavioral deterioration; synapse; neurotransmitter; mitochondrion; oxidative stress; epigenetic

2021-02-08;

2021-03-11

國家自然科學(xué)基金項(xiàng)目(編號：91949206)資助 [Supported by the National Natural Science Foundation of China (No. 91949206)]

袁潔，博士，研究方向：帕金森病以及細(xì)胞死亡的機(jī)制研究。E-mail: yuanjiejane@gmail.com

10.16288/j.yczz.21-060

2021/4/1 17:12:00

URI: https://kns.cnki.net/kcms/detail/11.1913.r.20210401.1046.002.html

袁潔，2010年畢業(yè)于華中科技大學(xué)生命科學(xué)與技術(shù)學(xué)院，獲理學(xué)學(xué)士學(xué)位。2010—2018年就讀于中國科學(xué)院大學(xué)，在神經(jīng)科學(xué)研究所離子通道調(diào)控研究組攻讀博士學(xué)位，導(dǎo)師為蔡時青研究員。目前在美國約翰霍普金斯大學(xué)接受博士后訓(xùn)練。博士期間主要探究健康衰老的調(diào)控機(jī)制。通過全基因組RNAi篩選，找到一系列調(diào)控衰老相關(guān)行為退化的候選基因，揭示了新的神經(jīng)系統(tǒng)衰老的基因調(diào)控網(wǎng)絡(luò)；從中鑒定了兩個全新的抗衰老基因靶標(biāo)，并詳細(xì)闡明了它們以及它們在哺乳動物中的同源基因在衰老相關(guān)行為和認(rèn)知功能退化中的作用，為如何實(shí)現(xiàn)健康衰老提供了全新的線索；此外，還揭示了表觀遺傳抑制線粒體功能在衰老大腦和神經(jīng)退行性疾病發(fā)生和發(fā)展中發(fā)揮重要作用，為老年性疾病的干預(yù)方法開發(fā)提供了方向。博士論文《表觀遺傳調(diào)控因子BAZ-2和SET-6調(diào)節(jié)衰老的機(jī)制研究》獲得2020年中國科學(xué)院優(yōu)秀博士學(xué)位論文。

(責(zé)任編委: 郭偉翔)