Epigenetics and Cognitive Aging
J. David Sweatt
Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
E-mail: dsweatt@uab.edu
Cognitive decline, especially in memory capacity, is a normal part of aging (1). Indeed, the painful reality is that aging-related cognitive decline likely begins when one is in their late 40s. This deterioration is particularly pronounced in declarative memory—the ability to recall facts and experiences—and has been associated with aberrant changes in gene expression in the brain's hippocampus and frontal lobe. However, the molecular mechanisms underlying these changes in gene regulation are not currently known (2, 3). On page 753 of this issue, Peleg et al. (4) bolster an emerging hypothesis that changes in the epigenetic modification of chromatin in the adult central nervous system drive cognitive decline.
認知能力下降，特別是在內存容量，是一種正常老化的一部分（1）。事實上，在痛苦的現實是，老齡化相關的認知能力下降時，一開始可能是在他們 40多歲的晚期。這是特別顯著惡化陳述性記憶，回憶事實的能力和經驗，並已與相關基因表達的異常變化在大腦的海馬和額葉。然而，這些變化背後的分子機制在基因調控目前不知道（2，3）。 753頁上對這個問題，法勒等人。 （4）加強新興的假設，即改變染色質的表觀遺傳修飾在成人中樞神經系統驅動器的認知能力的下降。
Chromatin remodeling in the hippocampus is necessary for stabilizing long-term memories (5–8). The relevant molecular mechanisms include DNA methylation and the modification of histone proteins by acetylation, phosphorylation, and methylation. These epigenetic changes involve covalent chemical modifications by enzymes such as histone acetyltransferases and histone deacetylases. Whether alterations in these mechanisms contribute to age-related changes in gene transcription and memory decline are unknown (8).
染色質重塑在海馬穩定是必要的長期記憶（5-8）。有關的分子機制包括DNA甲基化和組蛋白的修飾蛋白的乙酰化，磷酸化和甲基化。這些表觀遺傳變化涉及共價化學修飾的組蛋白乙酰轉移酶，如酶和組蛋白脫乙酰。在這些機制是否有助於改變與年齡有關的基因轉錄的變化和記憶力下降是未知的（8）。
Peleg et al. found that aged mice exhibit a disruption of memory-associated activity- and experience-dependent epigenetic modification at the histone H4 lysine 12 (H4K12) acetylation site. This correlated with the loss of almost all normal memory-associated transcription in the hippocampus. Moreover, the authors identified a memory-associated gene, Formin 2 (an actin regulatory protein), and showed that its function is necessary for normal memory, and that its transcriptional regulation is disrupted in aging.
法勒等人。發現老年小鼠表現出混亂的記憶相關的活動和經驗依賴性表觀遺傳修飾組蛋白H4的賴氨酸在12（H4K12）乙酰化網站。與此相關的損失幾乎所有正常的記憶相關的海馬轉錄。此外，作者指出了記憶相關的基因，Formin 2（1肌動蛋白調節蛋白），並表明其功能是必要的正常的內存，並且它的轉錄調控是擾亂了老化。
In a final series of studies with potential clinical relevance, Peleg et al. show that intrahippocampal infusion of mice with suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, increased memory-associated H4K12 acetylation in the central nervous system, restored memory-associated transcriptional regulation, and improved behavioral memory function in aged animals.
在最後的一系列研究具有潛在的臨床意義，皮萊格等。表明小鼠海馬輸注 suberoylanilide羥肟酸，一組蛋白去乙酰酶抑製劑，增加內存相關 H4K12乙酰化在中樞神經系統，恢復記憶相關的轉錄調控，行為記憶功能和改善老年動物。
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Aging and memory. Experience-epigenome interactions may drive memory formation. Decline in this system is a hypothetical basis for cognitive aging.
CREDIT: C. BICKEL/SCIENCE
The study presents a major advance in thinking about the role of histone modifications in synaptic plasticity and memory formation, and ties together three different scientific areas: chromatin regulation, memory-associated transcriptional regulation, and the molecular basis of aging-related cognitive decline. But one cautionary note in considering the work of Peleg et al. is to not attribute all of the memory disruption and pharmacological rescue effects in the aged animals to a single histone modification, H4K12 acetylation. Alterations in a large number of chromatin-modifying events likely occur throughout the central nervous system in aging, and improvement of memory as a result of histone deacetylase inhibition is probably due to action at multiple acetylated histone sites. Also, given the possibility of a relevant "histone code" for memory (9), even the H4K12 alterations could be tied to another epigenetic mark that is more proximally involved in the aging-associated transcriptional alterations.
這項研究提出了一個重大進展想著組蛋白修飾作用在突觸可塑性和記憶的形成，聯繫在一起三個不同的科學領域：染色質調節，記憶相關的轉錄調控和分子基礎的老齡化有關的認知衰退。但有警示說明，在考慮工作皮萊格等。是不是所有的屬性內存破壞和藥理作用的拯救動物歲到一個組蛋白修飾，H4K12乙酰化。在大量的改變染色質修飾整個事件可能發生在中樞神經系統衰老，改善記憶，結果組蛋白去乙酰酶抑制可能是由於行動組蛋白乙酰化在多個地點。此外，由於有關的可能性“組蛋白密碼”的記憶（9），甚至可以改變的H4K12綁到另一個後生標記，更近端參與老齡化相關的轉錄變化。
There is an emerging understanding that chromatin is dynamic and is subject to extensive experience- and age-associated remodeling (7–15). For example, global loss of DNA methylation in aging, or the hypermethylation of regulatory regions (promoters) of genes associated with accelerated aging, such as the Werner syndrome and lamin A/C genes, has been proposed to control aging and longevity (13). In addition, the sirtuins, a family of nicotinamide adenine dinucleotide (NAD)–dependent histone deacetylases, link chromatin regulation, cellular transformation, and longevity (14). And chromatin modifications also regulate telomere-length control, an aging mechanism (15). These disparate findings suggest a unifying hypothesis: that the accumulation of aberrant epigenetic marks over the life span drives aging-related cellular and physiological changes.
有一種新興的理解是染色質是動態的，是受豐富的經驗和年齡的相關重塑（7-15）。例如，全球損失的DNA甲基化在老化，或甲基化的調控區域（發起人）與基因相關的加速老化，如沃納綜合徵和核纖層蛋白的A / C基因，已經被提出來控制衰老和長壽（13） 。此外，Sirtuins是一個煙酰胺腺嘌呤二核苷酸的家庭（NAD）的依賴組蛋白去乙酰化酶，連結染色質調節，細胞轉化，長壽（14）。與染色質的修改也調節端粒長度的控制，老化的機制（15）。這些不同的結果顯示一個統一的假說：即表觀遺傳標記異常積累在硬盤的壽命老化有關的細胞和生理變化。
These considerations have led to a new hypothesis that dysregulation of epigenetic control mechanisms and the accumulation of aberrant epigenetic marks underlie aging-related cognitive dysfunction (4, 8) (see the figure). Specifically, the decreased transcription of key memory-promoting genes during aging is thought to arise from aberrant epigenetic marks and control mechanisms within brain regions particularly vulnerable to the aging process (hippocampus and prefrontal cortex), thus resulting in cognitive deficits. Further pursuit of this unifying hypothesis will require investigating the role of epigenetic molecular mechanisms that control memory formation in aging at two critical loci: histone posttranslational modifications and DNA methylation.
這些因素導致了新的假設，即失調的表觀遺傳控制機制和積累的異常後生商標背後老齡問題有關的認知功能障礙（4，8）（見圖）。具體來說，重點記憶下降轉錄促衰老過程中的基因被認為是產生異常後生馬克和控制機制，特別是脆弱的大腦區域內的老齡化進程（海馬和前額葉皮質），從而導致認知缺陷。進一步追求統一這個假設將需要調查的作用，後生分子機制，控制記憶形成的老齡化在兩個臨界點：組蛋白翻譯後修飾和DNA甲基化。
The work of Peleg et al. and others (7–9) constitutes an initial test of the capacity of manipulating the epigenome to potentially reverse aging-associated memory dysfunction, and provide important proof-of-principle studies for evaluating whether this might be a viable approach to therapeutic intervention in cognitive aging. These studies will hopefully lead to more effective prevention strategies to improve quality of life in the aged, as well as contribute to a better understanding of memory function.
法勒的工作等。和其他人（7-9）構成的初步試驗能力操縱 epigenome潛在扭轉衰老相關的記憶障礙，並提供重要證據，對原則的研究，以評估是否這可能是一個可行的辦法治療干預的認知老化。這些研究可望帶來更有效的預防戰略，以改善生活質量的老年人，以及有助於更好地理解記憶功能。
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Shahaf Peleg, Farahnaz Sananbenesi, Athanasios Zovoilis, Susanne Burkhardt, Sanaz Bahari-Javan, Roberto Carlos Agis-Balboa, Perla Cota, Jessica Lee Wittnam, Andreas Gogol-Doering, Lennart Opitz, Gabriella Salinas-Riester, Markus Dettenhofer, Hui Kang, Laurent Farinelli, Wei Chen, and André Fischer (7 May 2010)
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