Escola Superior de Saúde do Vale do Ave-CESPU，葡萄牙
恒星生物分子研究-德国法兰克福
DOI: 10.15761 / IFNM.1000188
当代神经科学和抗衰老医学的进展表明，大脑和神经系统可以通过增加其神经源性和神经可塑性潜力来适应慢性压力、炎症和损伤机制。神经可塑性是功能神经元在一生中适应和修复的关键响应点，提供机会，通过DNA恢复，释放神经营养因子，抗氧化防御，线粒体，炎症和凋亡调节对抗神经老化的典型衰退。完美的神经可塑性发展将取决于多种必要的因素和概念，如表观遗传学、饮食抗炎/抗氧化营养、热量限制、正念冥想能力、新奇体验、睡眠周期质量、运动、生理和心理压力应对、激素平衡和细胞或组织再生分子。正分子医学建立了使用正确的分子来保持身体完美的生理和生化功能，通过使用这一广泛的Linus Pauling定义，本迷你综述旨在解决与认知和神经可塑性发展机制相关的主要问题，并为研究神经退行性变和衰老相关的神经疾病提供最佳视角。
抗氧化剂，衰老，大脑，饮食，锻炼，炎症，神经元，神经可塑性，正分子，氧化应激，多酚，再生，异种移植
AGEs:高级糖基化最终产物;AA:花生四烯酸;脑源性神经营养因子;BNP:脑利钠肽;COX-2:环氧合酶2型;DHA:二十二碳六烯酸;脱氢表雄酮:脱氢表雄酮;环保局:二十碳五烯酸;前体干细胞异种移植;FGF-2:成纤维细胞生长因子2; GABA: gabaminergic acid; GDNF: Glial cell-derived neurotrophic factor; IGF-1: insulin-like grow factor 1; Nrf2: Nuclear erythoid factor 2;iNOS: Nitric oxide synthase; IL-1β: Interleukin 1β; IL-6: Interleukin 6; IL-8: Interleukin 8; MSCs: Mesenchymal stromal cells; NF-κβ: Nuclear factor kappa β; NGF: Nerve growth factor; NMDA: N-methyl-n-aspartate; PG2: Prostaglandin-2; PUFAs: Polyunsaturated fatty acids; ROS: Reactive oxygen species; SCF1: Chemokine stromal cell-derived factor-1; SIRT1: Sirtuin 1; TNF-α tumor necrosis factor; TGF-β:转化生长因子-β；VEGF:血管内皮生长因子
全球人口老龄化带来的最大负担之一是认知能力的下降。专家警告说，痴呆症患者的数量到2030年将翻一番，到2050年将翻三倍。随着对痴呆症和衰老知识的发展，越来越清楚的是，与大多数年轻人的疾病不同，衰老状况涉及多种因素。当损伤超过大脑的自我修复能力时，细胞和代谢级联的触发就会开始，以完成神经退行性通路的机制。在40岁的时候，人类可能会达到延续物种的进化目的，因此，从生物学的角度来看;脑细胞的每日修复已经跟不上每日的损伤。因此，神经功能开始持续下降[2]。以前人们认为，大脑细胞的数量在一生中永远不会改变，死亡的神经元和突触也永远无法恢复。20世纪90年代，William Shankle和他的同事发现人类的大脑在出生后可以产生新的神经细胞和神经元，随后Gage、Gould等人的发现指出，“可塑性”的人类和灵长类动物的大脑在一生中会继续在大脑皮层产生神经元[3,4]。已建立的“神经源性”(起源于活跃的增殖神经细胞和生长因子)区域是海马的齿状回、心室下区(发育中的新皮层神经元的来源)和嗅叶[5,6]。 In summary, the number of new neurons produced, matches the number of neurons lost in each area, but as soon as the dying cells are being faster removing from the brain´s regions, the physiologic balance will be lost and the cognitive and neurologic function will decline. As a relative new concept in neurosciences, the neuronal plasticity refers to changes at the neuronal level, known to be stimulated by experience, e.g., neurogenesis, synaptogenesis, dendritic arborization, and network re-organization [5]. Cognitive plasticity refers to changed patterns of cognitive behavior, e.g., greater susceptibility to distractors, and dependence on executive control, both increased in aging. Manifestations of cognitive plasticity depend upon neural plasticity mechanisms and in the absence of disease; factors that enhance this interactive process can promote both cognitive integrity (preserved cognitive ability) and brain integrity (preserved brain structure) in healthy old age [5]. During lifespan, the brain may adapt to stress by triggering several regenerative mechanisms, such as DNA repair, neurotrophic releasing, enzymatic antioxidant defense and synaptic reconnections [7-9]. Since the discovery of the adult neurogenesis, much research effort has been devoted to study its mechanisms and implications in healthy and pathological conditions. Some elucidated neurogenic mechanisms involve neurotransmitters (such as dopamine, glutamate, and serotonin), hormones (such as thyroid hormones and melatonin), signaling pathways (Notch, Wnt/β-catenin, NAMPT-NAD, etc.), transcription factors (Sox-2, the orphan nuclear receptor TLX, Nrf2, etc.), growth factors (brain-derived neurotrophic factor BDNF, insulin-like grow factor-1, fibroblast growth factor 2, etc.) and epigenetic factors, which is the study of the influence of a particular gene expression and function into a specific phenotype [10,11]. The orthomolecular medicine establishes the use of the correct molecules to keep the perfect physiological and biochemical function of the body. Orthomolecular medicine is the restoration and maintenance of health through the administration of adequate amounts of substances that are normally present in the body. Nobel Prize winner Linus Pauling, one of the leading molecular chemists of the century, established this definition of orthomolecular medicine in 1968. The aging process is typically accelerated as a result of free radical exposure, frequent or chronic inflammation, and toxic exposures (such as to heavy metals or industrial and agricultural hydrocarbons). Reversing this process or slowing it down is one goal of orthomolecular therapy, along with treatment of health problems [12]. Within this orthomolecular concept, different factors will assist the ability to adapt cognitively and age successfully with the best neuroplastic potential, such as the natural retention of normal mechanisms of neuronal plasticity, the stimulation by novelty (new experiences, including learning), the sustained neural integrity supported by diet, hormones, own cell’s neurotrophic nutrients, exercise and other factors, including genetic polymorphisms, stress, immunity and environmental influences.
炎症是导致大脑健康下降的最高潜在机制。循环血液中促炎水平与大脑健康之间的联系已经在许多优秀的综述中得到了详细的研究。总之，在大脑衰老的研究中，一些外周血炎症标志物与转录核因子kappa β [NF-κβ]、白介素[IL]-6、IL-1β、肿瘤坏死因子[TNF]-α、IL-8[13]等关键标志物相关。与IL-1β和TNF-α的快速衰减相反，IL-6和c反应蛋白的水平可以在外周循环中可靠地检测到，并被广泛认为可以反映全身炎症水平[14]。例如，小胶质细胞与炎症有关，并且存在于阿尔茨海默病斑块中，激活了几种炎症标志物。促炎细胞因子增加β-淀粉样蛋白的表达，导致更多的炎症[15]。在慢性炎症刺激下，小胶质细胞会持续大量释放促炎因子，这将负责增强神经元毒性和促进大脑异常[14]。炎症也会导致氧化应激的增加。由于精神压力的增加，下丘脑-肾上腺轴的破坏和更高的皮质醇促进，自由基不断释放;氧化应激触发标志物，如高同型半胱氨酸、环境毒素、高血糖晚期糖基化终产物(AGEs)、酒精、盐、饱和脂肪、烟草等;或与遗传倾向有关，例如携带APOE4等位基因而不是2或3等位基因，这种等位基因通过降低大脑中的天然抗氧化能力而增加患阿尔茨海默氏症的可能性; also plays an important role in neurodegeneration. Once the radical reactive oxygen and nitrogen species are high, several called “death genes” will be switched on, for example, nitric oxide synthase [iNOS] and cyclooxygenase type 2 [COX-2] enzymes, which will convert arachidonic acid [AA] in prostaglandins and then the redundant production of cytokines. Connecting the idea of microglial activation, neurotoxicity and inflammation, there is indeed a previous mitochondrial dysfunction and reactive oxygen species [ROS] formation. The normal neuron´s mitochondria produce an adequate ATP that keeps the so-called N-methyl-n-aspartate [NMDA] receptor magnesium block. However, if there are deficiencies of ATP production, the electrochemical gradient is altered and the magnesium block in the NMDA receptor is relaxed, leading to an influx of calcium, damaging the mitochondria, which further exacerbates the energy production capabilities, trigger the apoptosis and causes again the inflammatory and ROS feed forward cycle [16].
饮食可能是大脑中最刺激的压力和炎症因素之一。机制研究表明，各种饮食成分可以调节炎症的关键途径，包括交感神经活性、氧化应激、转录因子核κ B [NF-κβ]激活和促炎症细胞因子[17]的产生。行为研究表明，压力事件和抑郁也可以通过相同的过程影响炎症[17]。促进炎症的饮食可以简单地概括为:摄入更多精制淀粉、糖、饱和脂肪和反式脂肪，摄入更少的omega-3脂肪酸和天然抗氧化剂(蔬菜、水果、全谷物等)。需要澄清的是，全谷物比精制谷物更健康，因为精制碳水化合物的过程会导致大量纤维、维生素、矿物质、植物营养素和必需脂肪酸[18]的消除。此外，精制淀粉和糖可以迅速改变血糖，导致胰岛素抵抗和高血糖，急剧增加氧化应激和炎症级联[17]的激活。事实上，一些证据表明，抗氧化剂或蔬菜的添加可能限制甚至逆转对高饱和脂肪[19]饮食的促炎反应。一些研究表明炎症与抑郁症的病理生理学有关。心理压力和抑郁促使人们选择不那么健康的食物，这与水果和蔬菜的摄入量减少、零食、糖果和快餐的摄入量增加有关。从这个角度来看，增强炎症的饮食可能加剧抑郁症状，从而增加炎症[20]。 For example, disturbed sleep, a common response to negative emotions and emotional stress responses, promotes IL-6 production [21]. A longitudinal data from Health Professionals Study showed that men decreased their vegetable intake following divorce and increased consumption after remarriage [17]．
热量限制是神经可塑性研究中另一个非常有趣的问题。热量限制和足够的营养与健康益处有关，通过增加从酵母到苍蝇、蠕虫和哺乳动物的有机体的寿命。研究表明,bu hara八公“吃到八分饱”是长寿的重要因素，一个人的健康寿命会延长[22]。3个月后，减少30%的热量与平均提高20%的非文字记忆相关。为了调节褪黑激素和皮质醇的平衡，调节昼夜节律，睡眠周期中的热量限制也有影响，这将有利于长寿。减少热量摄入似乎可以提高突触对损伤的恢复能力，并改变突触的数量、结构和性能。相反，高热量摄入被认为是阿尔茨海默病(AD)的一个危险因素，饱和脂肪的摄入已被观察到会促进AD类型β-淀粉样变性，而这可以通过减少碳水化合物[26]的饮食限制来预防。热量限制和间歇性禁食都不能掉以轻心。每种都需要健康的营养。不考虑卡路里的限制，长寿和神经可塑性的最佳饮食选择应该是冲绳饮食[22]或地中海饮食[27]。它们有一个非常重要的共同点，都富含蔬菜、水果、抗炎多酚、抗氧化剂、不饱和脂肪酸、鱼类和低血糖负荷食物。[28]。因此，从几个角度来看，食物和液体的摄入总量、摄入频率和摄入的含量将影响能量代谢和神经可塑性分子事件的所有因素[29]。
BDNF是一种神经营养因子，通常被认为有利于维持神经功能和促进神经损伤后的恢复。BDNF在海马体和大脑皮层中大量存在，在下丘脑和脊髓中少量存在。除了在发育过程中调节神经元的生存、生长和分化外，BDNF还刺激成人大脑[30]中的突触和认知可塑性。饮食中补充omega-3脂肪酸和姜黄素等营养物质已被证明能提高脑源性神经营养因子(BDNF)的水平，并能对神经回路的修复和维护产生影响，而神经回路对学习、记忆和运动非常重要。
对最佳中枢神经系统结构和功能也至关重要的是必需的omega-3脂肪酸二十碳五烯酸[EPA]和二十二碳六烯酸[DHA];而人类无法创造[32]。花生四烯酸[AA]衍生[-6或n-6]类烯二酮[主要来自于精制植物油，如玉米、向日葵和红花]增加促炎细胞因子IL-1、TNF-α和IL-6的产生，作为前列腺素[PG]2系列的促炎类烯二酮的前体。相比之下，ω -3 [n在某些鱼类(特别是野生鲑鱼)、鱼油、核桃、小麦胚芽和一些膳食补充剂(如亚麻籽产品)中大量发现的多不饱和脂肪酸(PUFAs)可以抑制aa衍生的类二十烷类化合物[33]的产生。ω -3脂肪酸为饮食因素对大脑的深远影响提供了一些最有力的证据。ω -3衍生的必需脂肪酸二十二碳六烯酸DHA是突触信号转导部位神经元膜的关键成分，这表明它的作用对大脑功能至关重要。DHA有助于支持突触膜的流动性，提高BDNF的水平，减少氧化应激，并调节细胞信号[35]。在弗雷明汉心脏研究中，DHA水平在前四分位数的人患痴呆的风险显著降低47%。一项补充鱼油的随机对照试验发现，“在有主观记忆障碍的老年人中，在更大的工作记忆负荷下，红细胞omega-3含量增加，工作记忆表现增强，后扣带皮层的BOLD信号增强”，这表明补充omega-3鱼油可以增强脑细胞对工作记忆[37]挑战的反应。
多酚是植物中发现的多种酚结构，具有强大的抗氧化和抗炎特性。在促进神经修复和神经可塑性方面最重要的一类多酚是类黄酮和姜黄素。类黄酮存在于许多水果和蔬菜及其子产品中，如浆果[如蓝莓、草莓]、茶和红酒[38]。例如，多酚白藜芦醇，一种非类黄酮多酚，有两种异构体形式:生物活性独联体-白藜芦醇，具有生物活性反式-白藜芦醇(反式- 3,4,5 -三羟基二苯乙烯]，在保持记忆和海马微结构的同时延长寿命。这种多酚天然存在于葡萄、紫葡萄汁和一些浆果中，如蓝莓和蔓越莓。白藜芦醇可能通过清除NADPH氧化酶产生的ROS发挥保护作用，激活SIRT1 [Sirtuin 1]，导致线粒体功能和生物发生的恢复，刺激“vitagenes”的生物合成，抑制小胶质细胞活化[40]。姜黄素来自姜黄属植物的根茎或根，经常用于印度菜肴中(产生我们熟悉的黄色咖喱)。姜黄素是在印度植物姜黄中发现的主要的姜黄素，姜黄因其强大的药用能力而闻名。姜黄素已被广泛研究，并被证明可以通过多种机制保护大脑，防止神经系统紊乱。姜黄素具有促进成年小鼠海马区神经发生和增加神经干细胞数量的作用。作为一种抗氧化、抗炎和抗淀粉样物质，姜黄素可以改善阿尔茨海默病患者的认知功能。60-85岁的健康人群对认知和情绪[42]的改善表示赞赏。其他被广泛接受的珍贵多酚是可可中的类黄酮，它以强大的抗炎和抗氧化作用而闻名。 A review of the neuroprotective effects of the flavonoids in cocoa suggested that they “provoke angiogenesis, neurogenesis and changes in neuron morphology, mainly in regions involved in learning and memory” [43]. Another review similarly found that cocoa flavonoids are neuroprotective and can enhance mood and cognitive function [44]. Humans aged 50–69 years who consumed 900 mg of cocoa flavanols daily for 3 months enjoyed improved dentate gyrus performance on cognitive testing as well as on fMRI [45]. Green tea is rich in flavonoids, particularly catechins such as epigallocatechin-gallate, epigallocatechin, epicatechin, and epicatechin-3-gallate. Green tea is commonly consumed in China and throughout Asia, and its consumption is perceived as beneficial for the general health of the organism [31]. Daily doses of the compound GT-catechin, an antioxidant found in green tea, has been shown to help prevent memory loss and DNA oxidative damage [46].
不同的营养物质由于其抗氧化和线粒体保护作用，对神经和认知功能都有积极的影响。叶酸或叶酸存在于菠菜、肉肝、豆类、西兰花等，在3年的补充中，可以减少或预防脑老化衰退和痴呆[47,48]。硫辛酸是一种重要的线粒体能量维持辅酶;存在于肾脏，肝脏，心脏，西兰花，菠菜和土豆[49]。α硫辛酸可减轻阿尔茨海默病的认知衰退[50]。维生素E修复细胞突触膜抵抗氧化，影响神经可塑性。辅酶Q10是一种非常有效的抗氧化剂，对增强线粒体活性有重要意义。CoQ10可能对线粒体功能受损、氧化应激和损伤存在的神经系统疾病的病程有潜在影响。在Shults的一项随机双盲研究中，80名没有接受其他治疗的帕金森病患者每天被给予1200毫克CoQ10。16个月后，接受CoQ10的组[52]的下降率降低了47%。 Vitamin D is a CNS active neurosteroid with the capability to cross the cell membranes and link to their vitamin D nuclear receptors, switching on more than 1000 genes and modulating a gigantic network of neurological mechanisms such as cellular proliferation, differentiation and calcium homeostasis [53]. Further antioxidants may be also part of a functional neuroplastic diet, such as choline, combination of vitamins [C, E, carotene], calcium, selenium, zinc and creatine, which delay brain decline, promote longevity and cellular energetic nerve tissues storage and repair etc. [54-58].
与适当的功能性饮食相结合，体育活动可以增强神经元的功能和可塑性，通过增强突触的可塑性，减少炎症和氧化应激。不同高水平的身体素质都能影响能量代谢和BDNF神经可塑性刺激，对抗衰老饮食选择起辅助作用。运动增强海马体积和完整性，平衡海马萎缩。它也是对抗大脑中高饱和脂肪和蔗糖促炎行为的有益竞争者[59-61]。有氧运动增加人体神经元的神经发生、存活和成熟[62,63]。一项针对老年人的随机对照试验综述表明，体育锻炼可以增加脑灰质，防止与脑萎缩相关的认知行为损失[64]。综上所述，运动可以提高多方面的学习和记忆能力，恢复神经功能，甚至促进脑损伤后的恢复。[65]。总之，有规律的锻炼是减缓神经退行性衰老过程和预防精神障碍的重要策略[66]。
新鲜感对于增强注意力和认知非常重要[67]。梅奥诊所的衰老研究，设计了1995名没有痴呆的人，年龄在70-89岁之间，其中277人有轻度认知障碍[MCI];显示了职业和学术成就与认知障碍延迟8.7年的程度之间的联系。独立于生命，处理新的挑战和障碍可以作为一种强大的智力工具，达到显著的结果，活得更健康，更长寿。[68]。关于艺术技巧和神经可塑性，音乐是促进神经可塑性的最多感官形式之一。一旦一个人能够阅读乐谱，他或她就必须将音符的视觉编码翻译或解释为数学值，从而将其转化为所选乐器的节奏或声音、主观和谐和运动技能。音乐能够同时激活数百万个神经网络，并刺激最多样化的大脑区域。很明显，这种视听和抽象的融合将发展神经发生[69,70]。2013年，研究人员对60至84岁的人进行了为期4个月的钢琴课程研究，结果显示，他们的注意力、情绪、认知技能、运动功能、视觉记忆和执行功能都有所改善[71-73]，这表明持续5至6周的60至75分钟的音乐训练足以帮助老年人逆转与年龄有关的衰退。 Speed Training Computer Analysis report a 5 years long maintenance with immediate cognitive and motor gains, regardless of age, education, mental status and health condition when someone receives a routine of music training [74]. Concerning meditation and neuroplasticity, long-term meditation practitioners, ages from 24-77 years old, demonstrated less brain gray matter atrophy with aging [75]. This and other continuously publishing scientific articles reinforce the hypothesis that mindfulness meditation is brain-protective and will benefit the white and gray brain plasticity, as much as will act on the anti-inflammatory and antioxidant cellular and molecular defence pathways, having the similar responsive mechanisms of the targeted prescription pharmaceuticals and function as a valuable brain anti-aging tool [76,77]. At last but not least, sleep well and respecting the circadian “chronorhythm” influences the energetic metabolism, restoring brain capacity during the periods of rest. Once awake, the neural consumption can be very high and the excess production of cortisol and adrenergic hormones during a long period of time can “burn” energy enough to reduce gray brain matter [78]. Research done in 2.822 from 67 years and older associates the sleep disruptions with inflammatory increasing, reduction of BDNF and cognitive decline [79,80]. A balanced restoring sleep is essential for the neuronal detoxification processes and distribution of glucose, lipids, amino acids, growth factors and neuromodulators throughout the nervous system, as well as to reduce the inflammatory and stress cascade [81].
认知能力下降与年龄增长有关，这是一个事实。在这一过程中，几种关键的神经保护激素逐渐减少，35岁后明显减少。褪黑素是松果体产生的一种神经激素，随着年龄的增长，褪黑素会下降，与神经元长期自我更新的潜力下降的方式相同，即褪黑素的减少会影响神经元的修复[82]。褪黑素参与了一个庞大的生物化学和分子连锁系统，作用于季节性和昼夜节律的调节、抗氧化机制、免疫反应等[83]。褪黑素是一种强大的自由基清除剂，抗氧化剂，改善线粒体能量生理，以保护神经，包括对抗β -淀粉样肽[a β]损伤[84-87]。褪黑素处方可增加海马、神经元和树突状前体细胞的发育、分化、成熟和存活[88,89]。脱氢表雄酮是一种由肾上腺、性腺和中枢神经系统细胞分泌的胆固醇衍生类固醇，其含量随年龄增长而下降，与认知缺陷、抑郁、海马萎缩和痴呆(包括阿尔茨海默病)的增加有关[90-92]。DHEA增加了胶质细胞源性神经营养因子[GDNF]的表达，促进了树突树化和神经发生[93,94]。瘦素是一种脂肪样脂肪因子，在食物摄入和能量消耗代谢中发挥多种作用，它还可以调节细胞凋亡，保护氧化损伤，刺激神经可塑性、轴突生长、突触生成和海马和树突状干细胞增殖[95-97]。关于其他激素，主要认识到类固醇激素在神经系统中的广泛作用，它包含来自最重要的外周器官如卵巢、睾丸和肾上腺皮质的特定受体[98]。 Testosterone takes part in the nervous system development and exerts neurotrophic actions on the neuronal differentiation and increasing in neurite outgrowth after activation of androgen pathways in the cultured neural cells [99-101]. Testosterone supplementation during 6 weeks improves both spatial and verbal memory in healthy older men aged 50–80 years [102]. There are several potential mechanisms of testosterone protection against neurodegeneration connected with Alzheimer Disease [AD]. One of them is prevention of tau protein hyperphosphorylation [103]. Testosterone increases expression of nerve growth factor and mediates promotion of neurite growth and interneural communication through branching and arborization [104]. Estrogens have also long been known to influence nervous system development and function [105-107]. It has become clear that estrogens can exert effects in multiple regions of the brain, including the cerebral cortex and hippocampus [108]. Estrogen induces rapid changes enhancements in memory consolidation and increases dendritic spine density [109]. Progesterone treatment increases the mRNA BDNF protein levels and protects against spinal cord injury by decreasing the chromatolysis cell number, which is a typical characteristic of motoneuron degeneration [98,110]. Progesterone acts on the GABA一个[gabaminergic acid]受体具有整体的抗焦虑作用，特别是在突触海马传递的平衡调节上[111]。总之，上述激素激活了与突触可塑性和神经保护相关的生物分子通路。它们的有益作用对记忆、学习和树突脊柱的结构和功能是基本的
干细胞疗法现在被纳入当代医学领域称为“再生医学”。这是医学的一个新分支，研究人类细胞、组织或器官的再生过程，以恢复其既定的正常功能。“它还包括刺激身体自身的修复机制，以治愈功能失调的组织或器官[112]。”然而，细胞疗法是一种古老的医学技术，它将人或动物的细胞植入人或动物体内，以修复细胞损伤并治疗疾病。这是再生医学领域最先进的治疗方法，1912年，诺贝尔奖得主亚历克西斯·卡雷尔(Alexis Carrel)首次证明了体外衰老细胞的再生。1931年，Paul Niehens博士将其应用于人体，取得了巨大成功[113]。目的是通过使用通常从培养的胎儿、新生儿、少年或成体阶段生物相同细胞中发现和分离的生物营养因子、分子和肽，恢复细胞、组织和器官的功能能力。细胞疗法包括使用新鲜细胞、冻干[冻干]细胞、冷冻细胞和原代组织培养制备的胎儿前体细胞干细胞移植植入[112]。有趣的是，就细胞类型的选择而言，一些小组研究指定了在经过认证的封闭菌落中饲养的胎儿或新生兔子的细胞。异种移植技术可能是替代人类细胞的一种聪明的方法，因为哺乳动物除了额叶(FCTI)之外，在其他动物中没有发现其他细胞(FCTI)之外，拥有所有相同的细胞学水平。这些动物是按照美国实验动物护理认证协会(AAALAC)和美国食品和药物管理局(FDA)的规定饲养的。 These xenotransplants might have some advantages comparing to human stem cells, as it is impossible to have humans subjected to such stringent regulations. The aim is to use fetal precursor stem cell xenotransplants [FPSCXT] prepared by primary tissue culture for treatment of diseases [112]. Currently, stem cells prepared by the primary tissue culture technique have been shown to be even safer because the eleven days of culture allows detailed daily evaluation of the cultures for bacterial contamination and endotoxins. In case of any suspicion of contamination, the stem cell transplants will be immediately discarded [114]. Research has shown that the cells processed this way are even less immunogenic [114]. These are implanted without the use of any immunosuppression. [114]. Studies in cell biology have established the importance of the cell membrane as the “brain of the cell”. Although the xenogeneic, heterologous or autologous cell implantation mechanisms are still unclear, the regenerative effects, most seen following live cell therapy, might be due to the cell signalling factors and molecules in the fetal precursors stem cells transplants acting on the corresponding cell membranes receptors ligands of the recipient and, thereby, regulating and reprogramming cell functions at epigenetic level [115]. For instance, it’s becoming clearer that protein phosphorylation in nerve tissues is of a paramount importance and has several roles; included enzymes involved in neurotransmitter biosynthesis and neurotransmitter receptors [116]. The large amount of phosphorylated neuronal proteins and their membrane receptors, once transplanted, should activate a molecular and biochemical cascade on the recipient´s site, boosting the neuronal repairing and neuroplasticity. The transplantation of human or animal stem/progenitor cells, for instance, can be an effective treatment for central nervous system [CNS] injury due to the self-renewing and pluripotential nature of these cells. Stem cells can repair injured nervous tissue by developing a regenerative appropriate environment of neuroprotection in which the damaged cells may be replaced by new functional ones. The stem cells can be distinguished by its origins, either from embryonic, fetal or adult and depending on that, the regenerative potential might be greater once transplanted into the impaired CNS [117]. The transplantation of bone marrow-derived mesenchymal stromal cells [MSCs] can be very promising because of the incredible potential of those cells in self-renewing, differentiating into multiple mesodermal tissues, including bone, cartilage, fat and muscle and been nonimmunogenic; which allows its prompt clinical using. As the mesenchymal stromal cells [MSCs] have the ability to produce cytokines and various neurotrophic factors [oligodendrocyte precursor cells, chemokine stromal cell-derived factor-1 [SCF1], brain natriuretic peptide [BNP], astrocytic BDNF, insulin growth factor-1 [IGF1], vascular endothelial growth factor [VEGF], fibroblast growth factor-2 [FGF2], transforming growth factor-β[TGF -β]、BDNF和神经生长因子[NGF]];可以从大脑可塑性的各个方面获益，包括调节血管生成、凋亡、神经发生、突触发生和树突增殖[117,118]。当然，细胞治疗和干细胞生物学的复杂网络显然需要进一步研究，但综上所述，细胞治疗有希望的创新是，外源性细胞因子、多肽和营养物质可能提供治疗效益，诱导中枢神经系统重构，从而提高神经功能的改善。
应用神经科学领域正处于一个渐进而广泛的发展中。每天，新的分子、生物途径和细胞机制都在被发现和发表。挑战在于整合之前讨论过的各种关于大脑神经可塑性的观点，以实现抗衰老神经元的广泛益处。正分子的概念建立在现代医生或神经科学家必须具有的广泛视野之上，即把心理压力的干扰与下丘脑-下垂体-肾上腺斧的破坏、应激激素(如皮质醇、肾上腺素和去甲肾上腺素)的增强联系起来;高氧化应激分子，免疫抑制，激素失衡和炎症的后果。除了生物衰老过程和遗传学和表观遗传学的影响外，还有社会行为的结果，这取决于学习新任务的好奇心、交流新经验、冥想、每天锻炼和合理饮食。从当代社会的观点来看，由于一些重要的压力和炎症诱因，人们的疾病越来越多，年龄越来越大。重金属污染、反复感染、过量的糖和精制“垃圾食品”、久坐不动的生活、过度的工作、很少有时间去好奇、社交和学习新鲜事物;缺乏放松和冥想的意识……每一条道路都可能导致压力、慢性炎症、免疫抑制、代谢和激素失衡以及疾病。无论是地中海饮食还是冲绳饮食都富含抗炎膳食多酚、多不饱和脂肪酸、蛋白质、纤维、益生菌、维生素和进一步的抗氧化剂。 By mixing all these key functional nutrients with caloric restriction and moderate exercises, the epigenetic expression will be activating in order to regulate the transcription of neuroprotective proteins and growth factors, slowing aging typical degeneration. As far we discuss the new aspects of neurodegeneration treatments, we must give high importance to the hormonal and cell therapy, which offer very important possibilities on the neurotransmitters balance, tissue repairing, cell restoration and neuroplastic stimulation. Of course, more basic and experimental researches, meta-analysis and other clinical global assays are needed to dissect the still unclear mechanism of neuroplasticity and its related integrative medical treatments. The moment is timing is imperative for such interventions with goals of enhancing brain health throughout lifespan [119-127].
功能性大脑有能力通过神经可塑性机制进行自我修复，这取决于抗炎/抗氧化型饮食、热量限制、适度锻炼、新体验、冥想、激素平衡和再生细胞神经营养因子。有了这种正分子的观点，就必须制定最佳策略来提高长寿的健康质量。
蕾妮Dufault
食品成分与健康研究所
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收稿日期:2017年5月03日
录用日期:2017年6月05日
出版日期:2017年6月07日
©2017 Moya RL。这是一篇开放获取的文章，根据创作共用署名许可协议(Creative Commons Attribution License)发布，该协议允许在任何媒体上不受限制地使用、分发和复制，前提是注明原作者和来源。
Moya RL(2017)脑营养-正分子方面。Integr Food Nutr Metab 4: DOI: 10.15761/IFNM.1000188
Escola Superior de Saúde do Vale do Ave-CESPU，葡萄牙
恒星生物分子研究-德国法兰克福
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