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Chinese Journal of Alzheimer's Disease and Related Disorders

Abbreviation (ISO4): Chinese Journal of Alzheimer's Disease and Related Disorders      Editor in chief: Jun WANG

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2020 , Vol. 3 >Issue 4: 310 - 314

DOI: https://doi.org/10.3969/j.issn.2096-5516.2020.04.011

Advantages and disadvantages of dietary fat in prevention and treatment of cognitive impairment in the elderly

  • TANG Feng ,
  • DING Xiaomi ,
  • WANG Li ,
  • JIANG Guohui
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  • Affiliated Hospital of North Sichuan Medical College, Institute of Neurology, North Sichuan Medical College, Nanchong 637000, China

Received date: 2020-08-18

  Revised date: 2020-09-05

  Online published: 2020-12-25

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Abstract

With the aging of the population, obesity, diabetes, hyperlipidemia, cardiovascular and neurodegenerative diseases are contributing risk factors in human health. These factors are the main causes of cognitive dysfunction in the elderly, which seriously reduce life expectancy and poor quality of life in patients and present an enormous financial burden to families and society as a whole. Therefore, the prevention and control of these diseases are very important for human beings. As the core link of primary prevention, diet regulation is focused by researchers, medical staff, and the public. A low-fat diet has been recommended for decades around the world, but its health benefits have been questioned more and more in recent years. However, the ketogenic diet with strict carbohydrate restriction and fat energy supply as the main energy source is favored. More evidence shows that a ketogenic diet has benefits in weight loss, chronic inflammation suppression, improvement of insulin receptor resistance, anti-aging, and cognitive improvement. Therefore, this paper reviews the effect of dietary fat on cognitive function in the elderly, and its possible advantages and disadvantages in the prevention and treatment of senile dementia.

Key words： Cognitive impairment; Dietary fat; Carbohydrate; Ketogenic diet; Insulin receptor resistance

Cite this article

TANG Feng , DING Xiaomi , WANG Li , JIANG Guohui . Advantages and disadvantages of dietary fat in prevention and treatment of cognitive impairment in the elderly[J]. Chinese Journal of Alzheimer's Disease and Related Disorders, 2020 , 3(4) : 310 -314 . DOI: 10.3969/j.issn.2096-5516.2020.04.011

阿尔茨海默病（Alzheimer's disease, AD）和血管性痴呆（Vascular dementia, VaD）是老年期认知障碍最常见的类型。首都医科大学宣武医院贾建平团队发表中国痴呆现状的研究,至2016年中国60岁以上人群痴呆患病率增长了5.6%,而全球平均患病率仅增加了1.7%,中国痴呆患者的发病率远超过全球平均水平。目前推算中国老年痴呆患者超过1000万,轻度认知障碍患者3100万,卒中后痴呆患者950万;我国认知障碍患者累计超过5000万,但仅有2%的患者能接受正规治疗和护理[1-2]。认知障碍是威胁人类健康的常见疾病,痴呆患者为社会和家庭带来极大负担,所以痴呆防治是我国面临的重大公共卫生问题。
AD分为临床前、轻度认知障碍和痴呆阶段,即痴呆早期阶段和痴呆症状期[3]。尽管AD新药的研发已超过15年,但仍没有证实任何一种药物可以逆转痴呆病理或者阻止痴呆进展,所以目前缺乏新的批准用于临床的AD治疗药物。据2018中国国民健康大数据报告：2020年我国60岁以上老龄人占人口比例的16.6%,至2050年将增至30%。随着中国人口老龄化的快速进程和照顾认知受损老年人的成本增高,对老年期痴呆最常见的AD和VaD早期筛查和预防极其重要。AD和VaD的高危因素包括不可控的年龄、性别及遗传因素,同时还与高血压、高脂血症、糖尿病、腹型肥胖等可控因素显著相关[4]。年龄是AD最大的危险因素,荟萃研究大数据的结果显示60岁以后AD发病率每10年会增高1倍[5-6]。除了早期开展认知功能训练和体力锻炼外,健康饮食是干预上述可控危险因素最便捷可行的策略。尤其在中年期加强饮食限制对这些危险因素的调控将有望降低AD和VaD发病的风险,并延缓AD进程[7-8]。近年来大量的研究数据强调饮食限制在延缓衰老和改善认知方面的重要性,但膳食脂肪的摄入对认知功能的影响仍有争议。

1 膳食脂肪比例对认知功能的影响

随着农耕社会向工业社会的转变,饮食结构在不断变化,更多精制碳水化合物和反式脂肪等加工食品被摄入,以及热量摄入过多是导致现代人肥胖发生率增加的罪魁祸首。高碳水化合物的摄入导致血糖快速增高,胰岛素释放激活胰岛素受体,长期刺激导致胰岛素受体信号敏感性下降,即胰岛素受体抵抗的发 生[9]。另一方面,富含饱和脂肪酸的饮食也有诱导胰岛素抵抗的能力,在不限制总热量时添加脂肪（高脂饮食）可诱导肥胖和胰岛素抵抗及饮食相关的慢性疾病如高血压、高脂血症及糖尿病[10]。
传统观念认为低脂肪饮食是预防和治疗肥胖相关疾病的公共卫生和临床指南的基石。美国参议院营养特别委员会在1977年发布了第一个国家饮食健康指南。建议低脂饮食,将碳水化合物的消耗增加到能量摄入的55%到65%,将脂肪消耗从42%降至34%。该指南建议理由是脂肪是高能量来源食物,摄入脂肪会导致肥胖[11]。尽管数据并不充分,1984年美国国 家卫生研究所（National Institutes of Health, NIH）关于降低血液胆固醇以预防心脏病的共识专家小组再次提出减少膳食脂肪的建议,因此,膳食脂肪一直被视为健康公敌。但数十年的低脂饮食推荐不仅没有降低肥胖和糖尿病的发病率,且肥胖和饮食相关的慢性病如高血压、血脂异常、心脑血管病发病和神经退行性疾病的发病率也在上升,最终反而出现预期寿命下降[12-13]。
国内[14]研究者报道了一项为期6个月的随机饮食对照试验,观察不同宏量营养素供能比对中国非肥胖健康人群体重及心脏代谢的影响;依据不同能量来源比例随机分为低脂-高碳组（LF-HC: 20%脂肪+66%碳水化合物+4%蛋白质）,中脂-中碳组（MF-MC: 30%脂肪+56%碳水化合物+14%蛋白质）和高脂-低碳组（HF-LC: 40%脂肪+46%碳水化合物+14%蛋白质）三组。研究结果发现接受低脂肪高碳水化合物干预组的受试者在体重、腰围和部分血脂水平较另外两组显著降低,而糖代谢相关指标在三组之间并未发现显著性差异。与此相反,更多的研究证据表明大量糖的摄入导致超重,增加糖尿病、心脑血管病、神经退行性变和认知功能障碍的风险,并增加全因死亡率[15]。几项荟萃分析和系统综述表明,习惯性饮用含糖饮料或者长期高糖饮食的摄入与2型糖尿病（T2DM）的发病率增高相关[16⇓-18]。一项超过13万名参与者的前瞻性城市与农村流行病学（PURE）队列研究,在18个国家进行的流行病学调查,结果显示高碳水化合物摄入与全因死亡率高风险相关[19]。

2 高脂饮食影响认知功能的机制

认知障碍即痴呆症是一个术语,描述一组认知功能下降的症状,包括记忆、思维、定向、理解、计算、学习能力、语言、判断、情绪控制、社会行为和动机障碍[20]。国际阿尔茨海默病协会（ADI）估计,每3秒钟,世界上就会有人患上一种痴呆症。认知障碍有上百种病因,其中。AD和VaD患病率最高,是老年期痴呆的常见形式。胰岛素抵抗（Insulin resistance, IR）在2型糖尿病（T2DM）、肥胖和痴呆的发病机制中起着重要作用[21]。人类衰老过程中,大脑代谢活动和功能网络连接下降,伴随神经元的丢失,突触可塑性和髓鞘形成的降低。研究发现以AD为代表的神经退行性疾病患者多个脑区能量代谢降低[22-23]。AD最核心的症状是认知与记忆下降,同时伴随中枢胰岛素信号通路受损,导致中枢胰岛素抵抗,因此被称为“3型糖尿病”[24-25],而超重和肥胖是T2DM和AD发展的最大危险因素。
高脂饮食（High-fat diet, HFD）诱导肥胖和胰岛素抵抗与饮食相关的慢性疾病,如神经退行性改变、认知障碍和脑卒中有关。Kothari等[26]研究者报道6周龄雄性C57BL/6NHsd小鼠,持续14周的高脂饮食（40%脂肪能量）加糖水（42 g/L）喂养组与正常鼠粮（12%脂肪能量）组比较：前者肥胖率增加,葡萄糖和胰岛素耐受性降低,提示高脂高糖饮食诱发脑胰岛素受体抵。表现为胰岛素受体酪氨酸磷酸化水平显著降低,胰岛素受体底物-1（IRS-1）丝氨酸磷酸化水平升高,诱发脑组织炎症反应和氧化应激相关信号NF-kappaB和p38 MAPK信号激活,促进淀粉样蛋白沉积和神经纤维缠结,降低突触可塑性。阐明高脂高糖饮食诱导的认知功能障碍与脑胰岛素受体信号的敏感性相关。长期HFD喂养和胰岛素受体（IRS2）基因突变导致A-beta沉积和胰岛素受体抵抗而出现认知受损。HFD喂养和糖尿病小鼠AD模型对周围胰岛素刺激大脑的反应降低,脑血浆胰岛素比值降低,导致脑胰岛素抵抗反应。
近年来,中枢胰岛素抵抗在神经退行性疾病和认知障碍中的作用及机制被阐明,在胰岛素抵抗条件下大脑氧化应激、神经酰胺生成、beta-淀粉样蛋白沉积和神经元凋亡显著增加[27]。血脑屏障调节外周和中枢神经系统之间的交流,调节胰岛素向大脑的转运,因此有助于调节中枢胰岛素水平,血脑屏障对胰岛素的反应变化可能影响中枢胰岛素抵抗。大脑胰岛素水平对血脑屏障细胞构成类型包括内皮细胞、神经元、星形胶质细胞和周细胞均有调控作用,并影响神经炎症与退变、A-beta沉积和Tau蛋白磷酸化水平;所以改善胰岛素受体抵抗可能是改善血脑屏障破坏和认知功能障碍的关键靶标[28]。但并非所有的高脂饮食都导致胰岛素受体抵抗和认知功能障碍,近年大量研究证实热量限制和生酮饮食在抑制慢性炎症、减肥、抗衰老与神经退变和认知改善方面的效果显著。

3 热量限制和生酮饮食改善认知功能

人脑是高能消耗器官,仅占成年体重约2%,但却消耗机体总能量需求的20%[29]。大脑能量代谢障碍不能满足神经元电活动和突触传递的高能量需求时,则导致高级神经功能障碍。适当的宏量营养素摄入对维持大脑能量代谢和脑功能具有重要意义。摄入能量和饮食中特定营养素过剩或不足均可能对认知、情绪、行为、神经内分泌功能和突触可塑性产生利或弊的影响[30]。
人类早已发现热量限制可延长许多实验动物的寿命,可能与热量限制减少年龄相关肥胖、代谢性疾病、肿瘤及脑卒中发生相关[14,31⇓ -33]。越来越多的证据表明,饮食限制的健康益处不仅是自由基减少或体重减轻的结果。同时,可通过CREB及SIRT1信号调控进化上保守的适应性细胞反应,这些反应以改善葡萄糖调节、增强机体免疫、抑制炎症反应,降低氧化应激、兴奋性毒性氨基酸导致神经元损伤[34]。在限食期间,细胞激活增强内在防御氧化和代谢压力的途径,通过胰岛素受体及下游PI3K/AKT、MAPK/ERK及mTOR等信号清除或修复受损分子[35]。最近一篇关于灰鼠狐猴的研究发现长期中度（30%）热量限制与对照组动物相比,热量限制将寿命延长了50%（平均寿命从6.4岁延长到9.6岁）,并改善认知功能,减少与衰老相关的疾病[36]。在热量限制或间断性禁食期间,甘油三酯被分解为脂肪酸和甘油,为大脑及其他组织提供能量。在进食状态,血液中酮体水平很低,在人类禁食后8~12 h增高,24 h可达到2~5 mmol/L;在啮齿动物中,血浆酮水平在禁食后4~8 h内升高,24 h内达到毫摩尔水平。酮体可刺激脑源性神经营养因子基因的表达,对大脑健康、精神和神经退行性疾病产生有利的影响[37]。
生酮饮食是一种高脂肪、极低碳水化合物的饮食,用于癫痫患者的临床治疗已有百年历史。经典生酮饮食脂肪比例高达90%,应用于儿童癫痫或癫痫综合征,以及成人难治性癫痫的治疗[38]。而柔性生酮饮食,近年来已广泛应用于非癫痫性疾病。其供能比例为：脂肪比例65%~80%,蛋白质20%~30%,碳水化合物小于5%[39]。生酮饮食以极低碳水化合物为特征,以脂肪供能为主,模拟饥饿状态,通过脂肪酸氧化产生酮体（KB）,作为替代能源。生酮饮食模拟饥饿时的酮症状态。生酮饮食通过这种能量代谢的转换导致一系列下游效应,如增强线粒体呼吸、减少活性氧（ROS）产生和炎症反应、促进神经元长时程、增加BDNF表达及调控表观遗传,还涉及胰岛素受体及下游Akt、CREB、SIRT1和mTOR等信号,参与衰老、神经退行性改变和认知功能的调节[39⇓⇓-42]。此外,生酮饮食在脑外伤、睡眠障碍、头疼、脑肿瘤、自闭症、精神分裂症、多发性硬化症和脊髓损伤等多种神经系统疾病中都有保护作用[30,43 -44]。
近年来,越来越多的研究支持短-中期的减肥中,涉及生酮饮食的严格控制碳水化合物的高脂饮食,通常比低脂饮食获得更好的效果,而且在抗衰老、延长寿命和改善认知方面更有优势[45-46]。荟萃分析的结果也显示胰岛素敏感的患者对低脂或低碳水化合物饮食的反应相似,而那些胰岛素抵抗、葡萄糖耐受不良或胰岛素分泌亢进的人采用低碳水化合物、高脂肪饮食减重效果更好[47-48]。

4 膳食脂肪摄入的个体化策略

膳食脂肪是外周和中枢代谢的“传感器”,对脑功能具有极其重要的影响,对膳食脂肪的调控已作为衰老与认知调控的关键策略。目前,新的膳食指南更多关注饮食模式,以及相关的食物和营养成分,而不是营养素的摄入比例[49]。精制谷物提供的营养单一,而且其高血糖负荷会导致餐后血糖和胰岛素升高,促进饥饿、炎症、胰岛素抵抗和血脂异常。尤其是加工碳水化合物的不良代谢影响的证据推动了人群对低碳水化合物和高脂肪含量的生酮饮食重新关注[50⇓-52]。中国专家共识推荐肥胖、代谢综合征和2型糖尿病患者进行生酮饮食干预[53]。
膳食脂肪主要成分是甘油三酯,而甘油三酯中的脂肪酸在链长、双键数目、双键位置以及双键是顺式还是反式构型上都存在差异。这些结构特征对脂肪酸的生物学功能有巨大影响,进而影响脂肪酸对饮食相关的慢性疾病的影响。虽然饱和脂肪是健康公敌,但不饱和脂肪对健康有益,尤其是中链多不饱和脂肪酸（PUFAs）家族,N-3和N-6脂肪酸是机体必需的,是细胞周期中合成细胞膜的关键成分,介导炎症、血栓形成、免疫和胰岛素抵抗的二十烷类激素的前体[54⇓-56]。有研究证实了多不饱和脂肪酸的摄入在抗衰老与神经退行性变,及改善认知功能方面的益处[12]。但也有营养专家提倡低脂肪饮食,强调摄入少量加工过的碳水化合物和不饱和脂肪,并限制饱和脂肪,建议食用蔬菜、水果、全谷物和脱脂或低脂牛奶作为碳水化合物的来源（而不是深加工食品）。同时也有人推荐低碳水化合物饮食,强调其对血糖和胰岛素水平以及对体重的有益影响。
总而言之,不同饮食方式对健康、老化与认知功能的影响仍在不断的探索,需要关注个性化营养需求,以及个体对不同饮食方式反应的巨大差异,实现宏量营养素摄入的个体化策略。

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