News Release 4-Mar-2020

jkzx.com editor’s note: Be aware of which carbohydrates you need to avoid. Simply put, you need to avoid simple carbohydrates like sugars.

Stony Brook University

STONY BROOK, NY, March 4, 2020 – A study using neuroimaging led by Stony Brook University professor and lead author Lilianne R. Mujica-Parodi, PhD, and published in PNAS, reveals that neurobiological changes associated with aging can be seen at a much younger age than would be expected, in the late 40s. However, the study also suggests that this process may be prevented or reversed based on dietary changes that involve minimizing the consumption of simple carbohydrates.

To better understand how diet influences brain aging, the research team focused on the presymptomatic period during which prevention may be most effective. In the article titled “Diet modulates brain network stability, a biomarker for brain aging, in young adults,” they showed, using large-scale life span neuroimaging datasets, that functional communication between brain regions destabilizes with age, typically in the late 40’s, and that destabilization correlates with poorer cognition and accelerates with insulin resistance. Targeted experiments then showed this biomarker for brain aging to be reliably modulated with consumption of different fuel sources: glucose decreases, and ketones increase, the stability of brain networks. This effect was replicated across both changes to total diet as well as after drinking a fuel-specific calorie-matched supplement.

“What we found with these experiments involves both bad and good news,” said Mujica-Parodi, a Professor in the Department of Biomedical Engineering with joint appointments in the College of Engineering & Applied Sciences and Renaissance School of Medicine at Stony Brook University, and a faculty member in the Laufer Center for Physical and Quantitative Biology. “The bad news is that we see the first signs of brain aging much earlier than was previously thought. However, the good news is that we may be able to prevent or reverse these effects with diet, mitigating the impact of encroaching hypometabolism by exchanging glucose for ketones as fuel for neurons.”

What the researchers discovered, using neuroimaging of the brain, is that quite early on there is breakdown of communication between brain regions (“network stability”).

“We think that, as people get older, their brains start to lose the ability to metabolize glucose efficiently, causing neurons to slowly starve, and brain networks to destabilize,” said Mujica-Parodi. “Thus, we tested whether giving the brain a more efficient fuel source, in the form of ketones, either by following a low-carb diet or drinking ketone supplements, could provide the brain with greater energy. Even in younger individuals, this added energy further stabilized brain networks.”

To conduct their experiments, brain network stability was established as a biomarker for aging by using two large-scale brain neuroimaging (fMRI) datasets totaling nearly 1,000 individuals, ages 18 to 88. Destabilization of brain networks was associated with impaired cognition and was accelerated with Type 2 diabetes, an illness that blocks neurons’ ability to effectively metabolize glucose. To identify the mechanism as being specific to energy availability, the researchers then held age constant and scanned an additional 42 adults under the age of 50 years with fMRI. This allowed them to observe directly the impact of glucose and ketones on each individual’s brain.

The brain’s response to diet was tested in two ways. The first was holistic, comparing brain network stability after participants had spent one week on a standard (unrestricted) vs. low carb (for example: meat or fish with salad, but no sugar, grains, rice, starchy vegetables) diet. In a standard diet, the primary fuel metabolized is glucose, whereas in a low-carb diet, the primary fuel metabolized is ketones. However, there might have been other differences between diets driving the observed effects. Therefore, to isolate glucose vs. ketones as the crucial difference between the diets, an independent set of participants was scanned before and after drinking a small dose of glucose on one day, and ketones on the other, where the two fuels were individually weight-dosed and calorically matched. The results replicated, showing that the differences between the diets could be attributed to the type of fuel they provide to the brain.

Additional findings from the study included the following: Effects of brain aging emerged at age 47, with most rapid degeneration occurring at age 60. Even in younger adults, under age 50, dietary ketosis (whether achieved after one week of dietary change or 30 minutes after drinking ketones) increased overall brain activity and stabilized functional networks. This is thought to be due to the fact that ketones provide greater energy to cells than glucose, even when the fuels are calorically matched. This benefit has previously been shown for the heart, but the current set of experiments provides the first evidence for equivalent effects in the brain.

“This effect matters because brain aging, and especially dementia, are associated with “hypometabolism,” in which neurons gradually lose the ability to effectively use glucose as fuel. Therefore, if we can increase the amount of energy available to the brain by using a different fuel, the hope is that we can restore the brain to more youthful functioning. In collaboration with Dr. Eva Ratai at Massachusetts General Hospital, we’re currently addressing this question, by now extending our studies to older populations,” said Mujica-Parodi.

“Additional research with collaborators at Children’s National, under the direction of Dr. Nathan Smith, focuses on discovering the precise mechanisms by which fuel impacts signaling between neurons. Finally, in collaboration with Dr. Ken Dill and Dr. Steven Skiena, at Stony Brook, we’re working on building a comprehensive computational model that can incorporate our understanding of the biology, from individual neurons to whole brains to cognition, as it develops.”

The research is currently funded under a new $2.5 million National Science Foundation BRAIN Initiative “Frontiers” grants (numbers (NSFECCS1533257 and NSFNCS-FR 1926781) awarded to Stony Brook, as well as by the W. M. Keck Foundation, which originally funded the team in 2017 with a $1 million seed grant designed to jump-start “pioneering discoveries in science, engineering, and medical research.”

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Collaborators included Stony Brook faculty from the Laufer Center for Physical and Quantitative Biology, Departments of Biomedical Engineering, Applied Mathematics and Statistics, Physics and Astronomy, and Computer Science; and scientists at the Athinoula A. Martinos Center for Biomedical Imaging (Massachusetts General Hospital and Harvard Medical School), Children’s National, the National Institutes of Health, and Oxford University.

About Stony Brook University

Stony Brook University, widely regarded as a SUNY flagship, is going far beyond the expectations of today’s public universities. With more than 26,000 students, 2,700 faculty members, nearly 200,000 alumni, an academic medical center and 18 NCAA Division I athletic programs, it is one of only four University Center campuses in the State University of New York (SUNY) system. The University embraces its mission to provide comprehensive undergraduate, graduate, and professional education of the highest quality, and has been ranked among the top 35 public universities in the nation by U.S. News & World Report. Fostering a commitment to academic research and intellectual endeavors, Stony Brook’s membership in the Association of American Universities (AAU) places it among the top 65 research institutions in North America. The University’s distinguished faculty have earned esteemed awards such as the Nobel Prize, Pulitzer Prize, Indianapolis Prize for animal conservation, Abel Prize and the inaugural Breakthrough Prize in Mathematics. Part of the management team of Brookhaven National Laboratory of the U.S. Department of Energy, Stony Brook is one of only eight universities that has a role in running a national laboratory. Providing economic growth for neighboring communities and the wider geographic region, the University totals an impressive $7.23 billion in increased economic output on Long Island. Follow us on Facebook (https://www.facebook.com/stonybrooku/) and Twitter(@stonybrooku).

2020年3月4日，纽约州斯托尼布鲁克–由斯托尼布鲁克大学教授，首席作者莉莉安妮·R·穆吉卡·帕罗迪（Lilianne R. Mujica-Parodi）博士领导并使用PNAS发表的神经成像研究表明，与衰老相关的神经生物学变化可以在很大程度上看到比40年代后期的预期年龄要年轻。但是，研究还表明，根据饮食习惯的改变（包括尽量减少简单碳水化合物的消费），可以预防或逆转这一过程。

为了更好地了解饮食如何影响脑部衰老，研究小组将重点放在了症状最明显的预防前期。他们在题为“饮食调节年轻人大脑中大脑衰老的生物标志物”的文章中指出，他们使用大规模的寿命神经影像数据集，发现大脑区域之间的功能性交流会随着年龄的增长而不稳定，通常是在40年代后期，并且这种不稳定与认知能力差有关，并随着胰岛素抵抗而加剧。然后，有针对性的实验表明，可以通过消耗各种燃料来可靠地调节这种大脑老化的生物标记物：葡萄糖减少，酮增加，即大脑网络的稳定性。在改变总饮食以及饮用特定燃料的卡路里匹配的补品后，这种效果得以复制。

生物医学工程学系教授Mujica-Parodi表示：“我们在这些实验中发现的消息既有坏消息也有好消息，”他是石溪大学工程与应用科学学院和文艺复兴医学院的联合任命，以及劳弗物理与定量生物学中心的教职员工。 “坏消息是，我们看到大脑衰老的最初迹象比以前想象的要早得多。然而，好消息是我们可以通过饮食来预防或逆转这些影响，通过将葡萄糖交换为酮作为神经元的燃料来减轻侵害性低代谢的影响。”

研究人员使用大脑的神经影像学发现，很早就出现了大脑区域之间的通讯中断（“网络稳定性”）。

“随着年龄的增长，我们的大脑开始失去有效代谢葡萄糖的能力，导致神经元缓慢挨饿，大脑网络不稳定，” Mujica-Parodi说。 “因此，我们测试了通过低碳水化合物饮食或喝酮补充剂以酮的形式给大脑提供更有效的燃料来源是否可以为大脑提供更多的能量。即使在年轻的个体中，这种增加的能量也进一步稳定了大脑网络。”

为了进行实验，通过使用两个大规模的神经神经影像（fMRI）数据集（共近1000个年龄在18至88岁的人），建立了大脑网络稳定性作为衰老的生物标记。大脑网络的不稳定与认知能力下降有关，并且随着年龄的增长而加速2型糖尿病是一种阻碍神经元有效代谢葡萄糖的疾病。为了确定该机制是特定于能量可用性的，研究人员随后将年龄保持恒定，并通过fMRI对另外42位50岁以下的成年人进行了扫描。这样一来，他们可以直接观察葡萄糖和酮对每个人大脑的影响。

大脑对饮食的反应通过两种方式进行了测试。第一个是整体的，比较参与者在标准饮食（无限制）与低碳水化合物饮食（例如：肉或鱼配色拉，但不加糖，谷物，大米，淀粉类蔬菜）上度过一周后的大脑网络稳定性。在标准饮食中，代谢的主要燃料是葡萄糖，而在低碳水化合物饮食中，代谢的主要燃料是酮。但是，饮食之间的其他差异可能会驱动观察到的效果。因此，为了分离出饮食中葡萄糖与酮的关键区别，在一天喝少量葡萄糖之前和之后，对另一组参与者进行了独立扫描，另一天则对酮进行了扫描，其中两种燃料的重量分别是剂量和热量匹配。结果重复显示，饮食之间的差异可能归因于它们提供给大脑的燃料类型。

该研究的其他发现包括：脑衰老的影响出现在47岁，最迅速的变性发生在60岁。即使在50岁以下的年轻人中，饮食性酮症（无论是在一周的饮食变化或30分钟的饮食改变之后）饮用酮后）可增加整体大脑活动并稳定功能网络。认为这是由于即使燃料热量匹配，酮也能为细胞提供比葡萄糖更多的能量。先前已经对心脏显示了这种益处，但是当前的一组实验为脑部等效作用提供了第一个证据。

“这种作用很重要，因为脑部衰老，尤其是痴呆与“代谢紊乱”有关，其中神经元逐渐失去了有效利用葡萄糖作为燃料的能力。因此，如果我们可以通过使用其他燃料来增加大脑可用的能量，则希望我们可以使大脑恢复年轻的功能。与马萨诸塞州总医院的Eva Ratai博士合作，我们目前正在解决这个问题，现在将研究范围扩大到老年人口。” Mujica-Parodi说。

“在Nathan Smith博士的指导下，与美国国家儿童基金会的合作者进行的其他研究着重于发现燃料影响神经元之间信号传递的精确机制。最后，我们与Stony Brook的Ken Dill博士和Steven Skiena博士合作，正在构建一个综合的计算模型，该模型可以结合我们对生物学的理解，从单个神经元到整个大脑再到认知，随着它的发展。”

该研究目前由国家科学基金会“脑部倡议”新拨款250万美元资助（编号（NSFECCS1533257和NSFNCS-FR 1926781），授予斯托尼·布鲁克以及WM凯克基金会，该基金会最初于2017年资助该团队并获得了100万美元的种子赠款，旨在启动“科学，工程和医学研究领域的开创性发现”。