【野生小科普】这项研究让我想起武侠小说里的邪教
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运动对于维持大脑，神经，认知的活跃度和年轻态有非常积极的作用。然而很多人因残疾或衰老无法定期运动，科学家们一直在寻找保证这类人群神经健康的方法。
这周发表在Science上的一项研究指出，给久坐不动的老年小鼠注入爱运动的年轻小鼠的血浆可以使它们的大脑和神经状态更加年轻，学习能力和认知能力增强。
不仅是运动的年轻小鼠的血浆有效果，很多年轻小鼠与年老小鼠换血的实验证据表明通过血浆“返老还童”似乎有一定可能。
这让我联想起了一些小说里的换血治病和邪教，魔道的血祭之类的，瑟瑟发抖，哈哈。
抛开这些联想，这项研究结果很有价值，它表明了运动对神经系统的益处可以通过血液循环因子传递，同时发现了一种很少被研究的肝脏蛋白Gpld1 ，可能与身体锻炼对认知能力提高有关。
锻炼对大脑的好处可以通过一种蛋白质获得，这简直太棒了，这一发现为延缓大脑衰老的药物研发奠定基础。
以下是音频原文
Meagan Cantwell: Aging can impact so many parts of your brain, from the cells themselves to general cognitive function, like memory. But there has been a pretty widely accepted intervention to prevent cognitive decline and even rejuvenate some parts of the brain that doesn't involve surgery or taking pills. It's exercise. But in elderly people with mobility issues, this can be a difficult task, which is why figuring out the mechanisms behind how exercise improves the brain is so important. Saul Villeda and colleagues wrote in Science this week about their experiment, which transferred the benefit of physical exercise from one mouse to another. Thank you so much for joining me, Saul.
Saul Villeda: Absolutely, it's my pleasure.
MC: Could you start by describing exactly what type of benefits are seen in the brain as a result of exercise?
SV: From my perspective, cognitive benefits are huge. Even when you're older, it can actually reverse some of those cognitive decline. Regeneration is another one. It can stimulate stem cell and neuron production. And just the plasticity, just overall, the communication between the neurons just improves, and I think we're even appreciating now that even inflammation goes down in the brain. So it just seems to hit almost all these hallmarks of aging.
锻炼对大脑的好处
MC: Another area of research that your paper builds off of are previous studies that show benefits from transferring the blood of younger mice to older mice. What do these studies reveal?
SV: In work that we and others have done, what we've realized is there's this communication between the periphery and the brain. Normally, we think of the blood-brain barrier in these two separate entities, and what we're realizing is, no, there's a lot of cross-talk. And it turns out that there's actually almost like a memory or a communication of youthfulness that is within the blood, so a series of signals, different proteins and cell types that are signaling youth, and then the brain can actually respond to that. And as you get older, if you re-introduce these signals, you can actually start promoting and reversing many of those same hallmarks. Stem cells get activated and cognition's improved, and even inflammation is sort of attenuated.
血脑屏障，血脑交流
MC: What your team's research focuses on is combining these two areas of study. You tested whether transferring plasma, which is blood without its cellular components, can actually transfer the benefits of exercise from a mouse that has exercised a lot to a more aged mouse. I'm curious how much of a workout these mice got before you transfered their plasma.
SV: One important thing to keep in mind is it's voluntary wheel running, so it's not forced running. You put basically a running wheel in a cage and these mice just go crazy and they love to run on it, so they're quite active. And we allowed them to have access to this running wheel for about a month and a half, six weeks, and then after that, we collected their blood and then isolated their plasma. And then we had, of course, the sedentary counterparts, which are age matched, many of them litter mates, that just don't have access to a running wheel.
小鼠们运动了6周
MC: Once you transfered this plasma to the aged mice, how did their cognitive function change?
SV: It doesn't quite get to the level of a young animal, but it is definitely... Let's say these animals are 18 months old, maybe the equivalent of someone that's around 65. They're performing much more closer to probably mid-30s to early 40s. They're performing more like maybe a sixmonth-old animal. And we see that transferring the plasma, those signals from exercise, it recapitulates quite a bit of that effect, maybe 80%, 85% of the effect that we're seeing with just the exercise.
注射血浆之后，老年小鼠的“年龄”变化
MC: This wasn't just one transfer of plasma. This happened multiple times?
SV: Yeah, so what we do is we give about 5% volume per mouse, and we do it eight times over about a month, and then we test them cognitively. And the reason that we do it over that time period is we wanna allow enough time for the stem cells to get activated, enough time for the neurons to be born and integrate into the brain circuitry, and just to allow also... We know that there's structural changes within these neurons that have been there the entire life, so we wanna allow enough time for these cellular and molecular changes to happen in the brain, that give us the best chance of seeing cognitive benefits.
实验剂量，频率设定
MC: What exactly is changing in the plasma that's contributing to these beneficial impacts?
SV: What we've found is that most of the changes that are occurring due to exercise are involved in metabolism, are involved in decreasing inflammation, but most of those signals, most of those proteins, were coming from the liver. So somehow the exercise is stimulating the liver to secrete these proteins, which then signal to the brain, "Go back to a more youthful state," or, "Restore cognitive function." So it really seems to be this liver to brain access that we seem to have identified that mediates these effects of exercise.
肝产生蛋白质，与大脑交流调控
MC: We touched earlier on studies that have shown the benefits of transferring young plasma. Did you see any relationship between younger mice who exercised producing more of this protein than older mice that exercised?
SV: So what we did is we picked ages that were beyond that youthful state. So we wanted to tease apart the difference from young blood from the difference from exercise, and what we did is we had a second cohort that was what we call mature, so they were about seven to eight months of age. Normally, when we do that young blood transfer, that's in a two to three-month animal, so we did that on purpose. And what we see is even when we take the blood of these mature exercising mice, we still see the benefit of exercise in the old mice. So it doesn't have to be age matched. What we haven't done is we haven't exercised the young and then put it in. Is it additive? So that's still one of those pending questions that we have to look at. But it does go across ages. You can still transfer that signal. And this protein, GPLD1, also goes up in the blood, even of the younger mice and mature mice.
老年运动鼠的GPLD1水平也是高的，目前没有做年轻+运动的小鼠血浆是否有叠加的优势的实验
MC: So how does this protein that's produced in the liver then transported up to the brain end up improving brain function?
SV: Yeah, so from the proteomics that we did, we identified one enzyme, which is called GPLD1, and what that does is it actually cleaves other proteins that are linked to the cell's surface. So it's able to come and cleave a number of 'em. It's quite specific. It's specifically to these little, what's called GPI anchors, and it just cleaves to them and it lets them go. But I think the specificity is really important. And then we did additional proteomics, and what we found is when this protein goes up in the blood, it then cleaves a number of these targets and it causes inflammation to go down, particularly a type of immune response called complement. So that decreased. And it also stimulated wound healing processes like coagulation. Now, the interesting part is that we don't think the protein itself actually gets into the brain. So it's not actually going through the blood-brain barrier, but rather it's affecting that systemic milieu, and that's promoting this youthfulness in the brain.
GPLD1可能是通过降低血液中的炎症反应是大脑年轻化，而非通过血脑屏障
MC: It's interesting 'cause the applicability of the research isn't just, "Okay, we're improving the aging brain," but you're also learning just more about how the brain works in general.
SV: Absolutely. And I think it, again, points to this relationship between the immune responses and the brain. We know that the immune system seems to play a really important role, and here we're sort of pointing at the fact that there are changes in exercise that are targeting, again, this sort of immune component and leading to this improvement in cognition. I think it really sheds light and sort of gears us towards trying to understand these different inter-tissue communications. Exercise here, it's coming from liver, but there's other interventions. There's caloric restriction, like we had mentioned. There's young blood. Is each one of those eliciting a different response in a different tissue? Is that why we can improve cognition from different areas? I think that's good from a therapeutic standpoint, because you want multiple ways of causing an improvement because not everyone may respond the same way.
实验结果表明了免疫反应与大脑之间可能存在关系
MC: And most of these studies have been in mice. It's been a little harder showing these benefits in humans. Is the protein that you found, GPLD1, is that also found when humans exercise?
SV: The really exciting part was that we were able to collaborate with the UCSF Memory and Aging Center, and they had access to blood samples from elderly. These elderly were actually fitted with Fitbits, so we actually had access to the number of steps that they took, and we could actually segregate these over 70-year-old individuals into people that are active and people that are sedentary. In essence, voluntary exercise versus not. And we looked for this protein, again, GPLD1 in their blood, and just like in the mice, you have an increase in the circulating levels of GPLD1 in people that are doing exercise versus sedentary. And that's really exciting because that means we see this conservation across species, and it's applicable to humans, and that is really exciting when you're trying to find targets or potential downstream therapeutic agents.
GPLD1的水平在人类中的情况和小鼠也很类似
MC: This plasma transfer looks super promising in mice, but it's not something that's gonna be available for humans any time soon, right?
SV: This is really exciting research, and we've identified factors that we're now gonna explore that could potentially be a therapeutic. And talking to my mom... And I run everything from my mom. My mom comes from Guatemala, immigrant to the US, and she was like, "Oh my goodness, this is like exercise in a bottle." And I'm like, "Whoa, whoa, whoa. We're a ways away from calling this exercise in a bottle." So I always just warn people that, yes, of course, it's there. It lends itself to try and skip through a bunch of steps and go directly into like, "Yes, I want the pill." We have targets and that's exciting, and that leads us and gets us started on our way towards developing therapeutics, but definitely it's gonna take a little bit of time.
距离吃保健品不用运动就能“健脑”还有一定距离，但是值得期待
MC: There seems to be so many different ways that you can go from this paper that you're publishing in Science. What are your more immediate next steps with this research?
SV: Ongoing research is: How exactly is it that a protein that's not getting into the brain, a protein that's affecting more of this sort of immune component in the blood, how is it having the effect? And then the second one is, does it translate into a pre-clinical context of neurodegeneration? So we're also looking at, what about, not just in the context of aging where there is no cell death, but what about in the context of, say, an Alzheimer's model? Is it also having this beneficial effect? Can you actually restore some of the neurodegenerative phenotypes that are associated with a beta placques by doing, again, this sort of exercise factor or by just introducing GPLD1 itself?
未来研究
MC: Thank you so much for taking the time to speak with me, I really appreciate it.
SV: Absolutely.
MC: Saul Villeda is an Assistant Professor of Anatomy at the University of California, San Francisco. You can find a link to his research at sciencemag.org/podcasts.
