This is a painting from the 16th century from Lucas Cranach the Elder. It shows the famous Fountain of Youth. If you drink its water or you bathe in it, you will get health and youth. Every culture, every civilization has dreamed of finding eternal youth. There are people like Alexander the Great or Ponce De León, the explorer, who spent much of their life chasing the Fountain of Youth. They didn't find it. But what if there was something to it? What if there was something to this Fountain of Youth?
這是幅 16 世紀的畫作, 繪者是老盧卡斯·克拉納赫。 畫的是有名的「青春之泉」。 如果喝了泉水或是沐浴其中, 就會變得健康、年輕。 每種文化、每個文明, 都夢想能夠青春永駐。 亞歷山大大帝 或是探險家龐塞德萊昂, 終其一生追尋不老之泉。 最後無疾而終。 但它真的存在嗎? 青春之泉會不會是真的?
I will share an absolutely amazing development in aging research that could revolutionize the way we think about aging and how we may treat age-related diseases in the future. It started with experiments that showed, in a recent number of studies about growing, that animals -- old mice -- that share a blood supply with young mice can get rejuvenated. This is similar to what you might see in humans, in Siamese twins, and I know this sounds a bit creepy. But what Tom Rando, a stem-cell researcher, reported in 2007, was that old muscle from a mouse can be rejuvenated if it's exposed to young blood through common circulation. This was reproduced by Amy Wagers at Harvard a few years later, and others then showed that similar rejuvenating effects could be observed in the pancreas, the liver and the heart. But what I'm most excited about, and several other labs as well, is that this may even apply to the brain.
我要分享「老化研究」的驚人發展, 徹底顛覆我們對老化的了解, 以及未來老年疾病的治療。 首先是一些實驗顯示, 近期關於「成長」的研究指出, 動物,比如年老的老鼠, 被供應年輕老鼠的血液, 會變年輕。 這個情況就像人類的連體嬰, 雖然聽起來有點詭異。 但根據幹細胞研究員 湯姆‧蘭朵 2007 年的報告, 老鼠的老肌肉可以年輕化 藉由暴露在年輕的血液循環系統。 幾年後艾美‧維潔 在哈佛重做這個實驗, 結果發現類似的年輕化效果, 也發生在胰臟、肝臟、心臟。 但最令我和其他同業興奮的是, 這也可能發生在大腦。
So, what we found is that an old mouse exposed to a young environment in this model called parabiosis, shows a younger brain -- and a brain that functions better. And I repeat: an old mouse that gets young blood through shared circulation looks younger and functions younger in its brain. So when we get older -- we can look at different aspects of human cognition, and you can see on this slide here, we can look at reasoning, verbal ability and so forth. And up to around age 50 or 60, these functions are all intact, and as I look at the young audience here in the room, we're all still fine.
我們發現老老鼠 被暴露在年輕的環境中, 也就是模型中的「連體鼠」, 有更年輕的腦、 運作得更好的腦。 再重說一次: 藉由共享循環系統 獲得年輕血液的老老鼠, 腦部看起來、也運作得更年輕。 所以當我們老去, 用不同面向分析人類的知覺, 如這張投影片所示, 比如推理、言語或其他能力。 到了 50 或 60 歲, 這些功能都還正常, 告訴在座各位「年輕朋友」: 我們還算硬朗。
(Laughter)
(笑聲)
But it's scary to see how all these curves go south. And as we get older, diseases such as Alzheimer's and others may develop. We know that with age, the connections between neurons -- the way neurons talk to each other, the synapses -- they start to deteriorate; neurons die, the brain starts to shrink, and there's an increased susceptibility for these neurodegenerative diseases.
但可怕的是, 這些線會持續下滑。 隨著年紀漸長, 阿茲海默症之類的病就可能併發。 大家都知道隨著老化, 神經元之間的連結, 它們之間的溝通方式, 也就是「突觸」開始退化; 神經元死亡、大腦開始萎縮, 增加罹患神經組織退化疾病的風險。
One big problem we have -- to try to understand how this really works at a very molecular mechanistic level -- is that we can't study the brains in detail, in living people. We can do cognitive tests, we can do imaging -- all kinds of sophisticated testing. But we usually have to wait until the person dies to get the brain and look at how it really changed through age or in a disease. This is what neuropathologists do, for example. So, how about we think of the brain as being part of the larger organism. Could we potentially understand more about what happens in the brain at the molecular level if we see the brain as part of the entire body? So if the body ages or gets sick, does that affect the brain? And vice versa: as the brain gets older, does that influence the rest of the body? And what connects all the different tissues in the body is blood. Blood is the tissue that not only carries cells that transport oxygen, for example, the red blood cells, or fights infectious diseases, but it also carries messenger molecules, hormone-like factors that transport information from one cell to another, from one tissue to another, including the brain. So if we look at how the blood changes in disease or age, can we learn something about the brain? We know that as we get older, the blood changes as well, so these hormone-like factors change as we get older. And by and large, factors that we know are required for the development of tissues, for the maintenance of tissues -- they start to decrease as we get older, while factors involved in repair, in injury and in inflammation -- they increase as we get older.
這裡有個大問題, 當我們想了解大腦 分子、機轉層面的運作, 沒辦法在活人身上研究。 我們可以做知覺測試、掃描, 各種精細的檢查。 但通常要等到人死後, 剖析腦的內部, 才知道老化或疾病造成的改變。 這是神經病理學家其中一項工作。 假設腦只是大型有機體的一部份。 我們有沒有可能, 從分子的角度更了解大腦運作, 只把腦當作身體的某個部分? 如果身體老化或生病, 會影響到大腦嗎? 或相反,當腦老化, 會不會影響身體其他部位? 而連結身體各不同組織的 就是「血液」。 血液不只是夾帶輸氧細胞的組織, 例如紅血球, 或是抵抗傳染病, 同時也夾帶了訊息因子, 像賀爾蒙的因子,傳遞訊息, 從一個細胞到另一個細胞, 一個組織到另一個組織, 在大腦裡也一樣。 所以我們看血液 因為疾病或老化產生的改變, 會不會更認識大腦? 我們知道隨著年紀漸長, 血液也會改變, 這些像賀爾蒙的因子也會改變。 目前我們所知, 發展或是維持組織 所需的因子或多或少, 隨著年齡增長而減少, 會造成破損、受傷、發炎的因子, 卻隨著年齡增長而增加。
So there's this unbalance of good and bad factors, if you will. And to illustrate what we can do potentially with that, I want to talk you through an experiment that we did. We had almost 300 blood samples from healthy human beings 20 to 89 years of age, and we measured over 100 of these communication factors, these hormone-like proteins that transport information between tissues. And what we noticed first is that between the youngest and the oldest group, about half the factors changed significantly. So our body lives in a very different environment as we get older, when it comes to these factors. And using statistical or bioinformatics programs, we could try to discover those factors that best predict age -- in a way, back-calculate the relative age of a person. And the way this looks is shown in this graph. So, on the one axis you see the actual age a person lived, the chronological age. So, how many years they lived.
所以說起來, 好因子和壞因子之間失衡了。 為了說明怎麼改善這個情況, 我想解釋一下我們之前的實驗。 我們取了 300 份 健康人類的血液樣本, 從 20 歲到 89 歲都有, 測試了超過 100 種這些溝通因子, 這些像賀爾蒙在組織間 傳遞訊息的蛋白質。 我們首先發現 在最年輕和最年老的樣本間, 有半數左右的因子有顯著改變。 所以我們的身體在老化以後, 對這些因子來說, 是一個非常不一樣的環境。 藉由這些統計、生物信息資料, 我們可以試著去發現 最能預測年齡的因子, 也就是反推某個人的相對年齡。 如同這張圖所顯示。 橫軸是人的實際年齡, 也就是年齡序列。 看他們實際活了多久。
And then we take these top factors that I showed you, and we calculate their relative age, their biological age. And what you see is that there is a pretty good correlation, so we can pretty well predict the relative age of a person. But what's really exciting are the outliers, as they so often are in life. You can see here, the person I highlighted with the green dot is about 70 years of age but seems to have a biological age, if what we're doing here is really true, of only about 45. So is this a person that actually looks much younger than their age? But more importantly: Is this a person who is maybe at a reduced risk to develop an age-related disease and will have a long life -- will live to 100 or more? On the other hand, the person here, highlighted with the red dot, is not even 40, but has a biological age of 65. Is this a person at an increased risk of developing an age-related disease? So in our lab, we're trying to understand these factors better, and many other groups are trying to understand, what are the true aging factors, and can we learn something about them to possibly predict age-related diseases?
然後我們用剛剛的重要因子, 去計算縱軸的相對、生理的年齡。 你會發現兩者高度相關, 所以能預測人的相對年齡。 但偏離線外的點更值得注意, 他們不算少數。 你看綠點標記的這個人, 將近 70 歲左右, 但他的生理年齡, 如果我們的推論正確, 只有大概 45 歲。 所以這個人是不是 實際看起來更年輕? 更重要的是: 這個人是不是罹患 老化疾病的風險更小, 也會更長壽? 甚至超過 100 歲? 另一方面, 紅點標記的這位, 還不到 40 歲, 但生理年齡已經 65 歲。 罹患老化疾病的風險是不是更高? 所以我們實驗室 試著更了解這些因子, 其他團隊也在努力, 關鍵的老化因子是什麼? 我們找出來以後, 能不能有效預測老化疾病?
So what I've shown you so far is simply correlational, right? You can just say, "Well, these factors change with age," but you don't really know if they do something about aging. So what I'm going to show you now is very remarkable and it suggests that these factors can actually modulate the age of a tissue. And that's where we come back to this model called parabiosis.
我剛剛說的 只是簡單的關聯性, 你可能會說: 「這些因子會隨年齡改變嘛。」 但怎麼知道不是因子改變年齡? 所以我現在再說一個關鍵, 說明這些因子會改變組織的年齡。 回到剛剛的「連體鼠」實驗。
So, parabiosis is done in mice by surgically connecting the two mice together, and that leads then to a shared blood system, where we can now ask, "How does the old brain get influenced by exposure to the young blood?" And for this purpose, we use young mice that are an equivalency of 20-year-old people, and old mice that are roughly 65 years old in human years.
這是將兩隻老鼠, 用手術連接在一起, 共享同一個血液循環系統, 所以我們會問: 「比較老的腦接觸到年輕血液 會有什麼影響?」 所以我們找了一隻小老鼠, 換算大約是人類的 20 歲, 和大約人類 65 歲的老老鼠。
What we found is quite remarkable. We find there are more neural stem cells that make new neurons in these old brains. There's an increased activity of the synapses, the connections between neurons. There are more genes expressed that are known to be involved in the formation of new memories. And there's less of this bad inflammation. But we observed that there are no cells entering the brains of these animals. So when we connect them, there are actually no cells going into the old brain, in this model. Instead, we've reasoned, then, that it must be the soluble factors, so we could collect simply the soluble fraction of blood which is called plasma, and inject either young plasma or old plasma into these mice, and we could reproduce these rejuvenating effects, but what we could also do now is we could do memory tests with mice.
有個非常驚人的發現。 我們發現產出更多神經幹細胞 製造新的神經元 在這些老的大腦裏面。 突觸的活動變得更活躍, 突觸是神經元之間的連結。 大家所知 更多的基因顯示涉及 新記憶的資訊。 導致發炎的壞因子減少。 我們也觀察到, 沒有新的細胞進入大腦。 也就是說這個實驗中, 沒有任何細胞進入老腦。 所以可以推論, 這些因子一定溶於血, 所以我們只需要收集 血液裡的血漿, 然後把老血漿或年經血漿 注入老鼠體內, 就可以重現年輕化的效果, 但在此同時我們也可以, 幫老鼠做記憶測試。
As mice get older, like us humans, they have memory problems. It's just harder to detect them, but I'll show you in a minute how we do that. But we wanted to take this one step further, one step closer to potentially being relevant to humans. What I'm showing you now are unpublished studies, where we used human plasma, young human plasma, and as a control, saline, and injected it into old mice, and asked, can we again rejuvenate these old mice? Can we make them smarter?
老鼠老了就跟人一樣, 記憶力會衰退。 雖然不容易觀察, 但我等一下會說我們怎麼做。 我們還想更進一步, 更近一步把結果和人類做連結。 接下來要說的實驗還沒發表, 我們用年輕人類的血漿, 和生理食鹽水做對照, 注入到老老鼠體內, 想知道 能不能再次年輕化老老鼠? 能讓牠們變聰明嗎?
And to do this, we used a test. It's called a Barnes maze. This is a big table that has lots of holes in it, and there are guide marks around it, and there's a bright light, as on this stage here. The mice hate this and they try to escape, and find the single hole that you see pointed at with an arrow, where a tube is mounted underneath where they can escape and feel comfortable in a dark hole. So we teach them, over several days, to find this space on these cues in the space, and you can compare this for humans, to finding your car in a parking lot after a busy day of shopping.
我們用「巴恩斯迷宮」來測試。 這張大桌子有很多洞, 上面有一些指示標記, 像這個講台一樣有打光。 老鼠討厭光所以想逃跑, 要找到箭頭指的這個洞, 底下接了一根管子, 牠們可以藉此重返舒適的黑洞。 所以我們教了牠們幾天, 怎樣透過標記找到小黑洞, 拿人類來說, 就像逛了賣場一整天, 最後要在停車場找車。
(Laughter)
(笑聲)
Many of us have probably had some problems with that.
很多人都覺得那是大挑戰。
So, let's look at an old mouse here. This is an old mouse that has memory problems, as you'll notice in a moment. It just looks into every hole, but it didn't form this spacial map that would remind it where it was in the previous trial or the last day. In stark contrast, this mouse here is a sibling of the same age, but it was treated with young human plasma for three weeks, with small injections every three days. And as you noticed, it almost looks around, "Where am I?" -- and then walks straight to that hole and escapes. So, it could remember where that hole was.
回來看這隻老老鼠。 這是隻記憶力不好的老老鼠, 你等一下就知道了。 牠每個洞都看, 但對空間毫無頭緒, 對之前走過的路, 或昨天的事完全沒有印象。 這邊的對照組 是牠同齡的手足, 但已經連續接受人類血漿 3 週, 每 3 天一次的少量施打。 你會發現牠環顧四周說: 「這是哪?」 接著直直走到那個洞離開。 顯然牠記得洞的位置。
So by all means, this old mouse seems to be rejuvenated -- it functions more like a younger mouse. And it also suggests that there is something not only in young mouse plasma, but in young human plasma that has the capacity to help this old brain. So to summarize, we find the old mouse, and its brain in particular, are malleable. They're not set in stone; we can actually change them. It can be rejuvenated. Young blood factors can reverse aging, and what I didn't show you -- in this model, the young mouse actually suffers from exposure to the old. So there are old-blood factors that can accelerate aging. And most importantly, humans may have similar factors, because we can take young human blood and have a similar effect. Old human blood, I didn't show you, does not have this effect; it does not make the mice younger.
看來這隻老老鼠年輕化了, 活得比較像一隻年輕老鼠。 代表不只是 年輕老鼠的血漿裡面, 年輕人類的血漿裡, 也有能改善大腦能力的因子。 結論就是, 我們發現老老鼠, 特別是大腦,是具可塑性的。 決不是一成不變, 而是可以被我們改造。 可以被年輕化。 年輕的血液因子讓你返老還童, 但我沒說的是, 實驗裡的年輕老鼠, 卻因此被拖累。 所以年老血液的因子會加速老化。 更重要的是, 人類也有類似的因子, 因為用年輕人血做實驗 也有類似效果。 但是老年人的血液 在實驗裡卻無效, 沒有讓老鼠變年輕。
So, is this magic transferable to humans? We're running a small clinical study at Stanford, where we treat Alzheimer's patients with mild disease with a pint of plasma from young volunteers, 20-year-olds, and do this once a week for four weeks, and then we look at their brains with imaging. We test them cognitively, and we ask their caregivers for daily activities of living. What we hope is that there are some signs of improvement from this treatment. And if that's the case, that could give us hope that what I showed you works in mice might also work in humans.
所以這能不能套用到人類呢? 我們在史丹佛做小型的臨床實驗, 對輕度阿茲海默症患者, 施打 1 品脫 20 歲志願者的血漿, 每週一次連續 4 週, 然後再用儀器掃描他們的腦、 測試他們的知覺, 透過照護員了解日常活動。 我們希望透過這種治療, 看到一些好轉的跡象。 如果成功,我們會希望 老鼠實驗展現的成果, 也會在人類身上實現。
Now, I don't think we will live forever. But maybe we discovered that the Fountain of Youth is actually within us, and it has just dried out. And if we can turn it back on a little bit, maybe we can find the factors that are mediating these effects, we can produce these factors synthetically and we can treat diseases of aging, such as Alzheimer's disease or other dementias.
我不認為人會長生不死。 但也許我們發現, 青春之泉就在我們身體裡, 只是逐漸乾涸。 如果能稍微活化它, 找到讓我們年輕化的因子, 想辦法合成這些因子, 就可以治療老化疾病, 例如阿茲海默或其他失智。
Thank you very much.
非常感謝。
(Applause)
(掌聲)