WEBVTT 00:00:01.134 --> 00:00:05.793 This is a painting from the 16th century from Lucas Cranach the Elder. 00:00:06.160 --> 00:00:08.926 It shows the famous Fountain of Youth. 00:00:09.308 --> 00:00:15.034 If you drink its water or you bathe in it, you will get health and youth. 00:00:15.857 --> 00:00:21.406 Every culture, every civilization has dreamed of finding eternal youth. 00:00:22.044 --> 00:00:26.796 There are people like Alexander the Great or Ponce De León, the explorer, 00:00:26.820 --> 00:00:30.251 who spent much of their life chasing the Fountain of Youth. 00:00:30.726 --> 00:00:31.894 They didn't find it. 00:00:33.450 --> 00:00:36.050 But what if there was something to it? 00:00:36.074 --> 00:00:38.773 What if there was something to this Fountain of Youth? NOTE Paragraph 00:00:39.284 --> 00:00:44.462 I will share an absolutely amazing development in aging research 00:00:44.486 --> 00:00:48.096 that could revolutionize the way we think about aging 00:00:48.120 --> 00:00:51.322 and how we may treat age-related diseases in the future. 00:00:52.145 --> 00:00:54.654 It started with experiments that showed, 00:00:54.678 --> 00:00:57.972 in a recent number of studies about growing, 00:00:57.996 --> 00:01:03.997 that animals -- old mice -- that share a blood supply with young mice 00:01:04.021 --> 00:01:05.625 can get rejuvenated. 00:01:06.148 --> 00:01:10.757 This is similar to what you might see in humans, in Siamese twins, 00:01:10.781 --> 00:01:12.869 and I know this sounds a bit creepy. 00:01:13.338 --> 00:01:19.285 But what Tom Rando, a stem-cell researcher, reported in 2007, 00:01:19.309 --> 00:01:22.809 was that old muscle from a mouse can be rejuvenated 00:01:22.833 --> 00:01:27.462 if it's exposed to young blood through common circulation. 00:01:27.903 --> 00:01:32.546 This was reproduced by Amy Wagers at Harvard a few years later, 00:01:32.570 --> 00:01:37.165 and others then showed that similar rejuvenating effects could be observed 00:01:37.189 --> 00:01:39.975 in the pancreas, the liver and the heart. 00:01:40.974 --> 00:01:45.071 But what I'm most excited about, and several other labs as well, 00:01:45.095 --> 00:01:47.514 is that this may even apply to the brain. NOTE Paragraph 00:01:48.715 --> 00:01:54.046 So, what we found is that an old mouse exposed to a young environment 00:01:54.070 --> 00:01:57.083 in this model called parabiosis, 00:01:57.107 --> 00:01:58.899 shows a younger brain -- 00:01:58.923 --> 00:02:01.105 and a brain that functions better. 00:02:01.966 --> 00:02:03.556 And I repeat: 00:02:03.580 --> 00:02:09.793 an old mouse that gets young blood through shared circulation 00:02:09.817 --> 00:02:12.801 looks younger and functions younger in its brain. 00:02:13.998 --> 00:02:15.530 So when we get older -- 00:02:15.554 --> 00:02:18.226 we can look at different aspects of human cognition, 00:02:18.250 --> 00:02:20.003 and you can see on this slide here, 00:02:20.027 --> 00:02:23.410 we can look at reasoning, verbal ability and so forth. 00:02:23.899 --> 00:02:29.178 And up to around age 50 or 60, these functions are all intact, 00:02:29.202 --> 00:02:33.684 and as I look at the young audience here in the room, we're all still fine. NOTE Paragraph 00:02:33.708 --> 00:02:34.716 (Laughter) NOTE Paragraph 00:02:34.740 --> 00:02:38.547 But it's scary to see how all these curves go south. 00:02:38.571 --> 00:02:40.160 And as we get older, 00:02:40.184 --> 00:02:44.235 diseases such as Alzheimer's and others may develop. 00:02:45.004 --> 00:02:48.575 We know that with age, the connections between neurons -- 00:02:48.599 --> 00:02:53.250 the way neurons talk to each other, the synapses -- they start to deteriorate; 00:02:53.274 --> 00:02:56.580 neurons die, the brain starts to shrink, 00:02:56.604 --> 00:03:00.596 and there's an increased susceptibility for these neurodegenerative diseases. NOTE Paragraph 00:03:01.573 --> 00:03:06.482 One big problem we have -- to try to understand how this really works 00:03:06.506 --> 00:03:09.102 at a very molecular mechanistic level -- 00:03:09.126 --> 00:03:13.176 is that we can't study the brains in detail, in living people. 00:03:14.033 --> 00:03:17.019 We can do cognitive tests, we can do imaging -- 00:03:17.043 --> 00:03:19.739 all kinds of sophisticated testing. 00:03:19.763 --> 00:03:23.381 But we usually have to wait until the person dies 00:03:23.405 --> 00:03:28.499 to get the brain and look at how it really changed through age or in a disease. 00:03:28.888 --> 00:03:31.952 This is what neuropathologists do, for example. 00:03:32.333 --> 00:03:38.000 So, how about we think of the brain as being part of the larger organism. 00:03:38.024 --> 00:03:40.501 Could we potentially understand more 00:03:40.525 --> 00:03:43.454 about what happens in the brain at the molecular level 00:03:43.478 --> 00:03:47.064 if we see the brain as part of the entire body? 00:03:47.088 --> 00:03:51.965 So if the body ages or gets sick, does that affect the brain? 00:03:51.989 --> 00:03:56.412 And vice versa: as the brain gets older, does that influence the rest of the body? 00:03:57.050 --> 00:04:00.541 And what connects all the different tissues in the body 00:04:00.565 --> 00:04:01.715 is blood. 00:04:02.366 --> 00:04:08.191 Blood is the tissue that not only carries cells that transport oxygen, for example, 00:04:08.215 --> 00:04:09.456 the red blood cells, 00:04:09.480 --> 00:04:11.680 or fights infectious diseases, 00:04:11.704 --> 00:04:15.975 but it also carries messenger molecules, 00:04:15.999 --> 00:04:19.911 hormone-like factors that transport information 00:04:19.935 --> 00:04:24.068 from one cell to another, from one tissue to another, 00:04:24.092 --> 00:04:25.549 including the brain. 00:04:25.573 --> 00:04:30.711 So if we look at how the blood changes in disease or age, 00:04:30.735 --> 00:04:33.098 can we learn something about the brain? 00:04:33.651 --> 00:04:38.487 We know that as we get older, the blood changes as well, 00:04:38.511 --> 00:04:41.470 so these hormone-like factors change as we get older. 00:04:41.494 --> 00:04:45.693 And by and large, factors that we know are required 00:04:45.717 --> 00:04:49.138 for the development of tissues, for the maintenance of tissues -- 00:04:49.162 --> 00:04:52.039 they start to decrease as we get older, 00:04:52.063 --> 00:04:56.766 while factors involved in repair, in injury and in inflammation -- 00:04:56.790 --> 00:04:58.740 they increase as we get older. NOTE Paragraph 00:04:58.764 --> 00:05:03.806 So there's this unbalance of good and bad factors, if you will. 00:05:04.988 --> 00:05:07.981 And to illustrate what we can do potentially with that, 00:05:08.005 --> 00:05:10.657 I want to talk you through an experiment that we did. 00:05:10.681 --> 00:05:14.330 We had almost 300 blood samples from healthy human beings 00:05:14.354 --> 00:05:16.871 20 to 89 years of age, 00:05:16.895 --> 00:05:20.790 and we measured over 100 of these communication factors, 00:05:20.814 --> 00:05:24.908 these hormone-like proteins that transport information between tissues. 00:05:25.266 --> 00:05:26.942 And what we noticed first 00:05:26.966 --> 00:05:29.783 is that between the youngest and the oldest group, 00:05:29.807 --> 00:05:33.104 about half the factors changed significantly. 00:05:33.128 --> 00:05:36.263 So our body lives in a very different environment as we get older, 00:05:36.287 --> 00:05:38.038 when it comes to these factors. 00:05:38.062 --> 00:05:41.558 And using statistical or bioinformatics programs, 00:05:41.582 --> 00:05:46.276 we could try to discover those factors that best predict age -- 00:05:46.300 --> 00:05:49.943 in a way, back-calculate the relative age of a person. 00:05:50.337 --> 00:05:53.193 And the way this looks is shown in this graph. 00:05:53.618 --> 00:05:58.987 So, on the one axis you see the actual age a person lived, 00:05:59.011 --> 00:06:00.316 the chronological age. 00:06:00.340 --> 00:06:02.062 So, how many years they lived. NOTE Paragraph 00:06:02.086 --> 00:06:04.794 And then we take these top factors that I showed you, 00:06:04.818 --> 00:06:09.662 and we calculate their relative age, their biological age. 00:06:10.708 --> 00:06:14.342 And what you see is that there is a pretty good correlation, 00:06:14.366 --> 00:06:17.681 so we can pretty well predict the relative age of a person. 00:06:17.705 --> 00:06:21.620 But what's really exciting are the outliers, 00:06:21.644 --> 00:06:23.448 as they so often are in life. 00:06:23.922 --> 00:06:28.490 You can see here, the person I highlighted with the green dot 00:06:28.514 --> 00:06:31.110 is about 70 years of age 00:06:31.134 --> 00:06:36.140 but seems to have a biological age, if what we're doing here is really true, 00:06:36.164 --> 00:06:38.207 of only about 45. 00:06:38.231 --> 00:06:41.715 So is this a person that actually looks much younger than their age? 00:06:42.183 --> 00:06:46.699 But more importantly: Is this a person who is maybe at a reduced risk 00:06:46.723 --> 00:06:50.047 to develop an age-related disease and will have a long life -- 00:06:50.071 --> 00:06:51.566 will live to 100 or more? 00:06:52.402 --> 00:06:56.963 On the other hand, the person here, highlighted with the red dot, 00:06:56.987 --> 00:07:01.893 is not even 40, but has a biological age of 65. 00:07:01.917 --> 00:07:06.315 Is this a person at an increased risk of developing an age-related disease? 00:07:06.339 --> 00:07:09.995 So in our lab, we're trying to understand these factors better, 00:07:10.019 --> 00:07:12.257 and many other groups are trying to understand, 00:07:12.281 --> 00:07:14.357 what are the true aging factors, 00:07:14.381 --> 00:07:19.354 and can we learn something about them to possibly predict age-related diseases? NOTE Paragraph 00:07:20.281 --> 00:07:24.343 So what I've shown you so far is simply correlational, right? 00:07:24.367 --> 00:07:28.398 You can just say, "Well, these factors change with age," 00:07:28.422 --> 00:07:32.077 but you don't really know if they do something about aging. 00:07:33.031 --> 00:07:36.079 So what I'm going to show you now is very remarkable 00:07:36.103 --> 00:07:41.174 and it suggests that these factors can actually modulate the age of a tissue. 00:07:41.845 --> 00:07:45.143 And that's where we come back to this model called parabiosis. NOTE Paragraph 00:07:45.167 --> 00:07:47.707 So, parabiosis is done in mice 00:07:47.731 --> 00:07:52.643 by surgically connecting the two mice together, 00:07:52.667 --> 00:07:55.000 and that leads then to a shared blood system, 00:07:55.024 --> 00:07:59.811 where we can now ask, "How does the old brain get influenced 00:07:59.835 --> 00:08:01.573 by exposure to the young blood?" 00:08:02.144 --> 00:08:04.348 And for this purpose, we use young mice 00:08:04.372 --> 00:08:07.825 that are an equivalency of 20-year-old people, 00:08:07.849 --> 00:08:12.185 and old mice that are roughly 65 years old in human years. NOTE Paragraph 00:08:12.958 --> 00:08:15.784 What we found is quite remarkable. 00:08:15.808 --> 00:08:19.528 We find there are more neural stem cells that make new neurons 00:08:19.552 --> 00:08:20.884 in these old brains. 00:08:21.351 --> 00:08:23.933 There's an increased activity of the synapses, 00:08:23.957 --> 00:08:25.996 the connections between neurons. 00:08:26.020 --> 00:08:29.305 There are more genes expressed that are known to be involved 00:08:29.329 --> 00:08:31.076 in the formation of new memories. 00:08:31.659 --> 00:08:34.167 And there's less of this bad inflammation. 00:08:35.427 --> 00:08:41.923 But we observed that there are no cells entering the brains of these animals. 00:08:41.947 --> 00:08:43.333 So when we connect them, 00:08:43.357 --> 00:08:48.733 there are actually no cells going into the old brain, in this model. 00:08:49.379 --> 00:08:53.040 Instead, we've reasoned, then, that it must be the soluble factors, 00:08:53.064 --> 00:08:57.847 so we could collect simply the soluble fraction of blood which is called plasma, 00:08:57.871 --> 00:09:01.815 and inject either young plasma or old plasma into these mice, 00:09:01.839 --> 00:09:04.207 and we could reproduce these rejuvenating effects, 00:09:04.231 --> 00:09:05.945 but what we could also do now 00:09:05.969 --> 00:09:08.419 is we could do memory tests with mice. NOTE Paragraph 00:09:08.443 --> 00:09:12.296 As mice get older, like us humans, they have memory problems. 00:09:12.818 --> 00:09:14.411 It's just harder to detect them, 00:09:14.435 --> 00:09:16.779 but I'll show you in a minute how we do that. 00:09:16.803 --> 00:09:19.498 But we wanted to take this one step further, 00:09:19.522 --> 00:09:23.562 one step closer to potentially being relevant to humans. 00:09:23.586 --> 00:09:26.783 What I'm showing you now are unpublished studies, 00:09:26.807 --> 00:09:31.340 where we used human plasma, young human plasma, 00:09:31.364 --> 00:09:33.213 and as a control, saline, 00:09:33.237 --> 00:09:35.113 and injected it into old mice, 00:09:35.137 --> 00:09:39.989 and asked, can we again rejuvenate these old mice? 00:09:40.013 --> 00:09:41.673 Can we make them smarter? NOTE Paragraph 00:09:42.104 --> 00:09:45.393 And to do this, we used a test. It's called a Barnes maze. 00:09:45.417 --> 00:09:48.572 This is a big table that has lots of holes in it, 00:09:48.596 --> 00:09:52.079 and there are guide marks around it, 00:09:52.103 --> 00:09:54.709 and there's a bright light, as on this stage here. 00:09:54.733 --> 00:09:57.866 The mice hate this and they try to escape, 00:09:57.890 --> 00:10:02.146 and find the single hole that you see pointed at with an arrow, 00:10:02.170 --> 00:10:04.115 where a tube is mounted underneath 00:10:04.139 --> 00:10:07.332 where they can escape and feel comfortable in a dark hole. 00:10:07.977 --> 00:10:09.779 So we teach them, over several days, 00:10:09.803 --> 00:10:12.706 to find this space on these cues in the space, 00:10:12.730 --> 00:10:15.524 and you can compare this for humans, 00:10:15.548 --> 00:10:19.778 to finding your car in a parking lot after a busy day of shopping. NOTE Paragraph 00:10:19.802 --> 00:10:20.803 (Laughter) NOTE Paragraph 00:10:20.827 --> 00:10:24.578 Many of us have probably had some problems with that. NOTE Paragraph 00:10:24.602 --> 00:10:26.620 So, let's look at an old mouse here. 00:10:26.954 --> 00:10:29.130 This is an old mouse that has memory problems, 00:10:29.154 --> 00:10:30.843 as you'll notice in a moment. 00:10:31.305 --> 00:10:36.029 It just looks into every hole, but it didn't form this spacial map 00:10:36.053 --> 00:10:41.300 that would remind it where it was in the previous trial or the last day. 00:10:41.873 --> 00:10:47.340 In stark contrast, this mouse here is a sibling of the same age, 00:10:47.364 --> 00:10:52.783 but it was treated with young human plasma for three weeks, 00:10:52.807 --> 00:10:55.340 with small injections every three days. 00:10:55.741 --> 00:10:59.964 And as you noticed, it almost looks around, "Where am I?" -- 00:10:59.988 --> 00:11:02.895 and then walks straight to that hole and escapes. 00:11:02.919 --> 00:11:05.783 So, it could remember where that hole was. NOTE Paragraph 00:11:06.742 --> 00:11:10.430 So by all means, this old mouse seems to be rejuvenated -- 00:11:10.454 --> 00:11:12.833 it functions more like a younger mouse. 00:11:12.857 --> 00:11:15.563 And it also suggests that there is something 00:11:15.587 --> 00:11:20.578 not only in young mouse plasma, but in young human plasma 00:11:20.602 --> 00:11:24.262 that has the capacity to help this old brain. 00:11:24.834 --> 00:11:25.986 So to summarize, 00:11:26.010 --> 00:11:30.209 we find the old mouse, and its brain in particular, are malleable. 00:11:30.233 --> 00:11:33.684 They're not set in stone; we can actually change them. 00:11:33.708 --> 00:11:35.181 It can be rejuvenated. 00:11:35.680 --> 00:11:38.277 Young blood factors can reverse aging, 00:11:38.301 --> 00:11:40.013 and what I didn't show you -- 00:11:40.037 --> 00:11:45.259 in this model, the young mouse actually suffers from exposure to the old. 00:11:45.283 --> 00:11:48.663 So there are old-blood factors that can accelerate aging. 00:11:49.725 --> 00:11:54.042 And most importantly, humans may have similar factors, 00:11:54.066 --> 00:11:58.144 because we can take young human blood and have a similar effect. 00:11:58.592 --> 00:12:02.148 Old human blood, I didn't show you, does not have this effect; 00:12:02.172 --> 00:12:03.934 it does not make the mice younger. NOTE Paragraph 00:12:05.071 --> 00:12:08.699 So, is this magic transferable to humans? 00:12:08.723 --> 00:12:12.352 We're running a small clinical study at Stanford, 00:12:12.376 --> 00:12:16.252 where we treat Alzheimer's patients with mild disease 00:12:16.276 --> 00:12:22.886 with a pint of plasma from young volunteers, 20-year-olds, 00:12:22.910 --> 00:12:25.505 and do this once a week for four weeks, 00:12:25.529 --> 00:12:28.692 and then we look at their brains with imaging. 00:12:29.050 --> 00:12:30.894 We test them cognitively, 00:12:30.918 --> 00:12:34.924 and we ask their caregivers for daily activities of living. 00:12:34.948 --> 00:12:38.867 What we hope is that there are some signs of improvement 00:12:38.891 --> 00:12:40.255 from this treatment. 00:12:40.758 --> 00:12:43.314 And if that's the case, that could give us hope 00:12:43.338 --> 00:12:45.758 that what I showed you works in mice 00:12:45.782 --> 00:12:47.560 might also work in humans. NOTE Paragraph 00:12:48.478 --> 00:12:50.836 Now, I don't think we will live forever. 00:12:51.955 --> 00:12:54.292 But maybe we discovered 00:12:54.316 --> 00:12:57.403 that the Fountain of Youth is actually within us, 00:12:57.427 --> 00:12:59.165 and it has just dried out. 00:12:59.574 --> 00:13:02.402 And if we can turn it back on a little bit, 00:13:02.426 --> 00:13:07.053 maybe we can find the factors that are mediating these effects, 00:13:07.077 --> 00:13:09.664 we can produce these factors synthetically 00:13:09.688 --> 00:13:13.701 and we can treat diseases of aging, such as Alzheimer's disease 00:13:13.725 --> 00:13:14.955 or other dementias. NOTE Paragraph 00:13:15.282 --> 00:13:16.433 Thank you very much. NOTE Paragraph 00:13:16.457 --> 00:13:19.750 (Applause)