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?
Ovo je slika iz 16.stoljeća, Lucas Cranacha starijeg. Prikazuje poznatu Fontanu mladosti. Ako popijete vodu iz nje ili se okupate u njoj,dobit ćete zdravlje i mladost. Svaka kultura, svaka civilizacija je sanjala o pronalasku vječne mladosti. Postojali su ljudi, poput Aleksandra Velikog ili Ponce De Leona, istraživača, koji su proveli većinu svog života u potrazi za Fontanom mladosti. Nisu ju pronašli. Ali što ako ima nešto u tome? Što ako ima nešto u Fontani mladosti?
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.
Podijelit ću apsolutno nevjerojatan razvoj u istraživanju starenja koji bi mogao revolucionirati način na koji mislimo o starenju i način na koji bismo u budućnosti mogli tretirati bolesti povezane sa starenjem. Počelo je s eksperimentima koji su pokazali, u nedavnim studijama o starenju, da se životinje-- stari miševi-- koji dijele zalihu krvi s mladim miševima mogu pomladiti. To je slično onome što možete vidjeti kod ljudi, kod sijamskih blizanaca, znam da to zvuči pomalo jezivo. Ali ono što je Tom Rando, istraživač matičnih stanica, izvijestio 2007. je da stari mišić miša može biti pomlađen, ako se izloži mladoj krvi zajedničkim optokom. Ovo je ponovno izvela Amy Wagers na Harvardu, par godina poslije te su i drugi pokazali slične učinke pomlađivanja gušterače, jetre i srca. Ali ono što mene najviše uzbuđuje, još neke laboratorije također, je da se ovo može primijeniti čak i na mozak.
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.
Dakle, ono što smo otkrili je da stari miš izložen mladom okolišu, u ovom modelu zvanom parabioza, pokazuje mlađi mozak-- i mozak koji bolje funkcionira. I ponavljam: stari miš koji dobiva mladu krv zajedničkom cirkulacijom izgleda mlađe i mozak mu funkcionira mlađe. Dok starimo-- možemo gledati različite aspekte ljudske kognicije, i možete vidjeti na ovom slajdu, možemo vidjeti razumijevanje, verbalne sposobnosti i tako dalje. I do negdje 50. ili 60.godine ove su funkcije netaknute i dok gledam u mladu publiku u ovoj prostoriji, mi smo svi još uvijek u redu.
(Laughter)
(Smijeh)
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.
Ali zastrašujuće je vidjeti kako sve te krivulje padaju. I kako starimo, bolesti poput Alzheimera i drugih se mogu razviti. Znamo da s godinama veze između neurona-- način na koji neuroni komuniciraju, sinapse-- počinju propadati; neuroni odumiru, mozak odumire, povećana je podložnost tim neurodegenerativnim bolestima.
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.
Veliki problem koji imamo -- pokušati razumjeti kako to doista funkcionira na molekularnoj, mehaničkoj razini -- je da ne možemo detaljno proučavati mozak u živučim ljudima. Možemo vršiti kognitivne testove, možemo oslikavati mozak-- razna sofisticirana testiranja. Ali obično moramo čekati da osoba umre da dobijemo mozak i uvid u to kako se stvarno promijenio s godinama ili u bolesti. To rade neuropatolozi, na primjer. Kako bi bilo da zamislimo mozak kao dio većeg organizma. Bismo li mogli razumjeti više o tome što se događa u mozgu na molekularnoj razini, kada bismo gledali mozak kao dio cijelog tijela? Dakle, ako tijelo stari ili se razboli, utječe li to na mozak? I obrnuto: ako mozak stari, utječe li to na ostatak tijela? A ono što povezuje sva različita tkiva u tijelu je krv. Krv je tkivo koje, ne samo da prenosi stanice koje nose kisik, na primjer, crvene krvne stanice, ili koje se bore sa zaraznim bolestima, nego i prenosi glasničke molekule, faktore slične hormonima koji prenose informacije iz jedne stanice u drugu, iz jednog tkiva u drugo, uključujući i mozak. Dakle, ako pogledamo kako se krv mijenja u bolesti ili s godinama možemo li naučiti nešto o mozgu? Znamo da se, dok starimo,naša krv također mijenja, tako da se ti faktori slični hormonima mijenjaju dok starimo. I većinom, faktori za koje znamo da su potrebni za razvoj tkiva, za održavanje tkiva- njihov broj se smanjuje kako starimo, dok se broj faktora uključenih u popravke, kod ozljede ili upale-- povećava kako starimo.
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.
Dakle, možemo reći da postoji neravnoteža tih dobrih i loših faktora. I da vam zornije prikažem što možda možemo napraviti s tim, želim vas provesti kroz eksperiment koji smo proveli. Imali smo gotovo 300 uzoraka krvi iz zdravih ljudskih bića, između 20. i 89. godine, i izmijerili smo preko 100 ovih komunikacijskih faktora, ovih proteina sličnih hormonima koji prenose informacije među tkivima. I ono što smo prvo primijetili je da se između najmlađe i najstarije grupe oko polovica faktora značajno promijenila. Dakle, naše tijelo živi u veoma drukčijem okolišu dok starimo, kada uzmemo u obzir te faktore. I koristeći statističke i bioinformatičke programe, mogli smo pokušati otkriti te faktore koji nabolje predviđaju dob-- na neki način, unatrag zbrojimo relativnu dob osobe. I kako to izgleda prikazano je grafom. Dakle, na jednoj osi vidite stvarnu dob koju je odoba doživjela, kronološku dob. Dakle, koliko su živjeli.
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?
I onda izdvojimo ove gornje faktore koje sam vam pokazao i izračunamo relativnu dob, biološku dob. I ono što zamjećujete je da postoji dosta dobra korelacija, tako da možemo predvidjeti relativnu dob osobe. Ali ono što je doista uzbudljivo su, iznimke, kao što su često i u životu. Ovdje možete vidjeti, osoba koju sam naglasio zelenom točkom, ima oko 70 godina, ali izgleda da joj je biološka dob, ako je ono što činimo stvarno istinito, samo 45 godina. Je li ovo osoba koja zapravo izgleda puno mlađe od svojih godina? Ali još važnije: hoće li ova osoba, koja možda ima smanjen rizik razvitka bolesti vezane uz starenje i proživjeti dug život- živjeti 100 ili više godina? S druge strane, ova osoba, naglašena crvenom točkom, nema ni 40 godina, ali biološka dob joj je 65. Je li ovo osoba povećanog rizika za razvoj bolesti vezane uz starenje? U našem laboratoriju pokušavamo bolje razumjeti ove faktore, i mnoge druge grupe pokušavaju razumjeti, koji su stvarni faktori starenja i možemo li nešto naučiti o njima da bismo predvidjeli bolesti starenja?
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.
Ono što sam vam do sada pokazao je jednostavno u korelaciji, je li tako? Možete reći: "Pa, ovi se faktori mijenjaju s godinama", ali ne znate zapravo imaju li veze sa starenjem. Ono što ču vam sada pokazati je izvanredno i predlaže da ovi faktori zapravo mogu modulirati starost tkiva. I tada se vraćamo ovom modelu zvanom parabioza.
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.
Dakle, parabioza se vrši na miševima, tako da dva miša kirurški povežu i to dovodi do dijeljenja krvnog sustava, sad se možemo pitati: " Kako mlada krv utječe na stari mozak koji joj je izložen?" Za ovaj pokus koristimo mlade miševe, koji se jednaki 20-godišnjim ljudima, i stare koji imaju otprilike 65 ljudskih godina.
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.
Ono što smo otkrili je prilično fascinatno. Otkrili smo da ima više živčanih matičnih stanica koje proizvode nove neurone u tim starim mozgovima. Povećana je aktivnost sinapsi, mjesta vezanja između sva neurona. Više je izraženih gena za koje se zna da sudjeluju u stvaranju novog pamćenja. I ima manje upala. Ali uočili smo da nema stanica koje ulaze u mozak tih životinja. Dakle, kada ih povežemo zapravo nema stanica koje ulaze u stari mozak, u ovom modelu. Umjesto toga, zaključili smo da to moraju biti topljivi faktori, tako da jednostavno možemo prikupiti topljivi dio krvi zvan plazma i ubrizgati, ili mladu plazmu, ili statu plazmu u te miševe i mogli bismo proizvesti te pomlađujuće učinke, ali ono što također možemo napraviti je testiranje pamćenja miševa.
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?
Dok miševi stare, kao mi ljudi, imaju probleme s pamćenjem. Samo ih je teže pronaći, ali za minutu ću vam pokazati kako. Ali htjeli smo ovo odnijeti korak dalje, korak bliže mogućem značaju za ljude. Ono što vam sada pokazujem su neobjavljene studije, u kojima smo koristili ljudsku plazmu, mladu ljudsku plazmu, i kao kontrolu, slanu otopinu, ubrizgali smo ju u stare miševe i pitali, možemo li opet pomladiti te stare miševe? Možemo li ih opametiti?
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.
I da bismo to napravili, koristili smo test. Zove se Barnesov labirint. Ovo je veliki stol koji na sebi ima mnogo rupa i oko njih su kazala, svijetli jako svijetlo, kao ovdje na pozornici. Miševi mrze to i pokušavaju pobjeći i pronađu jednu jedinu rupu na koju pokazuje strelica, ispod koje je cijev kroz koju mogu pobijeći i osjećati se ugodno u crnoj rupi. Mi ih učimo, nekoliko dana, da pronađu taj prostor na ovim preprekama u prostoru, a to možete usporediti s ljudima kada traže svoj automobil na parkiralištu nakon napornog dana kupovine.
(Laughter)
(Smijeh)
Many of us have probably had some problems with that.
Mnogi od nas su vjerojatno imali problema s tim.
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.
Hajmo pogledati ovog starog miša. Ovo je stari miš koji ima problema s pamćenjem, primijetit ćete to za trenutak. Gleda u svaku rupu, ali nije stvorio prostornu kartu gdje je bila prošloga pokušaja ili dana. U snažnom kontrastu, ovaj je miš jednako star brat, ali bio je tretiran mladom ljudskom plazmom tri tjedna, malom injekcijom svaka tri dana. Odmah primjećujete, gotovo gleda uokolo, "Gdje sam?"-- i onda dohoda ravno do te rupe i pobjegne. Dakle, sjetio se gdje je bila rupa.
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.
Dakle, ovaj se miš je prema svim pokazateljima čini pomlađen-- funkcionira više kao mladi miš. I to predlaže da također postoji nešto, ne samo u plazmi mladog miša, nego i u plazmi mladog čovjeka, što ima kapacitet pomoći ovom starom mozgu. Dakle, da sažmem, smatramo da je stari miš, i pogotovo njegov mozak, u mogućnosti promjene. Nisu zabetonirani; možemo ih mijenjati. Može se pomladiti. Faktori mlade krvi mogu preokrenuti proces tarenja i ono što vam nisam pokazao-- u ovom modelu, mladi miš zapravo pati od izlaganja starom. Dakle, postoji faktori stare krvi koji mogu ubrzati starenje. I najvažnije, ljudi možda imaju slične faktore, jer možemo uzeti mladu ljudsku krv i postići sličan učinal. Stara ljudska krv, nisam vam pokazao, nema taj učinak; ne pomlađuje miševe.
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.
Dakle, je li ta magija primijenjiva na ljudima? Provodimo malu kliničku studiju na Stanfordu, u kojoj tretiramo ljude oboljele od Alzheimera blagog oblika s malo plazme mladih volontera, 20-godišnjaka, činimo to jednom tjedno četiri tjedna i zatim pogledamo njihove mozgove oslikavanjem. Kognitivno ih testiramo i pitamo njihove njegovatelje za dnevne životne aktivnosti. Ono čemu se nadamo su neki znakovi poboljšanja od tog tretmana. I ako se to dogodi, to bi nam moglo dat nadu da ono što sam vam pokazao da funkcionira na miševima, možda također funkcionira na ljudima.
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.
Ne mislim da ćemo živjeti vječno. Ali možda smo otkrili da je Fontana mladosti zapravo u nama i da je upravo presušila. I ako ju opet možemo malo uključiti, možda možemo naći faktore koji sudjeluju u tim učincima, možemo sintetički proizvesti te faktore i možemo tretirati bolesti vezane uz starenje, poput Alzheimera ili drugih demencija.
Thank you very much.
Puno vam hvala.
(Applause)
(Pljesak)