Episode 134

Quick, name something that can extend your lifespan.  Diet?  Exercise?  A multivitamin?

Bet you didn’t think of a compound derived from a soil bacterium (Streptomyces hygroscopicus) found on Easter Island:  Rapamycin (named after the island’s native name — Rapa Nui).

In Episode 134, Jesse talks to Dr. Matt Kaeberlein, Professor of Pathology at the University of Washington, about the anti-aging and longevity implications of rapamycin — for everything from yeast to dogs to humans.

Important Disclaimer:  it’s far too early to tell healthy humans to start taking rapamycin.  The current research is very promising, but there’s a big difference between mice and humans.

Current Uses of Rapamycin

Rapamycin is currently FDA approved, just not for anything longevity-related.  The two primary uses of rapamycin are as:

  1. An immunosuppressant:  Rapamycin was first approved by the FDA for human use to prevent organ transplant rejection.  At low doses, rapamycin slows the rate of cell division, and at high doses it stops cell division.  Immune cells are one type of cell that rapidly divide.  This is great for people getting organ transplants.
  2. A cancer treatment:  Cancer cells are another type of cells that grow fast, and rapamycin slows their growth.  Derivatives of rapamycin are being used as treatments for kidney, lung, and breast cancers.

Possible Future Uses of Rapamycin

In studies on yeast, C. elegans, fruit flies, and mice, rapamycin has shown some pretty fantastic results in extending life and delaying or preventing the onset of age-related diseases, like Alzheimer’s, cardiac disease, and cancer.

The most exciting research so far has been a major study showing that rapamycin extends the lifespans of mice by 9% for males and 15% for females.

graph showing increased longevity for mice treated with rapamycin

Source:  Bloomberg

Particularly promising is exactly how rapamycin increases lifespan.  It inhibits TOR (target of rapamycin) pathways, known as mTOR pathways in mammals.  TOR is a protein that plays a key role in regulating growth and metabolism.

When TOR pathways are active, cells grow and divide; when they’re inhibited, cells switch into survival mode, becoming stress resistant and triggering autophagy (recycling of old cellular components).  It’s the inhibition of TOR pathways that leads to longevity.

Don’t start popping rapamycin just yet though.  We don’t have enough data to be confident that this effect on mice will apply to people.  It seems likely that humans will derive some longevity benefit from rapamycin, since other benefits seen in mice have also been seen in humans, but there may be a difference in magnitude of the benefit.

It’s a Dog’s (Long) Life

While human trials still need to be conducted, Dr. Kaeberlein has started studying the effects of rapamycin on dogs.  Looking at larger dogs (since they age faster than small dogs) that are at least 6 years old with no pre-existing medical conditions, Dr. Kaeberlein has completed the first phase of the trial, to make sure there were no serious side effects and to confirm preliminary benefits.

Middle-aged mice hearts start functioning like much younger hearts after just 10 weeks of rapamycin treatment, so the goal was to see if these initial benefits would be observed in dogs as well.

The good news:  compared to placebo, 10 weeks of rapamycin did improve heart function of healthy older dogs.  The next step is now to extend the study for the next five years to observe any effects on aging and longevity.

Rapamycin Links

Episode Highlights

0:26Our first dog-themed episode
2:03This Week in Neuroscience: Prenatal fruit consumption boosts babies' cognitive development
5:11The audience interaction section
7:45Intro to Dr. Matt Kaeberlein and The Dog Aging Project
9:19The discovery of Rapamycin and its mechanism of action
10:58Rapamycin as an immune suppressant
11:54Dr. Kaeberlein's first interest in aging and Rapamycin
12:48Unbiased geneteic screening
14:17Target of Rapamycin (TOR)
17:31How do studies in animals translate to projected results in humans?
20:27Extending healthspan
21:24The Dog Aging Project
25:07Purebred and mixed-breed dogs and life expectancy
26:10How close are dogs to humans on an evolutionary tree?
29:36Because of the huge variation in breeds and living conditions, what sample size will produce significant results?
31:52Sign your dog up for the study at www.DogAgingProject.com
33:02Rapamycin as an anti-aging compound in humans
36:57What is an acceptable risk profile for an anti-aging drug?
39:42Ruthless Listener-Retention Gimmick: 6 medical conditions that dogs can sniff out

PS:  You’ll find other ways to live longer and better in our weekly Brain Breakfast email.

Episode Transcript hideshow

— This Week in Neuroscience --

Jesse: Okay, so as I mentioned last week, when I ended my recent water fast I decided I would go back on to a high-fat diet, what's called a ketogenic diet, so that my body's primary energy supply would be based on metabolizing fats.  Not so much adipose tissue or the fat that I actually have on my body, but dietary fat coming in through my food, which is sort of the steady state that you want to be in if you're doing a long-term ketogenic diet, because eventually you're going to run out of things like love handles and butt cheeks and all that, and you're going to need to be getting your energy from your diet. 

But as I've mentioned many times, I'm famously a fan of fruit.  I really, really like my fruit, and I miss not being able to eat it to my heart's content or very much at all when I'm staying on a ketogenic diet.  So maybe it should be no surprise to you that I've been looking around for scientific excuses to work some fruit back into my diet and say, "Ah, maybe this ketogenic thing isn't such a good idea after all."  And the University of Alberta threw me a little bit of a bone here recently.  Just on May 25th of this year they published a study showing that prenatal fruit consumption in mothers significantly boosts the cognitive development of babies.  Now, admittedly there's some flaws in my logic hereóI am neither a mother nor a babyóbut this is still a pretty interesting study and one that I'd like to share. 

Canada did a cleverly acronymed study, with the acronym CHILDóthat's Canadian Healthy Infant Longitudinal Development.  This had a Canadian birth cohort of over 3,500 infants and their families, so a pretty good sample size.  What they found was that one of the biggest predictors of cognitive development was how much fruit the moms consumed during their pregnancies.  According to the study data, this was a continuous uptrend, so the more fruit the moms had, the higher the child's cognitive development.  So, if there's a top of this curve, a point of diminishing returns, they did not find it with the data from this study.  The researchers controlled for factors that would normally affect a child's learning and development, including things like family income, the parent's education, and the gestational age of the childóin other words, how long the child was inside the mom before birth. 

Now as we know, IQ is not a perfect measure of intelligence, but it's the best thing we've got right now, most commonly agreed upon.  And the way that IQ works is that the average IQ is, sort of by fiat, the number 100 with a standard deviation of 15, so that two-thirds of the population will have an IQ between 85 on the low end and 115 on the high end.  The remaining one-third of people fall either under the low end or above the high end.  So the study showed that pregnant women who ate six or seven servings of fruit per day, on average their infants had six or seven extra IQ points on the non-fruit-saturated kids that were in the same study.  So a standard deviation is 15, and just eating a bunch of fruit gets almost half a standard deviation of improvement in the mother's kid.  The study's senior author was Piush Mandhane, who further pointed out that having just one additional of fruit per day provided the baby with the same benefits as being born a whole week later, and it's pretty well-known that staying inside the mother longer is a boost to the baby's cognitive development.  So, one more piece of fruit per day for those nine months or so is as good or better than carrying the baby for another whole week. 

Now, the IQ test done in these studies were performed on one-year-olds, which, as you might imagine, is a little bit different than an adult IQ test.  One of the things that they do not know yet is whether these IQ improvements for babies that have fruit-eating moms is something that's going to persist throughout childhood development or if it might fade with age depending on a normalized diet once the baby is eating its own food.  They don't know about this yet, but further studies are in the works, with the researchers also looking to determine if fruit can influence childhood cognitive development in areas such as planning, organizing, and working memory. 

-- Main Interview --

Dr. Kaeberlein: So, I obviously wasn't involved in the discovery of rapamycin, but my understanding is that it originally was identified from soil samples on Easter Island or Rapa Nuióthat's where rapamycin gets its name fromóand it's produced by a soil bacteria called streptomyces tigrascopiscus.  And I honestly don't know exactly why they were looking specifically on Easter Island.  I think the idea was that we've known for decades that there are interesting biomedically relevant compounds produced by bacteria and we've also known that we've probably only cultured less than 1% of the bacterial diversity in the world in the lab.  So I think the idea was to go out into the field and identify some new bacteria and some new compounds that might have some sort of interesting medical properties. 

So in any case, rapamycin was identified as a compound that was found in the soil bacterias that could impair cell growth.  So, I think initially it was thought about both as a potential anticancer drug and also as a potential antifungal drug, and I think just kind of sat around for a decade or two without anybody really following up on it as a medically useful drug.  But there was a lot of work going on in the background on the research side in the lab, trying to understand how this drug was working.  So there were a series of genetic studies performed both in yeast and mammalian cells looking for mutants that were either resistant or sensitive to the drug, and that's how its mechanism of action in terms of inhibiting a protein called the Target of Rapamycinóor TORóthat's how that mechanism was discovered, by looking for various genetic mutants that showed differential sensitivity to the drug. 

Jesse: Yeah, and I guess one of the things that came out of these studies is that it's also an immunosuppressant, which at first blush sounds like it's not such a good thing, but there's actually a lot of times when that's a useful thing to have in the bag of tricks. 

Dr. Kaeberlein: Yeah, the immunosuppressive features of rapamycin, that wasn't what people first thought about using it for.  But because it does impair cell growth, so at relatively low doses you can slow the rate of division of cells in culture, and then at higher doses you can completely block cell division.  And so, when you think about what are the rapidly dividing kinds of cells in the body, cancer cells are obviously one type, and certainly there's been a lot of interest in using rapamycin as an anticancer drug, but immune cells are another kind of cell in the body that tend to go through these bursts of cell division.  And so, I think it started being studied in that context and it was discovered that, in fact, it was a fairly potent immunosuppressantóand in fact that's why it was first approved by the FDA, was to prevent organ transplant rejection in organ transplant patients. 

Jesse: How did you personally become aware of rapamycin and decide that this was something that you wanted to pursue in your research? 

Dr. Kaeberlein: Yeah, so I've been interested in the basic biology of aging for many years since I was a graduate student.  Really, my interest in rapamycin in the TOR pathway in particular came from genetic studies that we were doing, this was back when I was working primarily in budding yeast, saccharomyces cerevisiae.  We were looking for mutants, single-gene deletions that could extend the lifespan of individual yeast cells.  And through an unbiased screen, we identified the TOR gene as one of these mutants that had an extended lifespan.  And so, it was from this unbiased genetic screen that I got interested in the TOR pathway, and it turned out that in the literature at that point, rapamycin had already been identified as a drug that was a pharmacological inhibitor of this pathway, and so it made sense to us to test whether we could get the same effects on lifespan by using a drug that we were seeing in these genetic mutants. 

Jesse: So we just dropped a terminology bomb that I want to make sure that we clarify.  Could you tell people what an unbiased genetic screen is? 

Dr. Kaeberlein: Sure.  So, the idea here was to try to identify genes that affect the aging process, and so there are a few ways that you can go about that.  You can do what's called a biased screen, where you pick genes that have a known function that you think might be important for whatever it is you're studyingóin this case, aging.  But we thought that it would be more interesting to go in with no preconceived notions, and so our approach was to take a collection of about 4,500 unique single-gene deletion mutants and just ask the question, out of this entire collection, which of these mutants cause an increase in lifespan?  And I'm sort of saying that in one sentence, the reality was that was a 10-year project, we actually just published the paper for it last year.  But we were very fortunate that out of the first 500 or so that we looked at, it just, by random chance, the TOR gene deletion was in that first set of 500.  And it was long-lived, and so that really got us thinking, this was way back in 2004-2005 when we first started getting this data, this got us thinking that maybe the TOR pathway itself was an important regulator of longevity, and so that's what led us to look at rapamycin.  And then fortunately it's turned out that many other labs in parallel have made the same discovery, not only in yeast but in simple multicellular organisms, like C.  elegans and fruit flies, and now we know that even in mice, either genetic inhibition of the TOR pathway or treatment of mice with rapamycin is sufficient to extend lifespan. 

Jesse: One of the things that's always funny to be kind of looking at science from the outside is the way that things get named.  We'll have these compounds that are endogenous within the body, sometimes they're secreted by our own bodies, but they're named after things that are found first in the outside world.  Like endocannabinoids, that's something that we secrete ourselves but it's actually named after the cannabis plant because sort of a chemical analog was found within cannabis first before we discovered something similar in our own body.  It seems like TOR is another one of these, called TOR, Target of Rapamycin.  But if this is something that's wound up so tightly with our physiological process, it stands to reason there must be something internal that's very similar that we could be responding to even if we don't happen to live on Easter Island or wherever else this might be present in the environment. 

Dr. Kaeberlein: Yeah, no, that's true, and the way that genes or proteins get named, it's kind of all over the place.  It really, in some respects, depends on the organism you're working in; each model organism has their own unique way or nomenclature that they use.  But right, in this case it turned out that the drug was known first, and just because of the way it was used as a research tool, the target of the drug was identified second, and so it just got named Target of Rapamycin, which of course we now call TOR. 

Jesse: Right.  Is there something within the body though that would normally trigger that target? 

Dr. Kaeberlein: Yeah, right.  So now we know a lot about what TOR does.  So first of all, just to take a step back, TOR itself is alsoóyou'll probably more commonly see it referred to as mTOR, and the "m" initially stood for mammalian, and now it stands for mechanistic.  It doesn't really matter except it gets confusing because, again, the nomenclature is kind of all over the place.  So, mTOR is the protein that rapamycin inhibits, and mTOR is what's called a kinase, and really you can think of it as kind of a signaling molecule.  So, the mTOR pathway, of which a major component is mTOR itself, is a pathway that signals growth and reproduction in response to environmental cues, like nutrients or growth factors or hormones. 

So really, one way you can think about mTOR is it's kind of an on/off switch, or it kind of controls the speed at which a cell divides or an organism grows.  And the way it does that is it senses the environment and kind of makes the decision, is this a good time to grow and reproduce, or is it a good time to become stress-resistant and kind of just hunker down and survive a condition where it's maybe not favorable to grow and reproduce?  So, it senses nutrients primarily, and this is where things have gotten interesting in the aging field, is we've known since the 1930s that probably the most potent way to delay aging is to restrict calories.  It's called calorie restriction or dietary restriction.  And what TOR does, it's one of the major sensors in the cell that senses nutrient levels and, as I said, makes the decision whether to grow or not grow.  And so, rapamycin in many ways is mimicking this state of caloric restriction.  So when nutrients are low, TOR gets turned down, and what rapamycin does is it turns down TOR even when nutrients are high.  So getting back to your original question, the real job of TOR in the cell is to sense food and other conditions in the environment and then make a decision whether it's a good time to grow or not. 

Jesse: Yeah, if winter is coming, you probably don't want to get pregnant again or something like that. 

Dr. Kaeberlein: That's right, it's not a good time to have kids if there's no food around. 

Jesse: So, I guess a question that I've got when I hear about stuff like this, and probably a lot of people have, is what is the applicability of a mouse study to humans?  Sometimes you hear about these interventions on small creatures that can really radically, radically extend their lifespan two times, three times, whatever it is.  But when they try to do the analogist studies in larger, more complex creatures, they haven't necessarily scaled up. 

Dr. Kaeberlein: Well, I actually don't know that that's true.  I think that there's no data yet.  So the only data that we've got that you could possibly even draw a parallel with is the two caloric restriction studies that were done in monkeys, right?  So there have been two studies that have been done looking at the effects of caloric restriction on non-human primates, in rhesus monkeys.  In one of them, there was a pretty robust increase in lifespan and a very robust reduction in age-related diseases, and in the other one, there was no effect on lifespan, but again, there was a pretty robust reduction in age-related diseases.  So, I think we just don't have enough of a data set to say for sure that some of these effects that are seen in mice with respect to aging translate well to people.  We just don't know.  But certainly if you look at other areas of biomedical research, cancer is probably the obvious one, there are lots and lots of ways to reduce cancer in mice that haven't necessarily translated well to the clinic, right?  So, I think it's a valid point that we don't how well some of what we've learned in mice about aging is going to translate to people.  But I also think it's important to note that our data set is really small in terms of actual attempts to do that. 

And I think there are some reasons to be optimistic.  So as I said, we don't know.  My own intuition is that, like with rapamycin, the effects of rapamycin on lifespan are so broad evolutionarily, all the way from yeast to C.  elegans, to fruit flies, to mice, the relative distance evolutionarily between mice and people is much smaller than the evolutionary distance where we already know that this pathway affects aging the same way.  So, I think it would be somewhat surprising if mTOR and rapamycin don't also affect human aging, but obviously we don't know whether the magnitude of the benefits we might get will be conserved.  We just really have to do the experiment; I don't really want to predict how big those effects will be. 

There's a little bit of evidence though I think suggesting that at least some of the effects on health during aging are likely to be conserved.  So, there was a study that was published, it was from a group at Novartis, I think it was last year, maybe it was the year before, and what they were doing was sort of paralleling an experiment that had been done in mice looking at the effects of rapamycin on immune function in healthy elderly people, and what they saw was that short-term treatment with rapamycin in healthy elderly people was able to boost their immune system in the same way that rapamycin had been shown to boost immune function in older mice.  So, at least with respect to restoration of the aged immune system, that effect of rapamycin seems to be shared between mice and people.  Whether that will also be true of cardiac function and cognitive function and cancer and ultimately lifespan, all of which have been shown to be improved by rapamycin in mice, whether that will also be true in people, we'll just have to wait and see how the data comes out. 

Jesse: Ultimately, even if people aren't living any longer but they're having less diseases of old age, I feel like that's probably something that people would still sign up for rather than living longer but just being increasingly decrepit as they age. 

Dr. Kaeberlein: Absolutely.  And that idea of extending what we call healthspan, the period of life that's spent in relatively good health, is clearly first and foremost the goal of aging research or what is now often termed geroscience.  That's the main goal, is to extend healthspan.  My own personal feeling just from being in the field and my understanding of the biology is that almost always healthspan and lifespan are going to go together.  Whenever we extend healthspan, it's quite likely that we're also going to extend lifespan.  But certainly the first goal is to delay the onset and progression of age-related diseases and disability. 

Jesse: Right, it's like pulling on a slinky, the whole thing spreads out together. 

Dr. Kaeberlein: And that makes biological sense, as well.  Now, there may be cases where it's possible to uncouple those two things, healthspan and lifespan.  But I think the majority of the time they're going to track together. 

Jesse: So, I promised people a dog-heavy episode and so far we've been talking about fungus and humans and mice.  Can you tell me about the current study that you're doing with dogs as test subjects? 

Dr. Kaeberlein: So, the study that's just now wrapping upÖ So first of all, let me take a step back.  The overall goal is to try to take what we've learned about the biology of aging in laboratory animals and apply that to improve the length and quality of life in pet dogs.  And there are really two primary reasons for doing this.  One of them is that we will absolutely learn important lessons about how to translate what has come from studies in the lab to impact healthy longevity.  But also, I'm a dog person, I love my dogs, I see the intrinsic value in extending the length and quality of life for pet dogs as well in terms of improving the quality of life for the owners.  I view those as sort of parallel goals, both of which I think we're likely to achieve.  So that's kind of the big picture. 

And specifically, there are two things that we're really pushing forward with.  One of them is what we call a longitudinal study of aging in dogs, and the goal hereóit's not an interventionóis really to follow individual dogs throughout life and, at a very detailed level, try to assess what are the genetic and the environmental factors that cause some dogs to live a long time and age very well and other dogs to not live a long time and suffer from multiple diseases of aging.  Because if we can understand what those genetic and environmental factors are, that's really the first step in actually being able to do something about it.  Now, why do we want to do this in dogs?  Because you could do this in people and, in fact, there are some longitudinal studies of aging in people, but I think the obvious reason is dogs live a much shorter time than people do, and in a decade we could really figure this out.  And so that's one of the projects that we're just in the process of getting going now. 

And then the other project is actually an intervention trial with rapamycin, where we're treating pet dogs that are middle-aged, so the entrance criteria at least for the first phase of the study is the dogs have to be at least six-years-old.  They also have to be at least 40 pounds, and the reason for that is that big dogs age faster.  The idea is to treat dogs with a low dose of rapamycin and ask the question, are we delaying diseases and declines in functions that go along with aging, and ultimately we would like to know are the dogs living longer, obviously.  And so we've actually completed the first phase of that trial, which was a 10-week short-term study really to make sure that we aren't seeing any significant side effects but also to look at cardiac function, because we know in mice, that if you take an old mice and you give it 10 weeks of rapamycin and you look at the functions of its heart, you can actually see that that heart in the mice that have gotten rapamycin is now functioning more like the heart of a younger mouse, whereas the older mice that got the control, there was actually a decline in the function of their heart over the 10 weeks of the study. 

And so, we're doing the same thing in pet dogs, giving them 10 weeks of rapamycin, looking at cardiac function to ask, at least for cardiac function, can we get some indications that there's an improvement in cardiac function in older dogs even from just this short-term treatment from rapamycin?  And then hopefully, starting this year or early next year, we'll be able to scale up and turn this into a long-term study over three to five years to look not just at cardiac function but look at the effects of rapamycin on cancer incidents, and cognitive function, and kidney function, and all of the declines that go along with aging in both dogs and people, and really quantify to what extent are the effects of rapamycin in the lab translating to a real world population in pet dogs. 

Jesse: I was actually a little bit surprised when you just said that to make the threshold of being a dog involved in the study, they need to be over 40 pounds.  One of my questions was about various dog breeds and some of them being so much more inbred than others.  Oftentimes, I think of the small dog breeds as being these ones that have been really, really inbred and probably have more health problems as a result.  But even those breeds tend to be longer lived? 

Dr. Kaeberlein: Yeah, so there are two things that really seem to drive life expectancy in dogs.  The biggest one is size.  If you just look across all purebred dogs, smaller purebred dogs live longer than bigger purebred dogs.  There are very large purebred dog breeds as wellógreat danes are a good example.  So that's the primary determinant of lifespan in dogs.  Now, mixed breed dogs vs.  purebred dogs, that also affects life expectancy.  I think it's about one to two years.  So, for the same sized dog, a mixed breed dog will live one to two years longer than a purebred dog.  Now, that's a generalization and there are some breeds that kind of break that correlation, where they're predisposed to certain specific, maybe rarer diseases in the whole population.  But because of the inbreeding, those breeds have become predisposed to those diseases and so they die maybe earlier than they would normally for their size.  But in general, the trends that I just talked about hold, that size is the biggest determinant of life expectancy for a dog, and then there's also this effect of inbreeding, where the purebred dogs are a year to two years shorter lived when you normalize for size. 

Jesse: Between dogs and mice, are they equally far from humans on the phylogenetic tree, or is one closer than the other? 

Dr. Kaeberlein: This is not my area of expertise, but my understanding is that's still a matter of debate.  I think it's fair to say that they're roughly equally as far away from people on an evolutionary tree.  And in fact, if I didn't know that already, I might have thought that dogs were closer to people, but it turns out that at least at the level of the genome, that's not obviously the case. 

Jesse: Yeah, because dogs are so much bigger, it's kind of like the intuition is that dogs have to be closer, right?  But that's actually kind of not the right marker. 

Dr. Kaeberlein: That's right.  So people ask, "So, why are dogs a good model for doing this?"  I think the genetics are part of it, but not because dogs are closer to us than mice are, it's because we have this really interesting and phenotypically diverse genetic structure, right?  If you look at almost any trait in dogs, there's much more diversity for that trait than there is in mice.  So, size is a really good one.  You take the smallest dogs compared to the biggest dogs, and that's more than an order of magnitude difference in body size, and that's true for almost any trait you think about.  So that diversity of phenotypes is really useful when you're thinking about following a complex trait like lifespan, because we can actually start to figure out what's the relationship between this genetic diversity and lifespan in a potentially much more comprehensive way than you can do in mice. 

The other really big advantage to pet dogs in particular for this kind of study is that they share our environment, right?  So all of the studies that have been done on agingóto date, almost all of them have been done using laboratory-maintained animals, and that's a completely artificial environment.  Whereas our pets really share our environment in a way that almost no other animal can match.  There are lots of people whose dogs sleep in their bed with them.  So, I think it's hard to imagine a case where you've got an animal that has that sort of matched environment to the human condition, so I think that's a real strength for this type of study in terms of understanding how do our genes and our environment interact with the way that we age.  Dogs can be a really useful model for that particular aspect of it, capturing that environmental diversity. 

Jesse: Yeah, that's a really interesting point, because you'd be doing studies with dogs that are still living with pet owners rather than having a lab-grown dog? 

Dr. Kaeberlein: That's right, yeah.  So, when I first started thinking about this, like I already said, I'm a dog lover, I've always had dogs, and personally I would not want to run a study that was done on dogs in a kennel in a lab.  I think everybody has their own views on animals in research, but for me personally, it just wouldn't be a study that I would want to participate in.  So, when I first started thinking about is this idea of trying to extend what we've learned in the lab to dogs, is it something that's reasonable to actually pursue?  I very early made the decision that if we're going to do it, it's going to be done on pet dogs, and that has some benefits, as we already talked about, in the sense of the environmental diversity, but it also means that you have to be really cautious that whatever intervention you're doing is not going to harm anybody's pet.  In many ways, that makes it more akin to a human clinical trial, especially when you're talking about a trial for something that impacts healthy aging.  Because these dogs are not sickóin fact, that's one of the other entrance criteria for our study, that dogs cannot have a significant pre-existing conditionóso because they're not sick, the level of side effect that's acceptable is much lower than if this was a clinical trial, say, for a terminal cancer.  So that influences the way you design the study, and certainly it has affected the way that we've designed our rapamycin study. 

Jesse: It seems like because of the potential individual variability from one pet owner's environment that they're providing for their dog vs.  another's, you're going to need to have either a really large sample size or really, really strong results to get statistical significance out of what your findings are. 

Dr. Kaeberlein: Yeah, no, you're absolutely right, and that was and probably still is my second biggest concern.  So going in, my biggest concern was whether we could find a dose of rapamycin that was therapeutic without side effects.  Because as I already said, side effects were sort of the big challenge; we had to make sure that we didn't have significant side effects.  But then, if we can get past that, the question is is it even possible to detect a signal given this huge environmental and genetic variation.  This is where sometimes you just have to jump off the deep end and go for it.  So, the fact is we don't know what our sample size has to be, but we would really like to have a sample size that's in the hundreds for both the treatment and the placebo group. 

I will say that based on our phase one data, I've been really pleasantly surprised.  So our sample size there is about 26 dogs at this point that have made it all the way through the study.  We've actually had more than 40 come in for their initial exam, but we've had to exclude several of them because of pre-existing conditions.  But we've had about 26 go all the way through the study, and those are about equally distributed between placebo group and two different doses of rapamycin, and even at that relatively small sample size, we're seeing trends, certainly clear trends in the effects of rapamycin on cardiac function.  I don't want to make any comments about statistical significance at this point, but the fact that we can even see trends that look comparable to what's been seen in mice I think is suggestive that, maybe at least for cardiac function, the magnitude of the effects are going to be large enough that this isn't an impossible proposition. 

But you're absolutely right, the variation is a strength and a weakness for this kind of a study.  We thought about restricting based on breed or somehow trying to restrict based on genetics, and pretty rapidly came to the decision that because the goal here is really to understand to what extent can rapamycin improve healthy aging in pet dogs in general, we really wanted to know, across a representative cohort of pet dogs, is it having this effect?  And so we decided not to restrict based on genetics.  But that increases the noise, and so I think we'll have to keep building our sample size.  As I mentioned, based on our preliminary data, I'm very optimistic that we'll still be able to detect positive effects. 

Jesse: Yeah.  So you're at University of Washington.  I can imagine that people that are living in the area up there are going to raise their hand and say, "Ooh, I want my dog involved!" Is there some sort of open roll call for people that are interested in finding out more about this? 

Dr. Kaeberlein: That's right, so we have a website, it's www. dogagingproject. com, and there is an enrollment form on there for pet owners who are interested in potentially participating in either the longitudinal study of aging or the rapamycin intervention trial.  And so really we haven't done any advertising aside from a couple of articles that have been written on the project, and one was in the local Seattle Times, and then a couple of local radio shows.  We haven't done any advertising.  We're probably up to around 1,500 people.  I'd say about half of those are in the Seattle area and about half of them are throughout the rest of the United States or international.  In fact, we are encouraging people, even if you don't live in the Seattle area, to sign up, because now that we're moving into phase two for the rapamycin study, our intention is that this will be a nation-wide study.  I can't say for sure where the sites will be; at least I'm guessing five or six sites throughout the United States.  So if people are interested in potentially participating in either of those studies, even if you don't live in Seattle, please go to the website and sign up and we'll certainly be in touch as we move forward. 

Jesse: To transition back to humans for a little bit, there are even now, even with the amount of data that we have available currently, people who are enthusiastic advocates of rapamycin as an anti-aging compound.  Is this premature?  Do you have leanings, inclinations, gut instincts on this already?  Or do you want to see more research done? 

Dr. Kaeberlein: Yeah, I know a couple of people who are taking rapamycin.  I'm not one of them, but I do know a couple of people who are taking it for this effect.  I will say that I think that group of people who's really seriously talking about rapamycin, for healthy individuals to delay aging, is pretty small.  In part that's because there are some real side effects associated with high doses of rapamycin.  We already talked about it's used as an immunosuppressant, or at least as an immune modulator.  So there's concerns certainly that rapamycin could have effects on immune function, and then the patients who take rapamycin to cause immunosuppression have other side effects.  Now, none of them are really life-threatening, but some of them are unpleasant.  So, mouth sores is actually the dose-limiting toxicity usually for people taking rapamycin, but also some of them are potential health risks, like increase in circulating triglycerides, potential issues with glucose homeostasisÖ Maybe another one that's more of a concern is defects in wound healing.  So, I think there is reason to be cautious about, if you're healthy, just going out and asking your physician to prescribe you rapamycin. 

My own view is that the lower doses that seem to have effects on aging parameters probably are not going to be as much of a concern with respect to these side effects, and that's certainly what our very initial data in dogs is suggesting.  But, I do think it's a little bit early to really seriously start talking about people taking rapamycin if they want to live longer or live healthier into old age.  Having said that, I also think that it's probably a pretty good time to really start a discussion about a control clinical trial to actually look at this.  As I mentioned, Novartis is kind of going down this road in the context of immune function, where they've looked at a derivative of rapamycin and shown that you can boost the response to an influenza vaccine in elderly people.  So, I absolutely think that now is a good time to start doing clinical studies to see whether low-dose rapamycin in elderly people can improve other measures of aging.  Cardiac function is an obvious one since, as I've already mentioned, we know that in mice it can have this effect, and our initial data suggesting that in dogs it also can rejuvenate heart function to some extent, that's an obvious thing to look at in people.  So, I'm hopeful that somebody will do that study.  Then I think once we've got a better understanding of dosing and side effects in people, then you can really start to think about whether or not this is something that maybe can be used more broadly in healthy people to try to prolong that period of health. 

Since we've started to talk about this idea of testing things in humans, I think it's worth mentioning how challenging that is to actually think about this translation from the biology of aging in animals to a human population.  You've probably heard about this TAME trial, or Targeting Aging with Metformin.  Metformin is another drug that has come, to some extent, out of the basic biology of aging literature, something that might impact aging.  And certainly, metformin is well-known and well-used clinically as an antidiabetic agent.  So there's an attempt now, an effort underway to start a clinical trial to assess whether metformin can delay the time of onset for a collection of age-related diseases.  Nir Barzilai at Einstein, along with other people, are trying to push this trial forward, and they're in lots of discussions with the FDA now about how you could actually do this.  I think this is one of the major challenges, is that it's not clear from a regulatory perspective that aging is actually something that you could get a drug approved for.  Is aging an indication that the FDA would even allow you to test a drug for in a clinical trial and then get approval for that drug?  And so that's a regulatory/policy issue that has to get worked out before we can really start to think seriously about testing these kinds of aging interventions in the human population. 

The other really complicated issue that comes up when we start thinking about translation to people is what is the acceptable side effect profile for an intervention that might allow you to live an extra 10, 15, or 20 years in good health?  We're used to thinking about acceptable risks if somebody has cancer or Alzheimer's disease or diabetes.  We're not really used to thinking about what's the acceptable risk for extra healthy longevity.  I think this is not something we can solve today, but I think it is an issue that people who are really interested in this topic need to start thinking about, both at the scientific level but also at the policy and regulatory level.  Because to my mind, that's the real barrier, and my own opinion here is there should be some level of risk that's tolerable if the potential benefit is one or two decades of extra healthy life.  Because we absolutely know what the outcome is going to be if we don't do anything, right?  We know what happens when people get old.  And so if there's the potential to significantly delay that, my own personal view is there should also be some level of risk that's tolerated for that potential benefit.  But I think this is a discussion that, you know, it's going to take a while to really work its way through all the various channels that it has to work its way through. 

Jesse: Yeah, those are great points and really interesting ethical issues.  Because I would easily give my right arm to live a decade more, or live multiple decades more.  Living without a right arm, it would kind of suck, but it's a pretty good trade. 

Dr. Kaeberlein: Exactly, and I think it's hard because our whole medical regulatory environment has been set up to protect people.  And, I mean, it should beóI'm not at all trying to say that we shouldn't have safeguards in place.  But I think this is kind of a different paradigm than what we're used to thinking about, and so I think it's going to take a while for people to wrap their minds around it.  But I think you're right, at the individual level many of us would be willing to look at this for ourselves and say, yeah, it's worth some risk to have this potential benefit. 

-- Ruthless Listener-Retention Gimmick --

Jesse: So, it will be a surprise to absolutely no one to say that dogs have a really, really good sense of smell.  This varies somewhat from dog breed to dog breed, but in general even the most underpowered smelling of dogs with a heavy cold and any other problem you could throw at it is going to have a stronger sense of smell than the absolute best-smelling human you can find.  Dogs can detect some odors in parts-per-trillion and can detect subtleties in scent that humans cannot begin to approach.  If you think of our sense of smell as being like looking at black and white words on a page, imagine a dog's sense of smell as being a full pallet of every color in the rainbow. 

Now, coming with proper physiological hardware, dogs can be trained to use this sense of smell in some amazing ways.  One drug-sniffing dog identified a plastic container packed with marijuana that was submerged in gasoline inside of a gas tank, which is pretty awesome.  But increasingly, service dogs, the dogs who are tasked with helping people with disabilities, are being used as early warning systems for a variety of conditions.  So, we're going to look at six of them quickly here, some of which are medically well-established, some of them less so. 

But probably least controversial and most well-known is a dog's ability to smell fear, as they say.  And dogs can apparently smell fear or the hormonal results of fear even if we aren't showing outward signs of those emotions.  What the dogs are smelling is a surge of chemicals related to that fear, particularly cortisol and adrenaline.  One teacher of young children keeps a dog around, and a dog knows to fix its gaze on a certain kid if that kid is about to freak out, like have a temper tantrum or a meltdown or something like that.  More surprising is a dog's ability to smell cancer.  This might not be true with all types of cancer, but it certainly is true for some types.  Trained dogs were able to detect breast cancer by smelling breath samples of women and displayed 88% accuracy on giving the thumbs up/thumbs down as to whether that woman had breast cancer.  With lung cancer, this went up to 99% accuracy and they could do this across all four stages of the disease.  Now, scientists do not know yet what exactly it is that the dogs are smelling, so the mechanism is still mysterious, but the ability seems to be conclusive. 

Other helpful dog alarms include service dogs that can tell their narcoleptic owners when they're about to have a narcoleptic attack.  Again, narcolepsy is when you fall asleep suddenly and without meaning to, which can be dangerous if you're driving or even if you're standing on pavement, going to fall and hit your head.  So, trained dogs can oftentimes give the narcoleptic early warning that an attack is coming on, do their little dog freak out so the person knows to sit down or lie down, and then after a couple seconds, they're going to wake up with a dog licking their face to bring them back to reality.  Migraine headache sufferers commonly report that their dog can give them early warning up to an hour or two before the migraine comes on, which in some cases can be really helpful because it gives the person enough time to take some anti-migraine medication before the headache really gets its feet under it. 

And finally, somewhat more controversially, but there are those who say that dogs can give early warning to diabetics when their blood sugar is either spiking or troughing, and to epileptic seizure sufferers before the onset of a seizure.  As you might imagine, you can't actually train a dog to see a seizure coming, because whatever it is the dog is clueing into, it's not just the physical acrobatics that come along with a seizure, there's something going on, whether it's an odor in the person's breath, possibly an odor in their sweat that the dog seems to get an early notice of.  Jennifer Arnold, the founder of Canine Assistants in Georgia, says that 9 out of the 10 service dogs that she's placed with epileptics has developed this ability to give early warning of seizures on their own within the first year of placement in the epileptic's home. 

So, pretty amazing stuff.  It's not like we didn't know that dogs have great senses of smell, but what's really interesting here is it gives science some new rocks to look under, trying to figure out physiologically exactly what it is that the dog is clueing into, and maybe this could lead to other therapies that don't include dogs when you don't have a service dog handy.  But in the meantime, way to go, dogs. 

Written by Hannah Sabih
Hannah believes there's nothing 8 hours of sleep and some kale can't cure (yes, she's from California). She's an avid runner, reader, and traveler, who brings you the latest and greatest in neuroscience via our social media channels.
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