The best funded Buck Institute for aging research celebrates its 20th birthday, and tells us its plans for the next 20.
For the scientists old enough to remember a time before it, there’s something both visually and conceptually improbable about the Buck Institute for Research on Aging.
From a 30 mile drive north of San Francisco, the bone-white modernist campus sits at the foothills of Marin County’s Mount Burdell. Looking out on a clear day, deer and horses can be seen grazing in the bordering Olompali State Historic Park; on an overcast one, the Buck rests at the shore of an endless sea of cloud that stretches far off to the horizon.
In a landscape suited to dreams of an almost Olympian grandeur, the Buck’s placement as the first biomedical institute dedicated to aging would have seemed strange to many when it first opened its doors in 1999. Back then, aging researchers were situated in popular consciousness at a grey hair’s breadth away from cable TV charlatans promising cure-alls for eternal life.
Fast forward to now, and as the best funded and most prestigious institute for aging research in the world, the Buck has, well, bucked this trend. The Institute’s projects and collaborations are wide and deep, spanning the full width of the Longevity field. From ground-breaking work on senescent cells to collaborations with Juvenescence, there aren’t many advances in the anti-aging space that the Buck hasn’t played a part in.
Following the launch of two spin-outs emerging from his work (NAPA Therapeutics and BHB Therapeutics) and on the eve of the Buck’s 20th anniversary, Longevity.Technology joined President and CEO Eric Verdin to discuss the past, present and future of aging research at his remarkable Institute.
Longevity.Technology: We’re very interested in your background. Before going into aging research, your work began with a particular focus on the immune system, especially in regards to the molecular virology of HIV, for instance. What came first for you? Your interest in the immune system? Or your interest in the mechanisms of aging, of which the immune system happened to tie into?
Eric Verdin: I started out working on the molecular biology of HIV. I was trying to understand how the virus worked and how we can tame it. During that work, we ended up cloning a family of proteins, called Sirtuins. And Sirtuins ended up being involved in aging! That’s when, about twenty years ago, my lab took a new direction — into aging research.
But there’s always a vast amount of benefit to having expertise in both. For instance, we’ve noticed that something really interesting is happening with the immune systems of HIV-infected patients — even though the virus should be suppressing their immune response, the systems all tend to show signs of accelerated aging, producing more chronic inflammation, which is why we’re considering getting more involved in HIV research again. We want to answer that question.
Longevity.Technology: We’ve spoken to people who got into aging from an endocrinological, insulin-dependent, angle, as well. The fact that aging is woven around so many of the body’s vital biological pathways means there are myriad ways to attack the research — it’s fascinating.
Eric Verdin: Absolutely, and coming at it from the HIV angle as I did, I thought it was an excellent way to bring an expertise that is, for some reason, lacking from the aging field. Immunology is a complex field so that it can intimidate many people getting into it, at first. But it’s essential to understand the process of aging.
Longevity.Technology: Is that because the two are tied together by chronic inflammation? Are we moving into senescence territory?
Eric Verdin: Exactly that.
To explain what chronic inflammation is, I may need to explain acute inflammation first.
Acute inflammation is something our bodies do that we all intuitively understand. If you have an infection (let’s say on your skin) the wound will turn warm, red and swollen. So it’s a very local problem, and the inflammation comes from all of the immune cells swarming in to fight the pathogen.
Now there’s another form of inflammation — chronic inflammation — that doesn’t come from infection; it comes from age. As we age, a pathway linked to tissue repair gets aberrantly activated and produces a lot of unnecessary inflammation. And it’s this inflammation that we see connected to many of the chronic diseases of aging. There’s a protective mechanism that has now become a part of the problem. There have been many proposals as to why that happens, and one of them is senescence. We don’t know the full picture yet, but we’re excited to be looking into the immunology and trying to figure it out.
Longevity.Technology: This November you’ll be entering your third year of tenure as President and CEO of the Buck Institute. The last four years have seen a rapid acceleration in the number of people talking about, and investing in, Longevity technologies. What do you think is driving that?
Eric Verdin: There are two major reasons. Firstly, there’s the population from a societal point of view. The population is aging: the fraction of people about 65 is rapidly growing in most of the western world, and a lot of the baby-boomers are entering the more advanced years of their lives. We’re all becoming a lot more aware of that shift.
Secondly, we have to reckon with recent scientific advances. The study of aging, in our modern understanding of it, is about 25 to 30 years old. The science is now entering a mature stage, going beyond just asking questions. We’re now wondering if we can start applying our knowledge. So, at some point, we have to see if we can test this on people.
Longevity.Technology: That’s quite a tipping point. Because it can really go one of two ways, it can translate out of the models well, or it can present immediate roadblocks.
Eric Verdin: Yeah and I think it’s going to be based on past experience. People will initially start thinking that everything is going to be solved because we can do it in mice. However, when we look at other fields, it’s quite easy to cure mice of a whole series of diseases and ailments. Then when you start in humans, it gets a whole lot more complicated. Right now, the field is brimming with optimism that we will be doing amazing things — and I’m sure we will! But I’m also sure there will be some bumps in the road.
Longevity.Technology: We saw a clip of the Buck’s Dr Judy Campisi. She was saying that if you were to go to a typical aging symposium, you would hear lots of science talks, but you wouldn’t hear people asking questions like: “What’s the most important thing we don’t know?” So, here we go: What is the most important thing we don’t know?
Eric Verdin: In the last 20 years, we have gained an understanding of the whole series of pathways that play a significant role in how we age and how quickly we age. What we don’t know is how to put them all together.
Right now, people are talking about how aging is pleiotropic (caused by multiple things). But I hope we’re going to be able to find a central theory of aging. Some will argue that it doesn’t exist; my feeling is that no theory exists until we discover it. We’re deep into the forest, and we can only describe the trees at the moment. It’s the same as the parable of the elephant in the dark room — the person at the trunk can describe the trunk, the person at the tail, the tail, and they’re all so sure that their theories of what they’re describing couldn’t possibly join up.
If you want specifics into known unknowns, we know there’s a direct correlation between size and lifespan. Smaller animals have much shorter lives, sometimes dramatically so compared to larger ones, and we have no idea why that’s happening. There are also glaring exceptions to this rule: Things that are mouse-sized can live for two to three years, but bats can reach 30 to 40!
Longevity.Technology: Who is looking into these comparative biology problems?
Eric Verdin: Oh there’s a lot of really top-class scientists working on this stuff, Rachel Brem is working here at the Buck on a novel technique to investigate this, we have Steve Austad at Alabama, Vadim Gladyshev at Harvard. It’s a tricky area of biology because you’re not just looking at one species but at many, but that also means the insights into the biology are going to be profound.
Longevity.Technology: We’re also very interested in some of the commercial spinouts you’ve been working on. Take us into your work with NAPA therapeutics, NAPA’s work is to find drugs that boost NAD+ levels, yet there are already supplements on the market that do the same by dosing NAD+ straight into the body. What’s different about NAPA’s approach?
Eric Verdin: Yeah, very good. So we know that NAD+ levels decrease during aging, so the question is: What is the cause? The supplements work by putting NAD+ into the body and then you can raise the levels somewhat. But what’s happening in the body is that, as we age, there are more and more proteins that are chewing up NAD+. The NAD+ is effectively leaking out, so taking NAD+ supplements is like pouring water into a leaky sink. We’re trying to understand the cause of the leak and what we can do to plug it. And that will come from identifying those proteins. That’s the difference in our approach.
Longevity.Technology: You’ve also said that if you take too many NAD+ supplements, they could have a downstream effect of promoting cancer?
Eric Verdin: Yeah, I think I was a little more circumspect than that. Some tumours use increased levels of NAD to grow. So I’m more concerned about it being a possibility than convinced that it’s a reality. There could be increased cancer growth from it, but we don’t know for sure. Biological regulatory systems exist in a fragile equilibrium with each other. When we add drugs to that, you never know where you’ll shift that equilibrium to. We have to be careful.
Longevity.Technology: And that’s because there are arguments out there that the things promoting aging could also be inhibiting tumour growth.
Eric Verdin: Exactly. One thing that distinguishes the aging field from other fields of medicine is that if you are giving someone a drug and they’re ill, then you’re trying to solve a problem, but if you’re giving someone an anti-aging drug, then you’re treating people who are already in good health. You’d better be sure that what you’re doing is going to be making them live better and longer. There’s always the risk that you’re going to make their lives shorter and more sickly.
Longevity.Technology: This raises a perennially interesting question: How much should we regulate a nascent field? What do you think of the FDA’s work on aging?
Eric Verdin: There’s a whole group of people in the aging field who think the FDA is the enemy, and that it’s slowing down progress. I think the FDA is the best friend we have. One of my biggest fears is that someone is going to deploy an anti-aging therapy in humans too fast, that it’s going to make people sick, and that’s going to be the end of the field. We saw the same thing with gene therapy in the late 90s. A treatment killed an 18-year-old patient, and the whole field was shut down for 20 years. We have to be cautious, but that doesn’t mean we can’t try. “First do no harm,” when you graduate from medical school, that’s the first thing they teach you.
Longevity.Technology: The Hippocratic oath! Tell us a little bit more about another Buck spinout which you’re personally involved in, BHB therapeutics?
Eric Verdin: We, and others, have discovered that if you go on a special diet — called a ketogenic diet — you tend to see a lot of the benefits associated with an increased lifespan and healthspan. We’ve replicated these results in mice, and there are many people, as well, who have seen benefits from ketogenic diets.
The problems are that it’s not always an effortless diet to adhere to, so there’s a lot of interest in trying to extract the critical aspect of the diet: the body’s increased production of ketone bodies. The most influential ketone body is called BHB (Beta-Hydroxybutyrate) and we, as a company, will be trying to give it to people who are on a more standard diet. We want to see if it recapitulates the benefits of the ketogenic diet.
Longevity.Technology: You have a 2017 interview with Dr Rhonda Patrick where you said that this is the big question you had. Now that you’re using a spinout to look into this in more detail, how much closer are you to answering it?
Eric Verdin: We are getting very close to testing it very rigorously. We’ve synthesised a series of imagined products, esters of BHB — which will carry the BHB into the body. And we’re about to test that delivery method in a whole variety of different models.
Longevity.Technology: That’s very interesting. How close would you project NAPA and BHB towards having available products?
Eric Verdin: So we’re talking two somewhat different models. BHB is likely going to be sold as a supplement, and as soon as we’re able to demonstrate that we have a safe and effective delivery system for BHB we’ll be ready to roll it out. We’re predicting within a couple of years.
The process for NAPA is going to be a lot more complicated, we’ll be looking for drugs that inhibit the ‘leak,’ which will need a much more traditional form of development. That’s looking more like five to ten years.
Longevity.Technology: And what about the short term challenges facing the rest of the field? Let’s say over the next five years?
Eric Verdin: One area that I find exciting, as we consider moving these discoveries into the clinic, is a relative lack of biomarkers of aging. Let’s say you’re developing drugs to fight cholesterol, you’ll need to measure cholesterol in the blood, right?
The problem with drugs and aging is that you end up doing a clinical trial for 50 years just to see if the drugs that you’re testing work. And absolutely no one wants to do that. So there’s a field of active investigation that’s trying to identify things that are detectable in the blood and predictive of how well you are.
We all have two different ages, we have our chronological age and our biological age; the latter being how healthily you’re aging. Even starting with people at age 40, for example, we’re able to distinguish the children of centenarians from non-centenarians.
There’s a growing need to develop a series of comprehensive biomarkers that we can measure in the blood. We want to be able to measure them in people and see whether certain therapies and recommendations are working to improve how they age. And that’s what we want to build here, as well — a whole programme on the biomarkers of aging.
Longevity.Technology: So this is touching on the work done by Steve Horvath on methylation?
Eric Verdin: The Horvath’s Clock is the first example of a biomarker for aging, and it’s been great for pointing people towards thinking that we can develop more. The problem is it may not be the whole answer, there are many people in the field who feel that we may need additional markers.
Longevity.Technology: Is there any indication right now of what those markers might be?
Eric Verdin: Yes, people are looking at transcriptomics (measuring all the ways that genes are synthesised) there’s proteomics (which is how proteins are made, and is currently being looked into by Judy Campisi and Birgi Schilling at the Buck. They’ve been able to identify a series of markers that senescent cells churn out) and finally there’s metabolomics. There’s a lot of novel technologies that let you look into all three of those categories for new biomarkers of aging.
Longevity.Technology: And finally, what have been the Buck’s most exceptional contributions to the field of aging in the past 20 years, and what do you think the next twenty may bring?
Eric Verdin: We’ve talked about senescence and the work of Judy Campisi, which has emerged as one of the major pathways. There’s the changes in mitochondrial function, as studied by Martin Brand. My lab does stuff on protein modification.
If I were to zoom out and tie all of those, and many other great contributions, into a bigger picture, I’d say the most significant accomplishment is the creation of a molecular understanding of what aging is.
We’ve made aging a tractable, respectable subject of investigation. And we’ve brought it to the point where pharma and biotech companies are coming to us with targets that we can identify.
The next challenge, and the biggest one over the next twenty years, is to do in humans what we have already done so successfully in mice.
All images courtesy of the Buck Institute for Research on Aging