Last week we heard the theoretical side of Dr. Michael Fossel’s mission to bring aging to its knees, and why his chosen point of attack was on the grand orchestrator of the body’s repair processes. This week he goes into the practical details: how does he plan to lengthen telomeres? What can we treat with such a therapy? Is it safe? And just how long could we live in the end, anyway?
Dr. Fossel, isn’t it a bit early to expect telomerase therapy to reverse aging in humans?
Actually, if you asked me when we would first able to reverse human aging, technically I’d have to say it already happened back in 1999. That was when we showed in the lab that when you reset the telomere length in individual human cells like fibroblasts, you reset the pattern of gene expression, and then they act like young cells.
Alright, but that’s cells. Let’s get a little more realistic: what about human tissue? There, the answer is the year 2000, when someone showed that you could grow young human skin cells. I used to joke back then that I could strip off your skin and give you a whole new one, reset your telomeres and then graft it all back again. (Of course, in the meantime you’d be dead.) And likewise you can do the same thing with endothelial cells, vascular structures, bone, and a number of other tissues. But if you look at the data on the supplement TA-65 and a number of other things, it’s just not impressive. It is suggestive and intriguing, though.
There are at least four ways, probably five, that we can reset telomeres in patients. The problem is that we need techniques that allow us to actually do that. Ronald DePinho at Harvard did some really nice work seven years ago where he showed that you could reset aging in a number of ways, including on behavioral measures. But what he’d done was to alter the germ cell line so that he could turn telomerase on and off. I can’t do that to you! Then Maria Blasco, a collaborator in Spain, did the same thing with gene therapy. And the viral vector she used has been used in humans already, so we can actually do this now.
How will that work in practice? Is telomerase therapy something patients will only need to do once?
Well, there are a couple of odd variables. Let’s say I put a telomerase gene into one of your cells and it resets your telomeres. The first question is, how long does it stay there before the tears up the little plasmid that I put in there, because it’s not on your chromosome? The answer is that it gets torn down at a certain rate that’s a little hard to predict, since it depends on which cells and which species you’re looking at. But it also depends on how fast your cells divide. If I put one little plasmid into a microglial cell and it divides, now I’ve got one cell with the plasmid and one without, or two with half a plasmid. So if this happens every time your cells divide, the more rapidly they divide, the less they have the telomerase. It’s not like I’ve made you immortal–all I’ve done is reset your telomeres and gene expression, and they will un-reset again over time.
I actually see this as an advantage in several ways. One of the academic fads in the last twenty years (that’s not well-substantiated) is that telomerase causes cancer. It really doesn’t, but it is permissive of cancer. Even then, telomerase’s effect on DNA repair means it’s a genomic stabilizer which decreases the rate of new mutations. That doesn’t mean telomerase is totally safe though.
I think of it as three different zones a cell can be in. If you have long telomeres, you repair DNA really quickly. If your telomeres are short enough, the cell can no longer divide, so it’s damaged, but it’s not a complex problem. But if they’re a bit less short, your cells are still dividing but you’re not repairing damage–cancer disaster. Most cancers maintain their telomeres just long enough that they remain unstable from a genetic standpoint, but not long enough that they can repair. So if I give you telomerase, I want to make sure that I either give you a lot, enough to get through that risk zone, or none at all.
While a lot of what I’ve just told you is based on theoretical constructs, there’s a fair amount of data that suggests that telomerase could be protective against cancer. Back twenty years ago, one of the first longevity companies, Geron, basically had three groups of patents: telomerase inhibition, telomerase activation, and stem cell work. The only one they kept was telomerase inhibition for cancer treatment, and yet here they are twenty years later and still without a product. It’s kind of a disaster from a biotech standpoint. So I suspect that we’ll be able to find a way to use telomerase as a protection against cancer, but things get so complex and so messy that the last thing I want to do is turn telomerase on and just walk away. I’d like to turn it on transiently and make sure that I don’t step in a hole I didn’t know was there.
Will telomerase be effective in treating diseases that affect terminal cells, like neurons, which don’t divide and therefore don’t experience telomere shortening?
That’s what you might think, but it gets complicated. First let me say that adult neurons do divide, just not very often, so that old saw about neurons not dividing technically isn’t true. But practically speaking, you’re dead on. While microglial cells divide all over the place, and oligodendrocytes do but not very often, it’s taken us centuries to track down a neuron doing that. So let’s assume you’re right. It turns out that that’s not the problem, though. In a disease like Alzheimer’s, neurons are basically innocent bystanders, and it’s the microglia that are causing problems. And that’s become a sort of consensus over the past five years, although people disagree about exactly what that means.
I used to see the same sort of misunderstanding when perfectly good scientists would say that cell senescence can’t possibly play a role in heart attacks because myocardial cells don’t divide. Well, nobody ever claimed myocardial infarctions starts in the myocardium–it starts in the primary arteries. So to say cell senescence can’t cause heart attacks would be like saying cholesterol can’t cause heart attacks because it doesn’t accumulate in muscle cells. Well, of course it doesn’t, it accumulates in the arteries, and the myocardium is minding its own business when the coronary artery comes along and steals its blood supply.
Do you expect telomerase therapy to work well on certain diseases of aging, but not on others?
That’s the interesting thing, it should work on almost any age-related disease, including the dementias broadly, and even ALS. The much bigger target is vascular aging. In almost every community in the developed world–and a lot of the undeveloped world, too–the major cause of death is arterial aging.
But I’m going after Alzheimer’s strategically, even though it has a smaller patient population and you’re much less likely to die of it. People tend to be much more frightened of Alzheimer’s than they are of heart attacks. If I tell you that you have a 50% chance of having a heart attack in ten years, we can lower your risk, give you a statin, in an extreme case we could spend an incredible amount of money and give you a heart transplant. The point is, you have options. But if I say you’ve got a 50% chance of getting Alzheimer’s in ten years, it’s really hard to come up with something that everyone agrees would be effective. It’s a much scarier disease because options are fewer, and they’re harder to credit directly. So it’s a more tempting target.
Another reason to go after Alzheimer’s specifically, rather than aging more broadly or a disease like osteoporosis, is that if I go to the FDA and tell them we could wipe out osteoporosis, the problem is that no one has ever died of osteoporosis. They die of complications related to it. You fall down, break your hip, and the next thing you know you’ve got pneumonia and die in the ICU. But osteoporosis itself isn’t fatal.
So imagine you’re the FDA commissioner and I tell you I want to give some group of patients an experimental gene therapy that we’re pretty sure won’t cause cancer, but we can’t prove it to you, and we want to use it to treat osteoporosis. Reasonably enough, you’re going to ask if I’m out of my mind. Likewise, if you’re a patient you’ll say, “I think I’ll stick with my phosphates and calcium, and you can get back to me in a couple of years.”
But that’s not what happens when I come to treat Alzheimer’s. If I say I think the risk of cancer in our treatment is very low, but I can’t prove it yet, most people on the FDA committees would grab it in a heartbeat. So it’s a lot easier from an ethical standpoint, a patient volunteer standpoint, and from a regulatory standpoint generally. But we suspect that we can essentially treat all human age-related disease in a way that has never occurred in human history, and after the dementias, the next target is vascular aging.
How would this affect healthcare costs?
I think it could lower the global cost of healthcare by something in excess of 95%. Right now the US spends about 20% of GDP on medical-related care, and of course that includes a lot of things, not just drugs. But what if we could actually lower it, rather than raise it? And I think we can do that.
Even if people are living quite a bit longer?
Yeah, I think so.
I’m not ever going to suggest we won’t die, I don’t care how well you take care of your 1930 Duesenberg, and if nothing else you might get wiped out by an asteroid sometime. But what if, instead of living getting old and cranky at sixty like our grandparents did, and coming down with Alzheimer’s at some godawful age–a third of Alzheimer’s patients are younger than I am, by the way–what if you could live to be 200 before coming down with some sort of dysfunction? That means you’ve got 200 years not only of life and pleasure and family, but also to invest or put some savings aside to deal with those costs at the end.
So I think we can do a much better job than we do now. I think back on the old days, when I would gather progeric kids from around the world and camp in front of the White House, and dealing with that disease is expensive. These kids can die of all sorts of things.
You mention 200 years–is that how far you think telomerase therapies could extend human lifespan?
I think we’ll do a lot better than that, but it’s hard to give you figures. One question is, how far back can we reset the pattern of gene expression? And how effectively have you repaired the damage?
In the last 15 minutes, you’ve probably had a DNA mutation in almost every cell in your body, and you’ve probably repaired it almost within a matter of milliseconds, certainly within a matter of seconds–it’s fast. But that probably didn’t repair it entirely. Even in young cells, you probably every now and then inherit a mutation, and that adds up.
If I take a sixty year old you and set your DNA repair back to what it was at twenty, even at twenty it wasn’t perfect, it was just damn good. The question is, how damn good? How far back can we reset it? I don’t know. I sometimes use the figure of 200 just to raise eyebrows. I suppose I could say 1000 years or 130 years. I don’t really have a way to predict it, and the variables are so many and so messy.
One of our questions is whether we can reverse the cognitive decline in human Alzheimer’s, like we’ve been able to do with animal studies. As you’ve probably seen, the problem with Alzheimer’s is not that you don’t have the memories, it’s that you can’t access them. But we’re finding that we can reset a lot of that, including neural stem cells and neural stem cell differentiation. So let’s say that at age sixty you’ve got Alzheimer’s, and I reset your telomeres to an age forty level–whatever that means. Well, in twenty years you’ll get it again, so does that mean you’ll need treatment again? Yes, it would, but what is the time to re-treatment? One year, twenty years, two years? I have some ideas, based partly on data and partly on theory, but the fact is that we can’t tell before we do it.
Tegan is Geroscience's lead editor, and writes on a variety of topics--mainly science, medicine, and humans--here and elsewhere on the web.