Fall 2017

Science and Environment

Interview

How to Undo Aging

Dan Cloer

Neurobiologist Michael Fossel is actively working on a way to cure age-related diseases. He and his colleagues are targeting Alzheimer’s in particular. Other researchers, he says, “hope to merely slow the disease. They don’t think they can actually stop it or reverse it. We do.”

Michael Fossel, like most of us, didn’t think about getting old when he was a child. But now, he says, “I’m 66 and I want to avoid some of the problems” of aging. To that end, as a medical doctor and neurobiologist, he specializes in the treatment of age-related disease. Fossel has written numerous articles and books, from Reversing Human Aging (1996) to The Telomerase Revolution (2015), as well as a textbook on the subject. He is the founder and president of Telocyte, a biotech company that aims to cure Alzheimer’s disease. Vision’s Dan Cloer spoke with him about his pioneering work.

 

DC       We see an increased interest in regenerative medicine these days—stem cells, gene therapy, genetic engineering. Is it inspired by baby boomers getting older? There’s a lot of money and sway in this aging bubble of people.

MF      Maybe, but it’s also true that aging isn’t new. People have always gotten old and had Alzheimer’s, arthritis and osteoporosis; but a thousand years ago there weren’t as many of them. Some people have always lived to a hundred; but now there are more of them, so diseases of aging are a more pressing problem.

In the United States in the 1950s polio was rampant, but less so in the United Kingdom and many other parts of the world. The fact that it was happening in a very developed country with a lot of money made it an incredibly pressing issue. So here we had the March of Dimes and the development of the vaccine that eradicated the disease.

I found some projections for polio rehab in the 1950s—care, leg braces, iron lungs—predicting that by 2000 the costs would equal the Gross National Product. That didn’t happen. Now we’re worried about the same thing in regards to Alzheimer’s disease. And I suggest that won’t happen either, but only if we make some advances.

DC       Theories about life span have shifted dramatically from ideas of cell immortality to current models of wear and tear causing aging. I believe your view is that there’s a battle between degenerative and regenerative processes, and that aging is the process of losing that battle.

MF      That’s essentially correct, but some people say aging is just a matter of entropy—just wear and tear, which is simplistic. You’d have to explain why dogs have seven times the entropy we have. Aging isn’t just entropy; it’s entropy in the face of maintenance. It’s a balance between the two. That makes a lot of sense. It actually explains what we see around us—what I call a reverence for reality.

Look at physics, for example. A hundred years ago physics went through the quantum mechanics and relativity revolutions, because our concept of reality changed. We saw the world in a new way. Before then, classical physics had just been about day-to-day things: we looked at known forces and saw objects, even atoms, as simple “billiard balls” rolling around. When we began to look carefully at the very small and the very fast, new theories were needed. Atoms aren’t merely billiard balls, and we had to reevaluate our view of the world.

The same thing is true in biology. If I only look at aging in people, dogs, cats and cows, then clearly everything ages. But if we examine biology more deeply, the reality is more complex. Some things don’t age. The question is why some cells age when others don’t. And why do some organisms age faster than others? There are times when cell maintenance is essentially perfect. These cells aren’t immortal, but they don’t age, and they have an indefinite cell life span. How malleable is this maintenance program? As it turns out, we can now reset aging in cells and tissues, but how can we apply our understanding to extend the healthy human life span?

We can now reset aging in cells and tissues, but how can we apply our understanding to extend the healthy human life span?”

DC       Several genes involved with aging have been discovered in fruit flies and round worms. But your explanation of aging is not genes but how genes are expressed—turned on or off—and this is affected by telomere length.

MF      Each species has genes involved with aging, but how they operate is different because each species has its own pace of aging. Compare a dog to a human; we have similar genes but don’t age at the same pace. But whatever that pace is, the mechanism of changing gene expression is the critical factor in aging. Shortening telomeres result in a changing pattern of gene expression, and the result is loss of cell maintenance and aging. Aging isn’t so much a matter of genes as it is of changing gene expression. As we get older we gradually turn down the expression of genes that are responsible for cell maintenance, and entropy begins to get ahead. No wonder we age.

When we look at age-related disease, and Alzheimer’s is just one example, the model that we’ve been promulgating for 20 years—the idea that telomeres, epigenetic changes and cell senescence are the key to understanding aging—is consistent with all known data, and that’s not true of other models. Our model is complete in that it explains all age-related human disease from a pathological perspective, and so far it’s been predicatively valid as well. For example, last year when Eli Lilly announced their clinical results for Solanezumab (an Alzheimer’s drug), we predicted ahead of time what the data would look like, and we were right on. That doesn’t mean we are right, but having a model that predicts correctly is a good sign.

DC       Do you have a name for your model? Telomere Theory of Aging? Senescence Theory?

MF      I think of it as the epigenetic model of aging. I don’t call it the Telomere Theory of Aging because that implies that telomeres cause aging. I’m not saying that at all. My suggestion is that telomeres are just one portion of an aging cascade. My interest is in finding the best point of intervention to prevent and reverse age-related disease. Telomeres are probably the single most effective point of intervention, because they affect the epigenetic pattern of gene expression throughout all the chromosomes.

Here’s my analogy. Think of a high-speed boat going across a lake. We travel back and forth across the lake without a problem. That’s just day-to-day life when we’re young and healthy. Below the surface are rocks and snags and sand bars, but the water is high above them, keeping them hidden. These are our hidden genes—for high cholesterol, ApoE4 [the gene associated with increased risk of Alzheimer’s], hypertension, etc. But as time passes and the lake level goes down (as telomeres shorten and gene expression changes), these hazards will become exposed. So what causes us to hit the rocks? Is it the rock? Or is it the dropping water level?

The practical question is, what can you do about it? Most people argue that you need to “blow up” the rocks; that is, treat the cholesterol, fix the “bad” gene, lower the blood pressure. But the rocks and the water are both important, so why not just raise the level of the water again? Not only is that doable, but it deals with all the genetic problems at the same time. That is what telomerase does.

DC       In terms of regenerative medicine, that idea seems to create fewer cellular pushbacks than attacking the genes or trying to replace cells with engineered stem cells. So the idea is not to excavate the rocks, or replace the lake, but just to keep the lake full.

MF      Yes. If you have a particular rock that sticks up and is a clear danger, like sickle-cell disease, the level of the lake is not the main problem. But for age-related diseases, it’s not the rock, it’s the water level. So it’s a practical question of what to do. In the case of a genetic disease like sickle cell, you need to deal with the rock; but in the case of age-related diseases, you reset the level of the lake.

You could make the case for going in and altering each and every gene, but in the case of the entire gamut of age-related diseases, you’re dealing with thousands of genes. If you try to intervene further downstream from the genes, you can aim at each of the various proteins, such as beta-amyloid or tau in the case of Alzheimer’s. Or in the case of heart disease you can treat patients with stents, statins and even heart transplants. These approaches are not only expensive (and there are complications and side effects), but they don’t treat the underlying pathology at the epigenetic level. The question is, where is the single most effective point of clinical intervention? Where do you get the most bang for your buck? The answer is the telomere.

But don’t confuse the telomere with aging. The telomere doesn’t cause aging; it’s simply the most effective place to cure age-related disease. This really is a theory of aging, not just telomeres. More importantly, a proper theory of aging needs to be testable. Many so-called theories of aging are not; they are philosophies of aging. But to call it science, it must be testable. Our theory is not only consistent with everything we know about aging and disease, but it’s practical and clinically testable.

A proper theory of aging needs to be testable. Many so-called theories of aging are not; they are philosophies of aging.”

DC       How does molecular biologist María Blasco’s paper fit into the founding of Telocyte?

MF      We knew 18 years ago that we could reverse aging in human cells. Cells in tissue culture would reset their gene expression profiles when their telomeres were restored to a young state. Geron [a biopharmaceutical company] did this with human tissues soon after. Of course, we are organisms, so the primary question is whether we can reverse aging in animals and humans, not just in cells and tissues. A few years ago, [Ronald] DePinho edited the germ line of mice to switch on telomerase. It was a fascinating approach, but not a technique we could use with human patients.

María Blasco used a technique that could be applied directly to human beings. We use this same basic approach in our protocol with the FDA [the US Food and Drug Administration], and we will be starting our human trial next year.

DC       What will happen in this trial?

MF      If it goes as we currently plan it—because there could be changes between now and then, of course—there will be 12 patients with moderate Alzheimer’s disease. This in itself is very different than what everybody else in the world is doing; they’re all looking for early Alzheimer’s, because they hope to merely slow the disease. They don’t think they can actually stop it or reverse it. We do.

Our human trial will probably be done in Kansas City at the University of Kansas Alzheimer’s Disease Center. We’ll be injecting a virus that carries a normal human gene for telomerase. We should reset telomere lengths and demonstrate clinical improvement in one or two months. It’s a six-month trial.

Michael Fossel has graduate degrees in psychology, neurobiology and medicine. He was a clinical professor of medicine at Michigan State and other universities for more than 30 years before founding the biotech firm Telocyte.

Portrait ©Michael Fossel

DC       Elizabeth Parrish, the head of another biotech company, actually took a telomerase gene-therapy treatment herself. She doesn’t have Alzheimer’s, but she wanted to test the telomere-lengthening claim using her company’s protocols. Do you think this is helpful in getting gene therapies to patients?

MF      This brings up a question of compassion, which is difficult to answer. If you ignore the FDA, then you can treat one person for a million dollars, but you have to go to Colombia and Bali, where there’s no FDA oversight or regulatory compliance. If it works, the FDA, the NHS [the UK National Health Service], the American Medical Association, physicians, hospitals and insurance companies won’t believe the results, because they lack credibility.

If I ignore the FDA, then I can offer this treatment to the very few people who can pay several million dollars and fly off to Bali for the single treatment. On the other hand, if I carefully go through accepted FDA trials, then it takes at least two years to demonstrate that we can cure Alzheimer’s, which is a long time to wait. But we can treat everyone and for far less cost in the long run. Our emphasis is credibility; we don’t want to miss anything or have anyone be able to say our results are not believable. They may say that because they don’t believe we can do it, but we don’t want them to say it because we ignored the FDA or did our trials in Colombia. In short, we want to do it right, and we want to be sure about both safety and efficacy.

The advantage for us is having global credibility (meaning acceptance by major health-care systems, insurers and patients). The disadvantage is that patients are dying of Alzheimer’s disease, and none of us want to see delays in finding a cure. You can treat fewer patients for more money quickly, or you can treat far more patients for less money, but it takes two more years to get there.

So which approach is right? I don’t know, but I know what we’re going to do: We’re going through the FDA, we’re going to be sure it’s safe, and we’re going to cure Alzheimer’s disease. But I don’t want to cast stones either.

I know what we’re going to do: We’re going through the FDA, we’re going to be sure it’s safe, and we’re going to cure Alzheimer’s disease.”

DC       The tricky and expensive part is to build a virus particle that will deliver the gene to the right cells, the glial cells of the brain?

MF      Everything is complicated, but that’s the basic plan, yes. The gearing-up process is the big cost. Imagine if I wanted to build the first iPhone from scratch; it would cost a ton of money. But now, with such volume, the actual cost of making one is a bit more than $200, even if the commercial price is several times that.

Making a therapeutic virus follows the same pattern. For our 12 patients, it will cost $2 million. But even that cost is less than the cost of treating Alzheimer’s patients in the nursing home for a few years, and that cost will fall once we get past the initial phase. The best estimate right now, without considering lower costs due to volume or improved techniques, is about $40,000 per patient for this treatment. That’s not bad to cure your Alzheimer’s. Compare that to Alzheimer’s care, which runs about $100,000 a year, and Alzheimer’s patients typically spend several years needing that sort of expensive care. It will be a lot cheaper for us to cure Alzheimer’s than to watch people go downhill in nursing homes. Better yet, the costs drop as the volume increases. It’s a lot cheaper per patient for us to treat 12 million patients than to treat 12, and the final cost will be a lot lower than you might imagine.

I think there’s a greater potential for what we’re doing than for what’s happening with stem cells. The first articles I wrote about this were 20 years ago (1997) in JAMA [Journal of the American Medical Association]. If we’re right, I think two things will occur. One, we will be able to essentially wipe out—that is, prevent or cure—most age-related human disease. And two, this approach will reduce global health-care costs by 95 percent.

DC       And the emotional costs and suffering that could be avoided are incalculable.

MF      Yes. I call Alzheimer’s the disease that steals souls. I think we can give some of those souls back.

I call Alzheimer’s the disease that steals souls. I think we can give some of those souls back.”

DC       The downside most people note is that telomerase is associated with cancer cells. Twenty years ago you wrote that telomerase doesn’t cause malignant transformation—the conversion of normal cells to cancer cells. Is that still true?

MF      That’s still true, but it gets wildly complicated. It is clear that telomerase does not cause cancer. On the other hand, telomerase can be permissive of cancer under certain circumstances.

Imagine a very long telomere and a really short telomere. Cells with long telomeres have very active DNA repair, and so they’re continually preventing malignancy. Cells that have lost their telomeres are not repairing their DNA, but they’re also not dividing; they’re senescent, so these are not much of a risk. The risk for cancer comes just before the cell senesces, when repair is slow but the cell is still dividing. What we would like to do is reset the telomere so that it is longer in this high-risk zone. You don’t want to just lengthen the telomere back just a tiny bit, to the point where cell division is still happening but where repair is badly down-regulated [turned down]. About 92 percent of clinical cancer cells have telomeres that are just long enough to sustain division and growth but not long enough to up-regulate DNA repair. That’s the problem.

I think we can use telomerase to actually cure or prevent cancer. There are four families of DNA repair mechanisms, and each one gets down-regulated as the telomere shortens. We can up-regulate them if we lengthen the telomeres, making it easier for the cell to repair errors and damage.

DC       This would be an almost miraculous change in how we do things. Do you sometimes feel like the guy who said that bloodletting was a bad idea?

MF      Yes. I used to do consulting about global health records and the standardization of care. Standardization is good, but if standards did not progress, we would still be bloodletting. You’ve got to allow for innovation and change.

Most people still can’t get their arms around telomerase therapy. They still think aging “just happens,” everybody “rusts”; they think aging is just entropy at work. After all, they think, when it comes to aging, what can you expect? But nature isn’t that simple; nature is more interesting than that. Aging is a far more complex phenomenon than most people realize, and our intervention is therefore a remarkably innovative approach. As I often say, everyone is in favor of innovation and diversity unless you are innovative or diverse.

There’s a book by Elizabeth Blackburn about telomeres [The Telomere Effect]. She won the Nobel Prize about eight years ago for her work on telomeres, and she well deserved it. But what she did is sort of the equivalent of doing the crystallography of the polio virus, which described its shape and core proteins. That’s useful information, but not as useful as finding something that will stop polio. She’s a very good scientist, but she doesn’t see the value of telomerase to stop disease. To her it’s a marker of aging; for me it’s a point of intervention.

It’s like the castaways on a desert island discovering a metal structure. They measure it carefully and decide it’s a good place to get some shade or lay clothes to dry or get inside out of the rain. But I see that it’s actually an airplane that we could turn on and fly off the island.