Michael Fossel Michael is President of Telocyte

January 23, 2018

Aging and Disease: 0.1 – A Prologue

Aging and Disease

0.1 – A Prologue

Over the past 20 years, I have published numerous articles, chapters, and books explaining how aging and age-related disease work, as well as the potential for intervention in both aging and age-related disease. The first of these publications was Reversing Human Aging (1996), followed by my articles in JAMA (the Journal of the American Medical Association) in 1997 and 1998. Twenty years ago, it was my fervent hope that these initial forays, the first publications to ever describe not only how the aging process occurs, but the prospects for effective clinical intervention, would trigger interest, growing understanding, and clinical trials to cure age-related disease. Since then, I have published a what is still the only medical textbook on this topic (Cells, Aging, and Human Disease, 2004), as well as a more recently lauded book (The Telomerase Revolution, 2015) that explains aging and disease, as well as how we can intervene in both. While the reality of a clinical intervention has been slow to come to fruition, we now have the tools to accomplish those human trials and finally move into the clinic. In short, we now have the ability to intervene in aging and age-related disease.

Although we now have the tools, understanding has lagged a bit for most people. This knowledge and acceptance have been held back by any number of misconceptions, such as the idea that “telomeres fray and the chromosomes come apart” or that aging is controlled by telomere length (rather than the changes in telomere lengths). Academics have not been immune to these errors. For example, most current academic papers persist in measuring peripheral blood cell telomeres as though such cells were an adequate measure of tissue telomeres or in some way related to the most common age-related diseases. Peripheral telomeres are largely independent of the telomeres in our coronary arteries and in our brains and it is our arteries and our brains that cause most age-related deaths, not our white blood cells. The major problem, howevere, lies in understanding the subtlety of the aging process. Most people, even academics, researchers, and physicians, persist in seeing aging as mere entropy, when the reality is far more elusive and far more complex. Simplistic beliefs, faulty assumptions, and blindly-held premises are the blinders that have kept us powerless for so long.

It is time to tell the whole story.

While my time is not my own – I’d rather begin our upcoming human trials and demonstrate that we can cure Alzhiemer’s disease than merely talk about all of this – I will use this blog for a series of more than 30 mini-lectures that will take us all the way from “chromosomes to nursing homes”. We will start with an overview of aging itself, then focus in upon what actually happens in human cells as they undergo senesceence, then finally move downstream and look at how these senescent changes result in day-to-day human aging and age-relate disease. In so doing, when we discuss cell aging, we will get down into the nitty-gritty of ROS, mitochondria, gene expression, leaky membranes, scavenger molecules, molecular turnover, collagen, beta amyloid, mutations, gene repair, as well as the mathematics of all of this. Similarly, when we discuss human disease, we will get down into the basic pathology of cancer, atherosclerosis, Alzheimer’s, osteoporosis, osteoarthritis, and all “the heart-ache and the thousand natural shocks that flesh is heir to”. We will look at endothelial cells and subendothelial cells, glial cells and neurons, osteoclasts and osteoblasts, fibroblasts and keratinocytes, chondrocytes, and a host of other players whose failure results in what we commonly think of aging.

I hope that you’ll join me as we, slowly, carefully, unravel the mysteries of aging, the complexities of age-related disease, and the prospects for effective intervention.

December 31, 2017

Human Nature

Many of you have written to me, expressing surprise about the lack of public reaction (such as media interest) regarding the potential for telomerase therapy to treat age-related diseases. Some of you wonder why people (and particularly the media) “don’t get it”. I’ve had the same thought for a bit more than two decades now, since I published the first book and the first articles on the potential of telomerase therapy. The lack of understanding applies not only to the media, which is neither critical nor surprising, but to many in the investment community and to the pharmacology industry, which is critical if we are to save human lives.

The major reason for that lack of understanding is human nature. Most people have a firmly-held misconception about how aging works and never realize the error. Without thinking about it (which is the fundamental problem), most people think of aging as entropy. In reality, aging is a lot more complicated (as are most things). Aging isn’t the same as entropy; aging is the gradual inability of cell maintenance to keep up with entropy, which is a very different kettle of fish. Aging hinges on the balance between entropy and maintenance. If you think about it, that’s really what biology is all about: maintaining a extremely complex system in the face of entropy. Life is resistance to entropy. Life is continually building, recycling, and maintaining a complex system, that is continually coming apart, thanks to entropy. This is a balance that works quite well generally, which is why life still continues quite splendidly on this planet, a good three and a half billion years after it began. Who says you can’t resist entropy indefinitely?

Nor is aging universal, just because we see it in ourselves, our pets, and the animals we raise. In some organisms (some multi-cellular and some unicellular), aging never occurs. In other organisms (again, some multi-cellular and some unicellular), aging occurs quite predictably as maintenance slows down, allowing entropy to have its way as the organism ages, fails, and dies. While aging is a lot more than just entropy, most people never even begin to consider the facts and sail along with the unexamined assumption that “aging is entropy”.

It’s not that simple. It never is.

Nor are telomeres the “cause” of aging. Telomeres don’t cauase aging, they are just one (very important) part of an enormously complicated cascade of processes that result in age-related pathology and aging itself. Telomeres are important only because they play a key role at the crossroads of this cascade of pathology. Being at the crossroads, telomeres represent the single most effective point of intervention, both clinically and financially. Theye are the only place that we can entirely reset the gradualy deceleration in cell maintenance with a single intervention and it’s the only place that we can leverage our interventions into a strikingly lower cost of health care. Better care, for less cost.

The other problem that keeps people from appreciating the potential of telomerase therapy is inertia, or perhaps inertia and the fear of undermining their own careers. It’s not merely the inertia of never examining our assumptions, but the professional inertia that occurs when we suspect that – should we examine those assumptions – our entire professional lifetime of work may have been not only misdirected, but be seen as valueless, a truly frightening thought and an understandable fear. Human nature being what it is, the result is a stolid inertia from professionals who have spent many decades pursuing a faulty (and incomplete) model of aging and age-related disease. If any of us had spent 40 years of our professional life working for certain global pharmaceutical firms, for example, we would be loathe to give up the assumption that beta amyloid causes Alzheimer’s disease. After all, that model (despite lacking any support) has been the central focus, the raison-d’etre, for everything we have done professionally for several decades. Would any of us be willing to look clearly at reality, knowing that an honest, thoughtful, and careful appraisal of reality might suggest we had wasted those years, along with our personal efforts and dedication? It is asking too much of human nature. In a corporate, rather than a personal sense, this is equally true of drug companies that have invested hundreds of millions of dollars in what has now been proven to be a fruitless endeavor. The endeavor has been aimed at the wrong target, but it’s a lot of years, a lot of money, and a lot of effort, making it difficult to be honest about the prospects, let alone willing to go back to square one and ask if our assumptions were wrong in the first place. Old adages notwithstanding, people and institutions really do “throw good money after bad” and we do it both with a will and stunning consistency.

Yet, there is reason for a realistic optimism. Over the past two decades, there are a growing number of people who look at the data, reexamine their assumptions, and develop a close relationship with the reality of how aging works. That number continues to escalate, and the time when we can take telomerase therapy to an effective clinical trial continues to shrink. We see resources and commitment moving steadily toward a more sophisticated understanding of both Alzheimer’s disease and aging itself. The combination of resources and commitment will soon bring us to a new ability to treat diseases that, until now, have been beyond our understanding, let alone beyond our help.

We have the compassion to save lives; we will soon have the ability.

December 1, 2017

Big Pharma: Still Looking for the Horse

About a century ago, in a small American town, the first automobile chugged to a stop in front of the general store, where a local man stared at the apparition in disbelief, then asked “where’s your horse?” A long explanation followed, involving internal combustion, pistons, gasoline, and driveshafts. The local listened politely but with growing frustration, then broke in on the explanation. “Look”, he said, “I get all that, but what I still want to know is ‘where is your horse?’”

About three hours ago, in a teleconference with a major global pharmaceutical company, I was invited to talk about telomerase therapy and why it might work for Alzheimer’s, since it doesn’t actually lower beta amyloid levels. I explained about senescent gene expression, dynamic protein pools whose recycling rates slow significantly, causing a secondary increase in amyloid plaques, tau tangles, and mitochondrial dysfunction. The pharmaceutical executive listened (not so politely) with growing frustration, then broke in on the explanation. “Look”, she said, “I get all that, but what I still want to know is how does telomerase lower beta amyloid levels?”

In short, she wanted to know where I had hidden the horse.

The global pharmaceutical company that invited me to talk with them had, earlier this year, given up on its experimental Alzheimer’s drug that aimed at lowering beta amyloid levels, since it had no effect on the clinical course. None. They have so far wasted several years and several hundred million dollars chasing after amyloid levels, and now (as judged by our conversation) they still intent on wasting more time and money chasing amyloid levels. We offered them a chance to ignore amyloid levels and simply correct the underlying problem. While not changing the amyloid levels, we can clean up the beta amyloid plaques, as well as the tau tangles, the mitochondrial dysfunction, and all the other biomarkers of Alzheimer’s. More importantly, we can almost certainly improve the clinical course and largely reverse the cognitive decline. In short, we have a new car in town.

As with so many other big pharmaceutical companies, this company is so focused on biomarkers that they can’t focus on what those markers imply in terms of the dynamic pathology and the altered protein turnover that underlies age-related disease, including Alzheimer’s disease. And we wonder why all the drug trials continue to fail. The executive who asked about amyloid levels is intelligent and experienced, but wedded to an outmoded model that has thus far shown no financial reward and – worse yet – no clinical validity. It doesn’t work. Yet this executive met with me as part of a group seeking innovative approaches to treating Alzheimer’s disease.

Their vision is that they are looking for innovation.

The reality is that they are still looking for the horse.

October 10, 2017

Should everyone respond the same to telomerase?

A physician friend asked if a patient’s APOE status (which alleles they carry, for example APOE4, APOE3, or APOE2) would effect how well they should respond to telomerase therapy. Ideally, it may not make much difference, except that the genes you carry (including the APOE genes and the alleles for each type of APOE gene, as well as other genes linked to Alzheimer’s risk) determine how your risk goes up with age. For example, those with APOE4 alleles (especially if both are APOE4) have a modestly higher risk of Alzheimer’s disease (and at a lower age) than those with APOE2 alleles (expecially if both are APOE2).

Since telomerase doesn’t change your genes or the alleles, then while it should reset your risk of dementia to that of a younger person, your risk (partly determined by your genes) would then operate “all over again”, just as it did before. Think of it this way. If it took you 40 years to get dementia and we reset your risk using telomerase, then it might take you 40 years to get dementia again. If it took you 60 years to get dementia and we reset your risk using telomerase, then it might take you 60 years to get dementia again. It wouldn’t remove your risk of dementia, but it should reset your risk to what it was when you were younger. While the exact outcomes are still unknown, it is clear is that telomerase shouldn’t get rid of your risk, but it might be expected to reset that risk to what it was several years (or decades) before you were treated with telomerase. Your cells might act younger, but your genes are still your genes, and your risk is still (again) your risk.

The same could be said for the rate of response to telomerase therapy. How well (and how quickly) a patient should respond to telomerasse therapy should depend on how much damage has already occurred, which (again) is partially determined by your genes (including APOE genes and dozens of others). Compared to a patient with APOE2 alleles (the “good” APOE alleles), we might expect the clinical response for a patient with APOE4 alleles (the “bad” APOE alleles) to have a slightly slower respone to telomerase, a peak clinical effect that was about the same, and the time-to-retreatment to be just a big shorter. The reality should depend on how fast amyloid plaques accumulates (varying from person to person) and how fast we might be able to remove the plaque (again, probably varying from person to person). The vector (slope of the line from normal to onset of dementia) should be slightly steeper for those with two APOE4 alleles than for two APOE3 alleles, which would be slightly steeper than for two APOE2 alleles. Those with unmatched alleles (APOE4/APOE2) should vary depending upon which two alleles they carried.

To give a visual idea of what we might expect, I’ve added an image that shows the theoretical response of three different patients (a, b, and c), each of whom might respond equally well to telomerase therapy, but might then need a second treatment at different times, depending on their genes (APOE and other genes) and their environment (for example, head injuries, infections, diet, etc.). Patient c might need retreatment in a few years, while patient a might not need retreatment for twice as long.


September 20, 2017

Genes and Aging

Several of you have asked why I don’t update this blog more often. My priority is to take effective interventions for age-related diseases to FDA phase 1 human trials, rather than blogging about the process. Each week, Outlook reminds me to update the blog, but there are many tasks that need doing if we are going to get to human trials, which remains our primary target.

In working on age-related disease, however, I am reminded that we can do very little unless we understand aging. Most of us assume we already understand what we mean by aging, but our assumptions prevent us from a more fundamental and valid understanding of the aging process. In short, our unexamined assumptions get in the way of effective solutions. To give an analogy, if we start with the assumption that the Earth is the center of the solar system, then no matter how carefully we calculate the orbits of the planets, we will fail. If we start with the assumption that the plague results from evil spirits rather than Yersinia pestis, then no matter how many exorcisms we invoke, we will fail. We don’t fail because of any lack of effort, we fail because of misdirected effort.

Our assumptions define the limits of our abilities.

When we look at aging, too often we take only a narrow view. Humans age, as do all the mammals and birds (livestock and pets come to mind) that have played common roles in human culture and human history. When most people think of aging, they seldom consider trees, hydra, yeast, bacteria, or individual cells (whatever the species). Worse, even when we do look at these, we never question our quotidian assumptions. We carry our complacent assumptions along with us, a ponderous baggage, dragging us down, restricting our ability to move ahead toward a more sophisticated (and accurate) understanding. If we looked carefully, we would see that not all cells age and not all organisms age. Moreover, of those that age, not all organisms age at the same rate and, within an organism, not all cells age at the same rate. In short, neither the rate of aging, nor aging itself is universal. As examples, dogs age faster than humans and, among humans, progeric children age faster than normal humans. The same is true when we consider cells: somatic cells age faster than stem cells, while germ cells (sperm and ova) don’t age at all. So much for aging being universal.

The key question isn’t “why do all things age?”, but rather “why does aging occur in some cases and not in others, and at widely different rates when it occurs at all?” The answer certainly isn’t hormones, heartbeats, entropy, mitochondria, or free radicals, for none of these can explain the enormous disparity in what ages and what doesn’t, nor why cells age at different rates. Nor is aging genetic in any simplistic sense. While genes play a prominent role in how we age, there are no “aging genes”. Aging is not a “genetic disease”, but rather a matter of epigenetics – it’s not which genes you have, but how those genes are expressed and how their expression changes over time, particularly over the life of the organism or over multiple cell divisions in the life of a cell. In a sense, you age not because of entropy, but because your cells downregulate the ability to maintain themselves in the face of that entropy. Cell senescence effects a broad change in gene expression that results in a gradual failure to deal with DNA repair, mitochondrial repair, free radical damage, and molecular turnover in general. Aging isn’t a matter of damage, it’s a matter of no longer repairing the damage.

All of this wouldn’t matter – it’s mere words and theory – were it not for our ability to intervene in age-related disease. Once we understand how aging works, once we look carefully at our assumptions and reconsider them, our more accurate and fundamental understanding allows suggests how we might cure age-related disease, to finally treat the diseases we have so long thought beyond our ability. It is our ability to see with fresh eyes, to look at all organisms and all cells without preconceptions, that permits us to finally do something about Alzheimer’s and other age-related disease.

Only an open mind will allow us to save lives.


July 17, 2017

Walking Toward a Cure for Alzheimer’s

Sometimes things go wrong, sometimes they go remarkably right.

        In clinical medicine, Swiss cheese theory is a explanation of why medical disasters occur, even if the explanation has a grizzly sort of humor. Basically, Swiss cheese theory says that “all the holes need to line up” for something to get through the cheese and for things to go drastically wrong in patient care. For example, if the physician is a moron (the first hole in the cheese) and orders the wrong medication, then the knowledgeable pharmacist usually cancels the order. But if the pharmacist is also a moron (the second hole in the cheese) and sends the wrong medication to the nurse, then the experienced nurse refuses to give the medication and stops the mistake long before the patient is injured. But, of course, if the nurse is also a moron (the third hole in the cheese) and simply gives the wrong medication, then you have a problem. When all the morons line up in a row, like holes in adjoining slices of Swiss cheese, then mistakes get all the way through the cheese and you have the perfect setting for a medical disaster. Medical errors are rarely the result of a single stunning error on the part of a truly epic moron; medical errors usually take a grizzly sort of teamwork among morons, all working together like clockwork. Swiss cheese theory strikes again.
Oddly enough, the opposite can also happen. If everything lines up in a positive sense then we have innovation, progress, and (very rarely) a miracle or two. For example, to have a success in the case of a biotech company, you need a series of positive events to line up. Over the past few years, that’s exactly what has been happening to Telocyte. While there have been no truly stunning single events that have created a fleeting (if flashy) success, there have been a collection of positive events that line up exactly as they need to. In our case, all the holes are lining up to build toward a successful cure for Alzheimer’s disease.
I first proposed that telomerase could be successful as a clinical intervention in 1996, but my proposal wouldn’t have gotten anywhere if a whole collection of groups and individuals hadn’t continued to move the field along over these past twenty years. From a purely practical perspective, it was the work of CNIO in Madrid (and that of their director, Maria Blasco) that demonstrated a technique that can easily be applied to human clinical trials. Yet, while we saw the potential for human disease, it was our CEO, Peter Rayson, who moved us along in a practical direction. Two years ago, Peter arranged to meet me in Boston, and we founded Telocyte. Our COO, Mark Hodges, joined us and helped shape our program. We had additional support from volunteers, spouses, and researchers, all of whom saw the value and shared our vision. Investors, such as Rob Beers, joined us, asking little and seeing much. We were approached by large global corporations, such as SAP and Amazon Web Services, who offered us support. We partnered with the world’s preeminent biotech law firm, Cooley LLP, who saw the potential and wanted to help. Other investors have come on board, investors who saw what we could do and who agreed with our goals.
Recently, we signed agreements with a major investor and submitted our protocols for FDA review, and we continue to move ahead, steadily and confidently, as we plan for our human trial next year. None of this has been the result of one person, nor even one group. Instead, it has been the result of a continual concatenation of just the right people at the right time. Everything has gracefully, carefully, and steadily lined up, creating an historic opportunity to save lives and rescue human minds. There have been no miracles, no sudden champagne, no instant success, nor wild celebrations. We haven’t seen wonders, but we’ve seen workers. We haven’t seen miracles, but we’ve met milestones. We haven’t had champagne, but now we have a chance.
With every step, a door has opened, people have helped, another step was taken.
And each step brings us closer to curing Alzheimer’s. Walk with us.

April 12, 2017

We Already Know It Works

Oddly enough, many investors don’t realize how far we are down the road to a cure.

In fact, most people don’t understand why such studies are done and – more to the point – why Telocyte is doing one. Just to clarify: we’re not doing an animal study to prove efficacy. We already know it’s effective in animals.

The reason we do an animal study is because the FDA, quite reasonably, requires an animal safety study in order to assess risks and side effects. Most people assume that animal studies are done to show that a potential therapy works in animals, so that it might work in humans as well. In fact, however, once you have shown that a therapy works in animals, as we have already, then before you can go on to human trials, you first need to do an animal safety study.

Animal studies are done to assess safety, not to assess efficacy.

For an initial human trial, the main question for the FDA isn’t efficacy, but safety. Sensibly, the FDA requires that the safety data be done carefully and credibly, to meet their careful standards. We know telomerase gene therapy works, but we still need to prove (to the FDA’s satisfaction) that telomerase gene therapy is safe enough to justify giving our therapy to human patients. So the question isn’t “Do we have a potential intervention for Alzheimer’s?” (which we do), but rather “Do we know what the risks are once we give it?” We’re fairly certain that we know those risk, but we need to document them rigorously.

In getting our therapy to human trials, you might say that there are three stages:

  1. Animal studies that show efficacy (already done by our collaborators).
  2. Animal studies that show safety (an FDA requirement).
  3. Human trials before release for general use (an FDA requirement).

Telocyte already has good data on the first stage: we know that telomerase is remarkably effective in reversing the behavioral decline seen in aging animals and that the same result will likely occur in aging human patients. In short, we are already confident that we can prevent and at least partially reverse Alzheimer’s disease. The FDA doesn’t need us to demonstrate efficacy: we already have good data on efficacy. What the FDA wants from us is more (and more detailed) data on the probable safety, which we’re about to provide.

While we are now ready to start on the FDA animal safety trial. Doing our FDA animal study isn’t a way of showing that telomerase gene therapy works – which is already clear from animal studies – but a detailed look at side effects, preparatory to our having permission to begin human trials next year.

Telomerase therapy works.

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