Michael Fossel Michael is President of Telocyte

December 13, 2016

Telomeres: The Purloined Letter of Aging

     “What is only complex is mistaken (a not unusual error) for what is profound.”

                                                Edgar Allen Poe

 Edgar Allen Poe is still well-known for his poetry, he is less well-known for his detective stories. Some 170 years ago, his Parisian amateur detective, Dupin, was the conceptual forerunner for Sherlock Holmes, who made his London debut almost half a century later. Poe also made a series of observations that echo, even today, as we try to understand aging, age-related disease, and how we can cure them.

Poe’s detective pointed out that even intelligent, meticulous investigators are often oblivious to the obvious. The same can even be true of modern scientific investigators, who may focus so closely on their hard-won facts that the relationships between those facts – and their implications – are often overlooked. In aging research, for example, many investigators focus so intensely on genes, proteins, and small-molecular therapies, that they can miss the broader picture and miss an effective approach to curing the diseases of aging. Putting it simply, too often we focus our intellect, our education, and our strenuous effort on the “nouns”, but we entirely miss the “verbs”. We know the data, we fail to see what it means.

The intellect, the education, the dedication, and the funding are enormous, but our focus is off-target and the results, as expected, are futile. Truth, Poe tells us, is frequently overlooked, regardless of how intense our investigation. In describing such a case (in Poe’s case a policeman, in our case a scientist), Poe put it this way:

“… he erred continually by the very intensity of his investigations. He impaired his vision by holding the object too close. He might see, perhaps, one or two points with unusual clearness, but in so doing he, necessarily, lost sight of the matter as a whole. Thus there is such a thing as being too profound. Truth is not always in a well. In fact, as regards the more important knowledge, I do believe that she is invariably superficial.”

 As Poe suggest, we seek truth in the depth of a well in a valley, while truth is usually sitting in plain sight on the (easily visualized) mountain tops surrounding that valley. Such is the case with aging. It’s not that the truth is simple, for aging is far more complex than most of us give it credit for, but the truth is not found in the narrow details so much as it found in the overview of those details. The truth really is on the mountain tops, not in the bottom of a well, even when that well includes reams of data. It’s not the amount of data that is crucial, but the implications of that data. To give an example from clinical medicine, I may know everything about a patient’s fever, their hypotension, their abnormal white count, and their vomiting, but the numbers alone aren’t nearly as important as the realization that the patient has Ebola. Curing an Ebola infection cannot be relegated to lowering a fever, increasing the IV fluid, removing white cells, and given an anti-emetic. It’s not the individual therapies that cure Ebola, it’s the realization that you’re dealing with a viral infection and the use of a more general – and more effective – therapy, whether an antiviral or an immunization.

There is a parallel in understanding aging.

Treating the diseases of aging is not a matter of using individual therapies, but a matter of understanding the more profound relationships that change in aging cells. Until we do so, we will continue to fail when we try monoclonal antibodies for beta amyloid – as Eli Lilly finally realized with its Solanezumab trials – or merely attack tau proteins, mitochondrial changes, inflammation, or other targets. In each case, we have mistaken a plethora of data for a profundity of data. Only when we realize the actual complexity, the dynamic biological relationships, the profound effects of epigenetic changes, the role of telomeres as a therapeutic target, and that the fundamental pathology of aging and age-related diseases is rooted in cell senescence, only then will we — to our own vast and naïve surprise — discover that we can cure most of the diseases that still plague humankind.


October 18, 2016

The Carpets of Alzheimer’s Disease

Why do Alzheimer’s interventions always fail?

Whether you ask investors or pharmaceutical companies, it has become axiomatic that Alzheimer’s “has been a graveyard for many a company”, regardless of what they try. But in a fundamental way, all past and all current companies – whether big pharma or small biotech – try the same approach. The problem is that while they work hard at the details, they never examine their premises. They uniformly fail to appreciate the conceptual complexity involved in the pathology of Alzheimer’s. They clearly see the technical complexity, but ignore the deeper complexity. They see the specific molecule and the specific gene, but they ignore the ongoing processes that drive Alzheimer’s. Focusing on a simplistic interpretation of the pathology, they apply themselves – if with admirable dedication and financing – to the specific details, such a beta amyloid deposition.

But WHY do we have beta amyloid deposits? Why do tau proteins tangle, why do mitochondria get sloppy, and why does inflammation occur in the first place? Focusing on outcomes, rather than basic processes explains why all prior efforts have failed to affect the course of the disease, let alone offer a cure for Alzheimer’s.

Let’s use an analogy: think of a maintenance service. Any big organization, (university, pharmaceutical firm, group law practice, or hospital) has a maintenance budget. Routine maintenance ensures that – in the offices, clinics, or laboratories – carpets are vacuumed, walls are repainted, windows are cleaned, floors are mopped, and all the little details are taken care of on a regular basis. These are the details that make a place appear clean and well-cared for, providing a pleasant and healthy location. In most offices (as in our cells), we are often unaware of the maintenance, but quite aware of the end result: an agreeable location to work or visit. In any good workplace, as in our cells, maintenance is efficient and ongoing.

That’s true in young cells, but what happens in old cells?

Imagine what happens to a building if we cut its maintenance budget by 90%. Carpets begin to show dirt, windows become less clear, walls develop nicks and marks, and floors grow grimy and sticky. This is precisely what happens in old cells: we cut back on the maintenance and the result is that cells becomes less functional, because without continual maintenance, damage gradually accumulates. In the nervous system, beta amyloid, tau proteins, and a host of other things “sit around” without being recycled efficiently and quickly. Maintenance is poor and our cells accumulate damage.

All previous Alzheimer’s research has ignored the cut back in maintenance and focused on only a single facet, such as beta amyloid. You might say that they focused only on the dirty carpet and ignored the walls, the windows, and the floors. Even then, they have focused only on the “dirt”, and ignored the cut back in maintenance. Imagine an organization that has cut its maintenance budget. Realizing that they have a problem, they call in an outside specialist to focus exclusively on the loose dirt in the carpet, while ignoring the carpet stains, ignoring the window, walls, and floors, and then only coming in once. What happens? The carpets look better for a few days, but the office still becomes increasingly grungy and unpleasant. In the same way, if we use monoclonal antibodies (the outside specialist) to focus on beta amyloid plaque, the plaques may improve temporarily, but the Alzheimer’s disease continues and it is definitely unpleasant. Various companies have focused on various parts of the problem – the floors, the walls, the windows, or the carpets – but none of them have fixed the maintenance, so the fundamental problem continues. You can put a lot of effort and money into treating only small parts of Alzheimer’s, or you can understand the complex and dynamic nature of cell maintenance. Ironically, once you understand the complexity, the solution becomes simple.

The best solution is to reset cell maintenance to that of younger cells. Neurons and glial cells can again function normally, maintaining themselves and the cells around them. The outcome should be not another “graveyard for companies”, but life beyond Alzheimer’s .


April 12, 2016

Rational Behavior

We waste stunning amounts of money and effort on comprehensively ineffective trials.

As a recent article points out, in the past 15 years, there have been 123 Alzheimer drug failures and, while four medicines have been approved, none of them affect the progress of the disease. Symptomatic therapy at best, we have no medications – none – that have any effect on the disease or on its mortality. A quick look at clinicaltrials.gov lists almost 1,500 interventional trials aimed at treating Alzheimer’s disease, yet once again there is no evidence that any of these trials has resulted (or will result) in an intervention that changes the outcome of Alzheimer’s disease.

Federal funding for Alzheimer’s is estimated at almost half a billion dollars and some have estimated that Eli Lilly’s potential treatment for Alzheimer’s, solanezumab, may end up costing the company one billion dollars to achieve approval of that drug alone, even though there is no evidence that it actually prevents or cures the disease. The most optimistic interpretation of the statistical data of thousands of patients over many years, would be stretching it to suggest it might possibly delay cognitive decline and death by 2-3 months over an eight year period from diagnosis to death. Even that wishful thought is doubtful and scarcely any consolation to those enduring an extra handful of weeks in a skilled care nursing home (or having to pay for it).

No matter what the current target of choice – beta amyloid, tau proteins, inflammation, or any other target-du-jour – none of these targets have ever been shown to offer a glimmer of hope. Despite the history of repeated and consistent failure, we continue to spend (and vote to spend) money on these same drug targets. We eagerly bash our empty heads against the same solid brick wall, naively hoping that one day we fill find that the wall will be made of air (like the air in our brains, which leads to our irrational behavior). The apocryphal observation pertains: the definition of insanity is doing the same thing over and over and expecting a different result. We waste money and effort on ineffective and expensive trials aimed at targets that we know are futile.

The irony – and the tragedy – is that we can both prevent and cure Alzheimer’s disease, both effectively and inexpensively if we understand the actual pathology and target the underlying causes. We could do, effectively and inexpensively, what big pharma has failed to do ineffectively and expensively. What big pharma can’t do for one billion dollars, Telocyte can do for 0.5% of that figure, simply by aiming at the right target.

We need rationality, insight, and just enough funding to prove it can be done.

August 18, 2015

Alzheimer’s: Why Learn to Live With Failure?

We are too often satisfied with failure. Not believing we can succeed, we eschew further thinking, and we call it quits. In the case of Alzheimer’s therapy, we define statistical flukes as “hope”, declare victory, and retire into platitudes and misconception. Rather than cure disease or improve human lives, we content ourselves with pessimistic delusions and hype the importance of “living with Alzheimer’s”. Simple-minded mottos and political cant, can’t hide reality. We’re not living with Alzheimer’s, we’re dying with Alzheimer’s.

A dozen years ago, when I was the Executive Director of the American Aging Association, we wondered whether or not vitamin E (tocopherols) could delay Alzheimer’s by a few months. The results were minimal and subsequent studies undermined any of the initial optimism. Similar claims came and went over the years, at best suggesting we might delay the disease by a few months, if even that much. Years have passed and hopes have faded. Even the Alzheimer’s Association slowly acquired an emphasis on futility, with a focus not on curing AD, but on living with it (as if we could). Yet even with our latest approaches, even with monoclonal antibodies and huge FDA studies, success escapes us. In July 2015, the results of a large solanezumab study came out and were hyped as having a “distinct impact on Alzheimer’s disease”, and it was claimed that the results “may well illustrate the disease-modifying effect” of the drug.

08-18-15 Figure A

Figure A


How big an impact? How modified was the disease? Not much.

At best, the statistics suggest that solanezumab might delay the symptoms by three months (see figure A, above). Given that average course of the disease — often 7-8 years from diagnosis to death — the 3 month statistical claim s is not much of a reprieve. And what does it give us? A longer sentence to the nursing home? Prolonged financial and human costs? Does it offer anything more than an illusion of hope?

08-18-15 Figure B

Figure B


If we look at the published results, the most obvious fact is that the vectors — control versus treated patients — are parallel as they decline toward death (see figure B, above). How can we claim to treat Alzheimer’s when the direction of the disease process has the same slope whether you are treated or not? If we fall off a cliff regardless of treatment, does it matter if we hit the bottom now or a few moments from now? Either way, it’s the same cliff, the same fall, the same outcome. Either way, the same fact remains: we’re not living with Alzheimer’s, we’re dying with Alzheimer’s. If there is any “distinct impact”, then it’s not the questionable impact on Alzheimer’s disease, it’s the unquestionable impact as the patient hits the ground.

We are too easily satisfied with failure. We work hard and we invest millions of dollars in research, but we don’t think hard enough and we don’t invest in the right trials. We use a faulty disease model and achieve disappointing results, then resign ourselves to fate and claim that we have succeeded by redefining failure as, oddly enough, a clinical success. A lack of meaningful success becomes a “distinct impact” and a failure is touted as “success”. Where is the success in being unable to alter the vector of a disease?

We could do much better: we can actually succeed. We can cure Alzheimer’s disease. What it takes is not more effort and money invested in failed models, but more insight and a deeper appreciation of how the Alzheimer’s disease actually works. We must come to see it in a broader context of the age-related CNS pathology that underlies not only Alzheimer’s (and not merely beta amyloid or tau protein changes), but Parkinson’s disease, microvascular dementia, and even animal models of age-related cognitive decline. We become so lost in the genetic and protein changes specific to Alzheimer’s that we lose track of the parallel changes (with different genes and different proteins) in Parkinson’s disease. We become so lost in the neuronal changes specific to the histology of these two diseases that we lose track of the overlapping changes that occur in the vascular pathology. And, finally, we become so lost in the pathologies specific to our human patients that we lose track of how much we can learn from the typical age-related CNS dysfunction that occurs in other animals, such as mice.

08-18-15 Figure C

Figure C


The pathology may differ, the pathways may differ, yet each of these age-related changes still share an underlying process, one that we can take advantage of, allowing us to intervene effectively. Once we grasp the broader process that underlies the specifics of these CNS pathologies, we can finally cure them. Rather than merely claim we have achieved a minimal displacement of the same downhill vector, we can alter the vector (see figure C, above) and achieve what so many have hoped for and so few have come to believe in: a successful cure of Alzheimer’s.

Ignore the hypocrisy of “living with Alzheimer’s”.

Let’s succeed at living WITHOUT Alzheimer’s.

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