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.

 

January 20, 2016

Long Past Time

History provides perspective, probably because we keep repeating it.

Several hundred years ago, smallpox was the scourge of Europe. Treatment, such as it was, consisted of compassion, fluids, and a gamut of various herbs, bark, roots, and fungal preparations, none of which changed the mortality. The diligent healer of the late middle ages tried hard to find just the right plant preparation that would prevent or cure smallpox. By the late 1700’s there had been multiple cases of successful use of cowpox to vaccinate (from the Latin vacca for cow) people, with good results, culminating in Edward Jenner’s publication in 1798. Mind you, like many human discoveries, the process had actually been around a long time, if not particularly well known, well understood, or even believed.

Regardless of its provenance, regardless of its success, the major problem facing those who used vaccination to prevent smallpox was not technology, but common preconceptions. The idea of using an active biological agent – the cowpox virus – flew in the face of the common certainties about how to treat disease. Everyone “knew” that treatment lay in finding just the right plant, whether a root or a bark. Herbalists knew that if they worked hard and put enough resources into finding that perfect mixture of plant compounds, they could cure smallpox. The fact that they were looking in the wrong place, didn’t seem to occur to them.

Back to the future and listen to the echo of history.

We now know that we can reset gene expression in the microglia that play the key role in driving the pathology of Alzheimer’s disease. The data has been accumulating for 20 years, as have the numerous articles in the medical literature and the books and textbooks on this field. And yet, regardless of its provenance, regardless of its success, the major problem facing those who work to prevent and cure Alzheimer’s disease is not technology, but common preconceptions. The idea of using an active biological agent – like the human telomerase gene – flies in the fact of common certainties about how to cure Alzheimer’s. Everyone “knows” that treatment lies in finding just the right drug, whether monoclonal antibody or small molecule. Pharmacology companies know that if they work hard enough and put enough resources into finding that perfect set of molecules, they could cure Alzheimer’s. And once again, the fact that they are looking in the wrong place, doesn’t seem to occur to them.

The echo is hauntingly familiar. Once again, the advance of medicine lay (and will lay) not in finding the right herb (or the right antibody), but in finding a sophisticated and accurate understanding of the disease we are trying to treat. Just as nothing worked in the 18th century until we understood vaccination as a way of preventing smallpox and other viral diseases, so nothing will work in the 21st century until we understand resetting gene expression as a way of preventing and curing Alzheimer’s disease.

It’s time to start looking in the right place.

And it’s long past time to cure Alzheimer’s disease.

October 30, 2015

Chaos, traffic, and Alzheimer’s disease

We’re going to take an odd detour into both chaos theory and traffic flow in order to understand Alzheimer’s disease, so fasten your seatbelt. The key cascade of pathology that we’re going to look at (and explain) is the presence of beta amyloid plaques in patients with Alzheimer’s, but the principle applies equally to tau tangles and several other hallmarks of pathology seen in aging human patients with cognitive decline. Chaos theory and traffic flow will serve as useful analogies and help clarify the dynamics involved in human pathology, as well as potential cures.

To start with, let’s consider a simple example of chaos theory, in which a continual, linear event results in a sudden inflection and an unexpected, non-linear outcome. Imagine that you are trying to retrieve your iPhone in the middle of the night in order to listen to, for example, an audible book. The lights are out, your spouse is asleep and you gently pull on the earphones, using them to pull the iPhone toward you. Realizing that the slower you pull it, the less noise you make (and the less likely it is that you will waken your spouse), you provide a very slow, gentle traction. Unfortunately, the iPhone is on the bedside table and once it gets to the edge, it suddenly falls and produces a terrible racket, regardless of how slowly and quietly you’ve pulled it up until you reached the edge. The point here is that regardless of how noise and speed were related until you got to the edge of the table, there will come a sudden inflection point with an unexpected and non-linear increase in noise. In short, the amount of noise correlates linearly with speed until the inflection occurs and then the relationship between speed and noise becomes suddenly non-linear. As we will see, much the same thing happens to the clearance of beta amyloid (or tau tangles) and its relationship to neuronal death. Things seem to be going fine until some inflection point is reached, after which there is a sudden, unexpected inflection and the pathology (and cognitive decline) begins.

For the next analogy, consider traffic flow and construction slowdowns. Commuting to work each day, you (and the traffic generally) are moving along at a steady 55 mph as you approach an area of construction. In this area, the traffic slows to a speed averaging 10 mph, as a result of a traffic light at which the speed is 20 mph half the time (green light) and zero half the time (red light). However, you notice that despite this construction slowdown (which has been going on for several weeks), the traffic congestion always becomes noticeable at about the same spot and it never actually backs up indefinitely (as it might if the road was completely closed while traffic continued to arrive). As you think about it, you realize that the actual speed (55 mph versus 10 mph) isn’t the key here. The key question is the number of cars passing per unit time as they approach and as they go through the congested area. If the 55 mph cars are approaching at a rate of (say) 30 cars per minute (with a good distance between them) and the 10 mph cars are getting through the construction and the traffic light at the exact same rate of 30 cars per minute (although they are almost bumper-to-bumper), then the line of slow moving cars will only grow to a certain length before it achieves an equilibrium. We might find, for example, that despite the traffic congestion and as long as the number of cars passing each point per unit time remains equal (e.g., 30 cars per minute, regardless of how close the cars are to one another), then the line will only grow so far and no further.

But this is only true to a point.

It might be, for example, that (as long as the number of cars per minute is equal both coming into and leaving the traffic congestion) the line will be a half-mile long if the construction zone has an average speed of 15 miles an hour twice as long at 10 miles an hour, but there comes a point – perhaps at 9 miles per hour, when the line suddenly has an inflection point and begins to grow wildly (and non-linearly) because the number of cars leaving per minute has no fallen below the number of cars arriving per minute. The relationship between speed (going through construction) and the length of the traffic line was linear until some critical point, at which the relationship took an inflection, the traffic backs up, and all hell breaks loose. Not merely an example of chaos theory, but chaos in action as traffic gridlock ensues.

Much the same is occurring in the brain as it ages. Microglial cells are perfectly adept at clearing beta amyloid as it is produced. Even as these cells senesce and their rate of clearance falls, the backup of beta amyloid “traffic” is not bad enough to cause pathology and it does not trigger neuronal death – or clinical Alzheimer’s disease. There comes a point, however, when chaos theory enters the picture, a sudden inflection occurs, neuronal death ensues, and inexorable cognitive decline becomes obvious.

Think of it this way. The key questions (with beta amyloid as an example) are these: 1) how fast is beta amyloid being produced (how many cars are coming down the highway per minute), 2) how likely are the beta amyloid molecules to be abnormal perhaps because of APOE4 genes (how fast are the cars moving), and 3) how well are the senescing microglia able to clear the beta amyloid molecules (how many cars can they get through the construction area per minute)?

These same questions play a role in understanding why current interventions (e.g., monoclonal antibodies) fail and why we might want to intervene directly in cell senescence. Most current experimental approaches, such a monoclonal antibodies, only serve to “tow away some of the backed-up cars in the traffic line”, while the critical variable is our ability to move cars through the area of congestion. In short, the problem is not a static one (can we remove cars), but a dynamic one (can we keep the cars moving). Once we get a problem with traffic flow (a non-linear accumulation of beta amyloid plaques), the key intervention is not “towing away cars”, but increasing the flow of traffic through the congested area. We should be treating microglia, not beta amyloid.

Curing Alzheimer’s requires that we understand the pathology and not in a naïve, static fashion. If we want to cure Alzheimer’s, we need to improve the traffic, not the cars. The most effective point of intervention is not beta-amyloid but microglia.

Which is how we plan to cure Alzheimer’s.

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.

July 20, 2015

Why Solanezumab Disappoints

Insanity is doing the same thing over and

over again and expecting different results.

                                    – Variously Attributed

 

[This blog was written and published on Monday July 20th, two days prior to the announcement of the results of Eli Lilly’s clinical trials of solanezumab for Alzheimer’s.]

 

Until now, there have been only two globally-approved drugs for Alzheimer’s disease (Aricept and Namenda), and neither of these have been shown to slow, let alone stop or reverse Alzheimer’s. Most current clinical hopes have been pinned to various attempts to use monoclonal antibodies to attack beta amyloid in the brain, and none of these have been shown to slow, let alone stop or reverse Alzheimer’s disease either.

At the current meeting of the Alzheimer’s Association (July 18-23, Washington, DC) there has been growing interest in the latest clinical trial of this disappointing approach, as Eli Lily announces (on Wednesday July 22nd) the latest results of using solanezumab (also called “Soli”), a drug which was a disappointment in its initial clinical trials. Nevertheless, and to the surprise of many, the FDA gave Eli Lilly permission to continue their phase 3 trials and expectations increased the price of the Eli Lilly stock as the upcoming announcement of the results approaches. Unfortunately (not only for the company, but for all of us), the results will be equivocal at best and certainly won’t show that we can slow, stop, or reverse Alzheimer’s.

Why not?

Why don’t any of the drugs that target beta amyloid have any effect on the underlying disease process? Why have all of the monoclonal antibody drugs — with Soli just the latest heartbreaking therapeutic (or non-therapeutic) disappointment — failed to stop the disease?

The unspoken assumption has been that beta amyloid “causes” Alzheimer’s.

Oddly enough, the assumption is false: beta amyloid doesn’t cause Alzheimer’s disease. Small wonder then when our attempts intervene in the wrong target fail every time. Mind you, beta amyloid is clearly implicated in the pathology and it clearly plays an important role, but to say that is “causes” Alzheimer’s is to confuse cause and effect. If we have a patient with an infection, a high fever, and an elevated white blood cell count, we wouldn’t blame the fever or the white cells for the infection. Likewise, it would be silly (and dangerous) to “treat” the infection by simply removing the patient’s white cells. Yet this is the same sort of logical error we routinely make with Alzheimer’s disease. We know that almost all cases of Alzheimer’s disease show amyloid deposits at autopsy (or now, using other tests, even in living patients with Alzheimer’s), and we know that amyloid deposits can damage neurons, but to automatically conclude that that’s the entire ball game is to go well beyond reality and enter the realms of wishful thinking (or insanity, if we were to believe the quote given above).

None of the clinical trials aimed at removing beta amyloid have ever shown efficacy.

The problem is that amyloid is the wrong target and monoclonal antibodies against amyloid are the wrong intervention. The current failure of solanezumab is simply one more in the list of such failures. If trying the same failed approach over-and-over is insanity, then sanity would be to try a new intervention, an intervention based on a sophisticated appreciation of the actual clinical pathology. In my new book The Telomerase Revolution, I not only discuss that more sophisticated view of the pathology, but how we plan to intervene in a more rational and effective fashion.

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