Michael Fossel Michael is President of Telocyte

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.

March 21, 2017

The Frustration of (Not) Curing Alzheimer’s

I am deeply frustrated by two plangent observations: 1) we squander scant resources in useless AD trials and 2) AD can easily be cured if we applied those same resources to useful AD trials. Applying our resources with insight, we will cure Alzheimer’s within two years.

The first frustration is that most pharmaceutical firms and biotech companies continue to beat their heads against the same wall, regardless of clinical results. Whether they attack beta amyloid, tau proteins, mitocondrial function, inflammation, or any other target, the results have been, without exception, complete clinical failures. To be clear, many studies can show that you can affect beta amyloid or other biomarkers of Alzheimer’s disease, but none of these studies show any effect on the clinical outcome. In the case of amyloid, it doesn’t matter whether you target production or the plaques themselves. Despite hundreds of millions of dollars, despite tens of thousands of patients, not one of these trials has ever shown clinical efficacy. Yet these same companies continue to not only run into walls, but remained convinced that if they can only run faster and hit the wall faster, they will somehow successfully breach the wall. They succeed only in creating headaches, accompanied by lost money, lost opportunities, and lost patients. The problem is not a lack of intelligence or ability. The researchers are – almost without exception – some of the most intelligent, well-educated, technically trained, and hard-working people I know. The irony is that they are some of the best 20th century minds I know. The problem, however, is that it is no longer the 20th century. If you refuse to adapt, refuse to change your paradigm, refuse to come into the 21st century, you will continue to get 20th century results and patients will continue to die of Alzheimer’s disease. Money and intelligence continues to be dumped into the same clichéed paradigm of pathology, as we aim at the wrong targets and misunderstand how Alzheimer’s works. And the result is… tragedy.

The second frustration is that we already know the right target and we already understand how Alzheimer’s disease works. We are entirely able to cure and prevent Alzheimer’s disease now. At Telocyte, we already have the initial resources we need to move ahead, but it is surprising how difficult it is for some people — wedded to 20th century concepts — to grasp the stunning potential, both clinically and financially of what we are about to do at Telocyte. We can not only reverse Alzheimer’s disease, but we can also cut the costs of health care while creating a stunningly successful biotech company in the process. We have the right tools, the right people, the right partners, and the sheer ability to take this through FDA trials. Already, we have several lead investors committed to our success. We are asking for a handful of additional investors, those who can see what the 21st century is capable of and who can understand why Telocyte is both the best clinical investment and the best financial investment in innovative medical care.

 

January 9, 2017

Conceptual Blinders

 

A week or so ago, an AI beat the world’s reigning champion in the game of Go.

The odd thing is not that it happened, but how it was done. By itself, the victory would just be one more example of “computers beating humans”, but there is a far more interesting and important facet to this event. Not only did the AI beat the world’s Go masters and the reigning world champion, but it did it, not by being better at using the known strategies and tactics, long the province of Go adepts, but by using “unconventional positions“ and “moves that seemed foolish but inevitably led to victory” (WSJ, January 5, 2017). In short, the AI went into playing the game without conceptual blinders. It developed novel (and effective) strategies based on reality, rather than on preconceived views of how the game “ought” to be played. Had the AI been programmed by Go masters, it wouldn’t have fared as well. It succeeded because it lacked the limitations that we as human beings unknowingly use when we approach a problem.

go-game-boardIF our assumptions create limits, then our outcomes are limited.

The same problem – our own assumptions – proscribes the limits of what we can do in science and medicine. If we simply program a computer to “delay the onset of Alzheimer’s disease by lowering all known risk factors”, it might succeed, but the solution would be limited by how we set up the problem. In short, assumptions limit outcomes. If we merely restrict the program to lowering risks, then a computer program can’t show us how to cure Alzheimer’s. Such a program might, for example, recommend dietary changes, moving away from major highways and pollution, lowering blood pressure, avoiding infections, improving dental hygiene, lowering stress, and a myriad other changes that might delay Alzheimer’s. But the programs, the questions we pose, presuppose that Alzheimer’s can’t cured or prevented, only delayed. If we preclude finding a way to win, then all we find is a better way to lose.

Consider the historical analogs. If I want more efficient communication, I don’t ask a computer to design a better telegraph. If I want more efficient transportation, I don’t ask the computer to design a faster horse. If I want to cure polio, I don’t program a computer to design a better iron lung. And if I want to cure Alzheimer’s, I shouldn’t design a better way to attack amyloid, tau proteins, inflammation, or mitochondrial dysfunction. Merely because I’ve already assumed that those are the only strategies, I have limited my outcomes. If Alzheimer’s interventions are restricted to merely optimizing old strategies, we will never cure it.

Why be satisfied with a better telegraph, a faster horse, or a more efficient iron lung?

Programmed solutions, based on preconceived limits are a case of GIGO: “garbage in, garbage out”. True advances in science and medicine are not incremental; they demand innovative perceptions and constant reexamination of our premises. The example of an AI beating the world’s reigning Go champion wasn’t the result of incremental improvements in coding all of the Go strategies known to previous champions into a program and then tasking the program with implementing those accepted strategies. The AI was tasked with winning, regardless of previously accepted strategies. As a result, the AI actually WON, unexpectedly, but reliably, using innovative, startling, and unexpected approaches.

If we want to cure Alzheimer’s disease, we can’t use incremental approaches to time-worn (and uniformly ineffective) strategies. Like the AI playing Go, we need to stop focusing on accepted strategies and ask the fundamental question: how do we win? Not “how do we optimize the same old strategies?”, but how do we actually WIN? We shouldn’t rely on “programmed” approaches; we should toss out our preconceived programs, and ask how to win. With regard to Alzheimer’s disease, we need to stop asking how to optimize losing strategies and ask how to cure Alzheimer’s. Not “how do we lower amyloid levels?” or “how do we reduce tau tangles?”, but how do we cure and prevent the disease in the first place? If we really want to make a difference, then we need to free ourselves from our preconceptions and our old programming, and begin to ask the fundamental question: how can we cure Alzheimer’s?

Truly innovative approaches demand a ruthless reassessment of our assumptions.

We will cure Alzheimer’s only if we have the wit to truly use our own intelligence, with honesty, perceptiveness, and a willingness to examine reality.

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 .

 

July 20, 2016

Curing Disease: More Insight Instead of Mere Effort

 

Curing disease correlates with insight, not blind effort.

There is an eternal trade-off between insight and effort. If we think carefully, understand the problem, and plan, then effort is minimized. If (as too often happens) we think carelessly, misunderstand the problem, and rely on hope instead of planning, then effort is not only maximized, but is usually a complete waste. Lacking insight, we foolishly flush both money and effort down the drain. In the case of clinical trials for Alzheimer’s disease – and in fact, all age-related diseases – this is precisely the case.

The major problem is a naïve complaisance that we already understand aging pathology.

If there was a single concept that is key to all of aging, it is the notion that everything in our organs, in our tissues, and in our cells is dynamically and actively in flux, rather than being a set of organs, tissues, cells, and molecules that statically and passively deteriorate. Aging isn’t just entropy; aging is entropy with insufficient biological response. Senescent cells no longer keep up with entropy, while young cells manage entropy quite handily. At the tissue level, the best example might be bone. We don’t form just bone and then leave it to the mercy of entropy, rather we continually recycle bony tissue throughout our lives – although more-and-more slowly as our osteocytes lose telomere length. This is equally true at the molecular level, for example the collagen and elastin molecules in our skin. We don’t finish forming collagen and elastin in our youth and then leave it to the vagaries of entropy, rather we continually recycle collagen and elastin molecules throughout our lives, although more-and-more slowly as our skin cells lose telomere length. Aging is not a process in which a fixed amount of bone, collagen, or elastin gradually erodes, denatures, or becomes damaged. Rather, aging is a process in which the rate of recycling of bone, collagen, or elastin gradually slows down as our shortening telomeres alter gene expression, slowing the rate of molecular turnover, and allowing damage to get ahead of the game. We don’t age because we are damaged, we age because cells with shortening telomeres no longer keep up with the damage.

The same is true not only of biological aging as a general process, but equally true of every age-related disease specifically. Vascular disease is not a disease in which our arteries are a static tissue that gradually gives way to an erosive entropy, but an active and dynamic set of cells that gradually slow their turnover of critical cellular components, culminating in the failure of endothelial cell function, the increasing pathology of the subendothelial layer, and the clinical outcomes of myocardial infarction, stroke, and a dozen other medical problems. Merely treating cholesterol, blood pressure, and hundreds of other specific pathological findings does nothing to reset the epigenetic changes that lie upstream and that cause those myriad changes. Small wonder that we fail to change the course of arterial disease if our only interventions are merely “stents and statins”.

Nor is Alzheimer’s a disease in which beta amyloid and tau proteins passively accumulate over time as they become denatured, resulting in neuronal death and cognitive failure. Alzheimer’s is a disease in which the turnover – the binding, the uptake, the degradation, and the replacement – of key molecules gradually slows down with telomere shortening, culminating in the failure of both glial cell and neuron function, the accumulation of plaques and tangles, and ending finally in a profound human tragedy. The cause is the change in gene expression, not the more obvious plaques and tangles.

Our lack of insight, even when we exert Herculean efforts – enormous clinical trials, immense amounts of funding, and years of work – is striking for a complete failure of every clinical trial aimed at Alzheimer’s disease. Naively, we target beta amyloid, tau proteins, phosphodiesterase, immune responses, and growth factors, without ever understanding the subtle upstream causes of these obvious downstream effects. Aging, aging diseases, and especially Alzheimer’s disease are not amenable to mere well-intended efforts. Without insight, our funding, our time, and our exertions are useless. Worse yet, that same funding time, and exertion could be used quite effectively, if used intelligently. If our target is to cure the diseases of aging, then we don’t need more effort, but more thought. However well intentioned, however much investment, however many grants, and however many clinical trials, all will be wasted unless we understand the aging process. Aging is not a passive accumulation of damage, but an active process in which damage accumulates because cells change their patterns of gene expression, patterns which can be reset.

Curing Alzheimer’s requires insight and intelligence, not naive hope and wasted effort.

 

 

July 5, 2016

Dynamic versus Static – Going to Mars or Curing AD

Innovation requires novel thinking, not incremental actions.

We can cure age-related diseases – such as Alzheimer’s – not with funding, intelligence, or effort alone, but only if we reassess our assumptions. Until we look carefully at our conceptual foundations, we cannot expect to build a therapeutic structure. Ironically, the key problem lies in our looking at biology, medicine, and disease as static, passive processes. One would think we would see these processes as active and dynamic, but oddly enough, we don’t.

Consider an analogy: going to visit Mars.

Clearly, we need some essentials of life-support, such as oxygen and water. If we start by asking ourselves how much of each we need per day per person, then how many days and how many persons, we end up with an enormous need for both: huge amounts of oxygen, huge amounts of water. After all, we don’t want to run out of oxygen or water, do we?

Remember, however, that in a closed system (such as a vehicle going to Mars), that neither oxygen nor water are actually used up en route, only changed from one form (such as oxygen molecules) to another (such as carbon dioxide molecules). The water molecules may be in the form of body waste, but they are still present in the vehicle. And both oxygen and water – given energy and technical forethought – can be recycled and reused indefinitely. The practical question is not simply “how much oxygen and water do we need”, but “how efficiently and quickly can we recycle oxygen and water?” In short, the key question isn’t the static and passive one of “how fast are we using up our oxygen and water?”. The key question is the active and dynamic one of “how does the rate of recycling compare to the rate of oxygen and water use?”

The analogy is exact.

In the case of Alzheimer’s, for example, the key question isn’t “how can we prevent the accumulation of beta amyloid and tau protein?”, but rather “how can we increase the rate of recycling of molecules such as beta amyloid and tau proteins?” The former question would be like asking “how can we prevent the use of oxygen and water?”, while we should be asking “how can we increase the recycling efficiency of oxygen and water?”

Current approaches to treating Alzheimer’s disease focus inordinate funding, intelligence, and effort on the wrong question. Small wonder they fail.

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.

February 16, 2016

Unexamined Assumptions

The problem with curing Alzheimer’s is, as with so much of our understanding of aging and age-related diseases, that we make unexamined assumptions. Let me admit that many of our unexamined assumptions are either useful or reasonable. I assume that the sun will come up again tomorrow morning and that’s a useful and reasonable assumption. Useful, in that it allows me to plan my future, reasonable in that the sun has been coming up every morning for quite a while and is therefore likely to do so tomorrow as well. Certain unexamined assumptions are equally justifiable in dealing with Alzheimer’s disease. In the strictly poetic sense, Alzheimer’s certainly is the disease that “steals our souls”, yet no physician or researcher would actually make the assumption that the mind is some vague ethereal quantity that can be stolen by demons, let alone go on to promulgate a theory of Alzheimer’s pathology based on this assumption.

Yet we make exactly that same error, using an unexamined assumption, when we blithely assume that aging is simply the accumulation of damage and, pari passu, that Alzheimer’s disease is simply the accumulation of damaged molecules, be they amyloid, tau tangles, or altered mitochondrial enzymes. This unexamined assumption lies behind almost innumerable multi-million dollar FDA trials, academic papers, and clinical interventions. We assume, without even realizing we have made the assumption, that Alzheimer’s is merely the accumulation of damaged molecules.

We make the same unexamined assumption in looking at other age-related diseases and in the broader field of aging itself. We delve into the details of advanced glycation end-products (AGE), lipofuscin, cross-linking, and other molecular pools showing “accumulative damage”, all the time never realizing that we are making the same fallacy. We are working with completely unexamined (and erroneous) assumptions about how aging works. We naively assume that aging occurs – and age-related diseases follow – merely because things “rust” over time. We age because “molecules fall apart.”

 

Yet the data and logic both say differently. Let me give you a useful analogy: the cell phone. Consider a large pool (several thousand) of people who own cell phones. We know that if we examine any SINGLE cell phone, the best predictor of failure is how long it has been since production. If, however, we want to predict the percentage of failures in any large pool of owners, the best predictor is not time-since-production, but length-of-contract, that is, how often does it get turned over and replaced? Imagine two large pools of cell phone owners. In group A, the cell phones are replaced annually, with a failure rate (at equilibrium) of approximately 1%. In group B, the cell phones are replaced every ten years, with a failure rate (at equilibrium) of approximately 80%. In both groups, the rate of failure of any individual phone is the same. Furthermore, the rate of failure is only marginally related to the “genes”, i.e., whether the phone is an Apple iPhone, an Android, or some other type (a different “allele”). As the turnover rate (contract length to replacement) lengthens, the percent of failed cell phones climbs dramatically, regardless of the failure rate of any individual cell phone. In a pool of cell phones, “aging” is not a matter of passively accumulated damage, but of how actively we replace them.

The same is occurring in molecular pools in biological systems. The key predictor of “denatured” or dysfunctional molecules (e.g., AGE, beta amyloid microaggregates, cross-linking, elastin failure, collagen stiffening, etc) is not the rate of damage but the rate of turnover. In the case of cell aging, when we reset gene expression (reset telomere length) we reset the turnover rates (anabolism and catabolism rates) of all molecular pools to those typical of “young” cells. The outcome is that molecule pool turnover is more than sufficient to deal with typical rates of damage.

Without realizing it, most of us make the mistake of thinking of molecular pools as static and damage as purely accumulative. The reality is that such pools are dynamic and the key dependent variable (as with cell phones) is not the passive rate of damage, but the active rate of turnover.

Unless we understand – and examine – our assumptions, we can never expect to cure age-related diseases. Once we start down the wrong path, all the logic and data in the world can’t make up for the fact that we are looking in the wrong place. It’s time we stopped blaming “demons” and starting thinking carefully.

December 7, 2015

21st Century Science: Isn’t It About Time?

The other day I was asked about the role of denaturation of a particular protein in aging. It was a typical question that pretty much sums up the problem we have had in understanding (and doing anything about) aging during the past century. The problem is the question hides a flawed premise. It presupposes that molecules simply sit around and accrue damage. Put another way, the problem is that we look at molecules as part of as static pool rather than looking at the dynamic turnover that is the hallmark of metabolism.

Imagine a 1930 Duesenberg that has been lovingly cared for and is in pristine condition, even though it rolled off the assembly line 85 years ago. Compare this to my two-year-old car that already has a few rust spots. Was the Duesenberg better made than my car, that is, did it come with “better genes”? Was the Duesenberg exposed to less damage than my car, that is, did it have “fewer free radicals, less denaturing of its proteins, or a smaller rate of cross-linking”? No. The difference between that “ageless” Duesenberg and my own “aging” car is not the quality of the production line nor the exposure to sun, snow, salt, and dirt. The difference lies exclusively in the dynamics of its care. That Duesenberg was polished, aligned, oiled, repainted, repaired, and “recycled” on a regular basis. My own car is “aging faster” because I don’t care for it as frequently or as carefully as did the owners of that Duesenberg, and therein lies the entire difference between young organisms and old ones.

In aging organisms, it’s neither the genes nor the damage, but the slowing rate of recycling and repair that results in old cells, old tissues, old organisms, and age-related diseases.

Bizarrely and ironically, most people still look at biological systems and ignore the fact that they are alive, that they are dynamic, that they are constantly in flux. We look at a particular molecule – whether beta amyloid, collagen, GDF-11, or a thousand others – and we ignore the fact that these molecules are constantly being created, broken down, and replaced, but instead, we blindly focus on the damage itself. It’s true that as an organism ages any given pool of molecules shows an increase in damage – such as the aggregates of beta amyloid in early plaque formation – but the key is not the damage, the key is the slowing of the metabolic turnover. An accumulation of damage is not static and passively accumulative; it occurs because the rate of turnover falls as a result of changes in the pattern of gene expression. Whether we look at tau proteins, elastin, or any other molecular pool you want to look at, the key to the problem lies not in any particular gene nor in any particular source of damage. The key lies in the rate at which both anabolism and catabolism are replacing those molecules.

We don’t age because we accumulate damage, we accumulate damage because aging permits damage to accumulate.

A doctrinaire attention to “aging genes” and a catalog of one’s favorite sources of molecular damage will never result in cures to age-related disease. The key to intervention lies in the rate of molecular turnover, which responds to changing patterns of gene expression. Those who focus on genes and damage, to the exclusion of molecular turnover and gene expression, are perhaps some of our most highly-educated and intelligent minds of the 20th century…

…but it’s now the 21st century.

It’s time we caught up.

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