Michael Fossel Michael is President of Telocyte

February 7, 2018

Aging and Disease: 1.1 – Aging, What it Isn’t

Filed under: Aging diseases,Alzheimer's disease,mitochondria — Tags: , , , — webmaster @ 9:29 am

It ain’t what you don’t know that gets you into trouble. It’s what you know for sure that just ain’t so.

– Mark Twain

Twain was right, particularly when it comes to the aging process: there is a lot we think we “know for sure that just ain’t so”. For example, most people (without even thinking about it and with a fair amount of naïve hand-waving) assume that all organisms age and equate aging with entropy. In other words, they think that “aging is just wear-and-tear”. We assume that aging “just happens” and that nothing can be done about it. After all, we all get old, things fall apart, things rust, everything wears out, so what can you expect? But as with Twain’s remark, the trouble is that we are quite sure of ourselves and we what we think is completely obvious, turns out to be completely wrong. We are content to gloss over our faulty assumptions and move to faulty conclusions. It’s bad logic, bad science, and a bad way to intervene in the diseases of aging. Without thinking about it, we conclude that aging is as simple as our preconceptions, which turn out to be erroneous.

Aging isn’t simple and our preconceptions are wrong.

As with most concepts that we don’t examine meticulously, aging is a lot more complex than we realize. Aging isn’t just entropy, it isn’t just wear-and-tear, and it isn’t many things that people blithely believe it to be. Let’s look at a few examples that make us back up and reconsider how aging works. Let’s start with your cells, and then your mitochondria.

We could take any cell in your body, for example a skin cell on the back of your hand. How old is that skin cells? Since we shed perhaps 50 million skin cells every day, there’s a good chance that the cell we are thinking about is only a day or so old, or at least a day or so since the last cell division. But that last division was from a “mother” cell that was there before the cell division resulted in two “daughter” cells. So perhaps our skin cell, counting the age of the “mother” cell is a week or so old? But that “mother” cell, in turn, derived from a dividing cell that was there several weeks ago, backwards ad infinitum to the first cells that formed your body. In fact, every cell in your body is certainly as the whole body, so perhaps that skin cell is a few decades old. You might say that the skin cell has the same age that you see on your driver’s license. Except that your entire body is the result of a cell (ova) from your mother and a cell (sperm) from your father, and each of those cells was already a few decades old (or however old your parents were) when the sperm and ovum became “you” when they joined at fertilization. But, of course, your parent’s germ cells came from their parents, whose germ cells came from their parents, and we can trace that lineage of germ cells back to… Well, all the way back to the origin of life on Earth. So in a very real, very strictly accurate biological sense, every cell in your body is 3.5 billion years old.

But if we assume that aging is just entropy, then we have explain why that line of germ cells (that resulted in your entire body) didn’t undergo any entropy (i.e., didn’t age) for 3.5 billion years and yet your somatic cells are now undergoing entropy (i.e., aging) in your body and have been aging since you were born. Why do somatic cells suffer from entropy, if germ cells don’t? Does entropy only work in certain cells and not in others? Apparently so. And if that’s true, then we can’t just wave our hands and invoke entropy as the entire explanation, can we? We have to explain something more subtle and complicated: why entropy results in aging in some cases (the somatic cells in your body) but not in other cases (the line of 3.5 billion year-old germ cells that led up to you having a body in the first place). How interesting. So much for just invoking the concept of entropy and walking away satisfied.

Entropy almost certainly plays a key role in aging, but we can’t simply leave it at that. We need to think a bit harder. Sometimes entropy wins (your body and most of its cells age in a matter of decades) and sometimes entropy doesn’t appear to win at all (your germ cell line didn’t age for 3.5 billion years). Why sometimes and not other times?

One way that some people have tried to explain this is to invoke mitochondrial damage, but an almost identical problem surfaces in the case of mitochondrial entropy. Given the prevalence of aging explanations based on free radical theory (reactive oxygen species, etc.), mitochondrial dysfunction is an obvious suspect for an explanation of aging. We know that older mitochondria make more free radicals, leak more, and those free radicals aren’t scavenged as well, so perhaps all of aging is a mitochondrial problem? Perhaps entropy simply causes mitochondrial damage and that’s why we age. Perhaps entropy works by aging our mitchondria, right?

Except that mitochondrial entropy can’t explain aging either.

If aging were the result of “aging” mitochondria, damaged by entropy (high internal mitochondrial temperature, free radicals, loose protons and electrons, and a general accumulation of mitochondrial damage over time), then we are still left with an embarrassing conundrum. To understand the problem, let’s ask a simple question: how old are your mitochondria? Mitochondria divide fairly constantly, depending on the cell and its energy demands. In some cells (such as liver cells), with high energy demands, mitochondria are dividing all the time, in others with low energy demands, mitochondria divide much less frequently. On the other hand, since every mitochondria in every cell in your body derived from the mitochondria that were present in you as a fertilized zygote, we might reasonably say that your mitochondria are all the same age as your body, i.e., all of your mitochondria are a few decades old, and as time goes by, your mitochondria simply wear out, right?

Well, no.

Every mitochondria that you had as a fertilized zygote was derived from your mother’s ovum, which supplied all of your original mitochondria, so your mitochondria are as old as you are. Well, as old as you are plus as old as your mother was when you were conceieved. Oh, and plus the age of her mother and her mother and so on, ad infinitum back as far as the very first mitochondrial inclusion in the very first eukaryotes (or so). So every mitochondria in your body is about 1.5 billion years old and they’re doing pretty well for their age. But that means that if we want to blame aging entirely on mitochondrial dysfunction (and mitochondria surely play a major role in aging), we are still left with a conundrum. We have to explain why all of those dividing mitochondria (which were at least 1.5 billion years old) hadn’t aged for 1.5 billion years, and now all of your mitochondria are having significant problems after only a few decades. Why do your mitochondria suddenly start aging when they were doing so well for the last 1.5 billion years? The problem is that your mitochondria really do showing aging changes, but the mitochondra from your mother clearly didn’t until you came along. Worse yet, we have to explain both of these effects (aging and non-aging) simultaneously if we want to explain aging at all. How can we do both? We can’t simply wave our hands (again) and blame entropy unless we can simultanously explain why entropy works sometimes and in some cells (liver cells, for example), but entropy doesn’t work at other times and in other cells (the mitochondria in the germ cell line, for example). Again, why sometimes and not other times?

If entropy were an entirely sufficient explanation, they why does entropy age some cells (and some mitochondria) and not other cells (and other mitochondria)? If we restrict our explanation of aging solely to entropy, then we have a problem. We can’t just say that entropy does cause aging (because sometimes it doesn’t) nor can we say that entropy doesn’t cause aging (because sometimes it does). Entropy plays a role in aging, but not always.Why? What we have to do, if we really want to explain aging, is explain why entropy varies in biological systems. Sometimes entropy wins, sometimes it doesn’t.

Our preconception about entropy – wear-and-tear – as the sole cause for aging is a common misconception and not always noticed. It creates a subtle, but pervasive bias in our thinking about biolgy and aging. Even once we realize that entropy can’t explain all of cell or mitochondrial aging, we still find entropy creeping back into our thinking, but disguised under a different form. We tend to think of Alzheimer’s, for example, as what happens when beta amyloid, tau proteins, or mitochondria undergo entropy and cause neuronal death and clinical disease. We think of skin aging as what happens when collagen and elastin undergo entropy and cause wrinkles and aging skin. Some people blame aging on entropy of the endocrine system, concluding that all of aging comes about because of entropy in a gland or hormonal tissue. The fact that aging can occur in some organisms without endocrine systems (and that replacing hormones doesn’t stop aging) doesn’t change their misconception. But whatever guise it hides under, entropy by itself, cannot explain aging or age-related disease. There are too many odd things to explain, too many exceptions, too many cases where entropy explains one finding, but not another finding. Entropy can explain this cell, but not that cell. Entropy can explain this mitochondria, but not that mitochondria. Entropy simply can’t explain aging in toto. We have to dig a bit further.

Entropy, as an explanation of aging, only works if we close our eyes and ignore most of biology. As we’ll see in the next blog, there is a lot of biology that needs to be accounted for if we are going to explain how aging works. However we try to shoehorn entropy into being the entire explanation, aging cannot be entropy alone. As we will see, entropy does play a crucial role, but we cannot simply cite entropy, wave our hands, and say we understand aging. Aging is not entropy: aging is entropy plus something else, something subtle and complex, but something crucial to a complete understanding of aging.

As we will soon see, aging is entropy in the face of failing maintenance.

 

Next: 1.2 – Aging, What We Need to Explain

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 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.

 

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.

 

November 15, 2016

Close to a Cure

We are now within two years of a cure for Alzheimer’s disease.

What a brash and disruptive claim! What hubris! Yet events are coming together, underlining a new and far more complete understanding of the disease, illuminating the cause, supporting the ability to intervene, safely and effectively. We finally see a way to intervene in the basic pathology, underlining the potential to both prevent and cure Alzheimer’s disease.

But why has it taken so long? Why was Alzheimer’s disease first defined 110 years ago, and yet remains totally beyond our ability to intervene even now? Why have all other approaches, whether those of big pharma or those of biotech, failed utterly? Why has not a single clinical trial shown any ability to change the progress of this frightening disease? Why is Alzheimer’s disease not only called “the disease that steals human souls”, but also called the “graveyard of companies”? Why has every single approach (which has at most shown only an effect on biomarkers, such as beta amyloid), still failed to show any change in the cognitive decline in patients with this disease? Why have we failed universally, until now?

Because every approach has concentrated on effects, not on causes.

Currently, most approaches target beta amyloid, many target tau proteins, and some target mitochondrial function, inflammation, free radicals, and other processes, but no one targets these problems as a single, unified, overarching process. Alzheimer’s isn’t caused by any one of these disparate processes, but by a broader, more complex process that results in every one of these individual problems. Beta amyloid isn’t a cause, but a biomarker. Equally, tau proteins, phosphodiesterase levels, APOE4, presenilins, and a host of other markers are effects, not causes. The actual cause lies upstream and constitutes the root cause of the dozens of separate effects that are the futile downstream targets of every current FDA trial aimed at Alzheimer’s disease. Understanding this, we will be targeting the “upstream” problem, rather than the dozens of processes that others target individually and without success. Our animal studies support the ability to effectively intervene in human disease: when we say that we are about to cure Alzheimer’s disease, we base claim that on a clear and consistent theoretical model, supported by equally clear and consistent data.

Within the next few months, we will begin our FDA toxicity study, preparatory to obtaining an IND that will permit us to begin our FDA human trial. Our toxicity study will take 6 months and will meet FDA requirements for human safety data. Our first human trial is planned to begin one year from now and is intended to show not only safety, but a clear efficacy. We will include a dozen human volunteers, each with (not just early, but) moderate Alzheimer’s disease and our human trial will last 6 months, including a single treatment and multiple measurements of behavior, laboratory tests, and brain scans. We expect to show unambiguous cognitive improvement within that six-month period. We are confident that we cannot merely slow, not merely stop, but reverse much of the cognitive decline in our twelve patients. We intend to demonstrate an ability to cure Alzheimer’s disease clearly and credibly.

Curing Alzheimer’s requires investments of money, time, and thought. The toxicity study costs 1 million dollars; the human trial costs 2.5 million dollars. Telocyte has half a million dollars committed to this effort and at least one group of investors with a firm interest in taking us all the way through the human trials. We are close and we grow closer each day.

After 110 years, we are about to cure Alzheimer’s.

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 .

 

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.

May 12, 2015

The Telomerase Revolution

My new book, The Telomerase Revolution, is now finished and is being copy edited by the publisher. Oddly enough, it’s already selling well in preorders. Amazon.com says that it is now the “#1 release in medical research”, which is a delightful surprise, since it won’t actually be published and available to the public until October. For those of you who would like to order a copy, here is the link to Amazon.com:

  • http://www.amazon.com/Telomerase-Revolution-Enzyme-Aging%C2%85-Healthier/dp/194163169X/ref=sr_1_1?ie=UTF8&qid=1426777801&sr=8-1&keywords=telomerase+revolution

The book is a careful and clear discussion of how aging works in cells, how it causes the clinical diseases of aging, and what we can do to cure age-related disease. There is a good clear chapter on vascular aging and neurodegenerative disease — especially Alzheimer’s disease — that a lot of reviewers find especially intriguing. Len Hayflick, the researcher who first described cell aging more than fifty years ago, calls the chapter “superb”. Matt Ridley, author of several best sellers including The Rational Optimist, Genome, and The Red Queen, says that he read the chapter with “real fascination” and tells me “I badly want to read more of the book”.

If anyone would like to do a book review, please contact me, and I will arrange to send you a review copy.

April 15, 2015

Alzheimer’s, Microglia, Mitochondria, and Arginine

Every several weeks, I notice publication of yet another article trumpeting another aspect of Alzheimer’s. Where once it was APOE-4, AB42, or SS31 (an antioxidant peptide), more recent work emphasizes arginine metabolism in the microglia. The good news is that research community has — ponderously and hesitantly — finally begun to shift the clinical focus from the neuron to the microglial cells, a shift that many of us have been pushing for almost two decades. Neuronal damage was always the more obvious pathology, at least under the optical microscope, but it was never the underlying cause of the cascade of damage that results in Alzheimer’s disease. Gradually, we have come to realize that the microglial cells, and often vascular changes, play an early role in starting the avalanche of this horribly tragic pathology.
And yet, even now, it is frustrating to watch how much of the research creeps along, staring myopically down at trivial and secondary problems. It’s not so much that we see the trees and ignore the forest, but that we see the specific lichen on the specific root of a specific type of tree, while missing the interactions and overall pathology that drives the entire forest. The recent focus on arginine is a case in point, but SS31 is a parallel example. In the case of arginine, we notice the microglia; in the case of SS31 we notice the mitochondria, but in both cases we fail to look harder and deeper and we fail to understand the broad processes that drive these changes.
Mitochondrial dysfunction within the microglia is a good example. The dysfunction is not seen in germ cells, nor in young somatic cells, but is prominent in aging somatic cells. How can a germ cell lineage, carrying a line of 1.5 billion year old mitochondria, have normal function, while a somatic cell, having undergone a few dozen divisions in a few dozen years, suddenly have a dysfunctional mitochondria that was doing well for the last few billion years? Actually, we know the answer to that. Not only is it due to changing gene expression within the cell nucleus, slowing the production of many key enzymes needed in the citric acid cycle within the mitochondria, but we know that when we reset this pattern of gene expression in the nucleus, the mitochondria resume normal function. While the aging cell makes less ATP and a higher proportion of ROS as the damaged mitochondrial enzymes permit electrons to “slip” down the chain, but these changes are entirely reversible when we reset telomere lengths within the nucleus.
Nor does it stop there. Just as the aging cell begins to have a lower ATP/ROS ratio, so too do the lipid membranes begin to leak those ROS species, so too do our scavenger enzymes (like SOD) fail to capture those escaped ROS species, and so too do our cells fail to rapidly recycle the molecules damaged by those ROS species. And in every case, these four issues can be traced directly back to the slower turnover induced by a changing pattern of gene expression within the nucleus, which is orchestrated by a gradual telomere loss.
Such changes can be (and have been) reset in human cells, in tissues, and in animal models. So why not reset the microglial telomeres and cure Alzheimer’s?

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