Michael Fossel Michael is President of Telocyte

February 13, 2018

Aging and Disease: 1.2 – Aging, What We Have to Explain

Our understanding is limited by our vision.

If we look locally, our understanding is merely local; if we look globally, our understanding becomes more global; and if we look at our entire universe, then our understanding will be universal. When we attempt to understand our world, we often start with what we know best: our own, local, provincial view of the world around us, and this limits our understanding, particularly of the wider world beyond our local horizon.

Trying to explain the shape of our world, I look at the ground around me and – perhaps not surprisingly – conclude that the world is probably flat. After all, it looks flat locally. Trying to understand the heavens, I look up at the sky around me and – perhaps not surprisingly – conclude that the sun circles the earth. After all, the sun appears to circle over me locally. Trying to understand our physical reality, I look at everyday objects and – perhaps not surprisingly – conclude that “classical physics” accounts for my universe. After all, classical physics accounts for typical objects that are around me locally. As long as we merely look around, look up, and look at quotidian objects, these explanations appear sufficient.

But it is only when we look beyond our purely local neighborhood – when we move beyond our provincial viewpoint, when we give up our simple preconceptions – that can we begin to understand reality. Taking a broader view, we discover that the Earth is round, that the sun is the center of our local star system, and that quantum and relativity physics are a minimum starting point in trying to account for our physical universe.

To truly understand requires that we step back from our parochial, day-to-day, common way of seeing world and open our minds to a much wider view of reality. We need to look at the broader view, the larger universe, the unexpected, the uncommon, or in the case of modern physics, the extremely small and the extremely fast. Time, mass, energy, and other concepts may become oddly elusive and surprisingly complicated, but our new understanding, once achieved, is a lot closer to reality than the simple ideas we get from restricting our vision to the mere commonplace of Newtonian physics. This is true of for branch of science, and for human knowledge generally.

The wider we cast our intellectual nets, the more accurately we understand our world.

To understand aging demands a wide net. If our knowledge of aging is restricted to watching our friends and neighbors age, then our resulting view of aging is necessarily naïve and charmingly unrealistic. If we expand our horizons slightly, to include dogs, cats, livestock, and other mammals, then we have a marginally better view of aging. But even if we realize that different species age at different rates, our understanding is only marginally less naive. To truly understand aging, we need to look at all of biology. We need to look at all species (not just common mammals), all diseases (e.g., the progerias and age-related diseases in all animals), all types of organisms (e.g., multicellular and unicellular organims, since some multicellular organisms don’t age and some unicellular organisms do age), all types of cell within organisms (since somatic cells age, germ cells don’t, and stem cells appear to lie in between the two extremes), and all the cellular components of cells. In short, to understand aging – both what aging is and what aging isn’t – we need to look at all life, all cells, and all biological processes.

Only then, can we begin understand aging.

To open our minds and examine the entire spectrum of aging – so that we can begin to understand what aging is and how to frame a consistent concept of “aging” in the first place – let’s contrast the small sample we would examine in the narrowest, common view of aging with the huge set of biological phenomena we must examine if we want to gain comprehensive and accurate view of aging, a view that allows us to truly understand aging.

The narrow view, the most common stance in considering aging, examines aging as we encounter it in normal humans (such as people we know or people we see in the media) and in normal animals (generally pets, such as dogs and cats, and for some people, domesticated animals, such as horses, cattle, pigs, goats, etc.). This narrow view leaves out almost all species found on our planet. This sample is insufficient to make any accurate statements about the aging process, with the result that most people believe that “everything ages”, “aging is just wear and tear”, and “nothing can be done about aging”. Given the narrow set of data, none of these conclusions are surpring, but then it’s equally unsurprising that all of these conclusion are mistaken.

A broad view has a lot more to take into consideration (see Figure 1), which is (admittedly) an awful lot of work. The categories that we need to include may help us see how broad an accurate and comprehensive view has to be. We need to examine and compare aging:

  1. Among all different organisms,
  2. Within each type of organism,
  3. Among all different cell types, and
  4. Within each type of cell.


Lets look at these categories in a bit more detail.

When we look at different organisms, we can’t stop at humans (or even just mammals). We have to account for aging (and non-aging) in all multicellular organisms, including plants, lobsters, hydra, naked rats, bats, and everything else. And not only do we need to look at all multicellular organisms, we also need to account for aging (and non-aging) in all unicellular organisms, including bacteria, yeast, amoebae, and everything else. In short, we need to consider every species.

When we look within organisms, we need to account for all age-related diseases (and any lack of age-related diseases or age-related changes) within organisms. Diseases will include all human (a species that is only one tiny example, but that happens to be dear to all of us) age-related diseases, such as Alzheimer’s disease and all the other CNS age-related diseases, arterial aging (including coronary artery disease, strokes, aneurysms, peripheral vascular disease, cogestive heart failure, etc.), ostoarthritis, osteoporosis, immune system aging, skin aging, renal aging, etc. But we can’t stop there by any means. In addition to age-related diseases within an organism, we need to look at aging changes (and non-aging) whether they are seen as diseaeses or not, for example graying hair, wrinkles, endocrine changes, myastenia, and hundreds of other systemic changes in the aging organism.

When we look at different cells, we need to account for the fact that some cells (e.g., the germ cell lines, including ova and sperm) within multicellular organisms don’t age, while other cells in those same organims (e.g., most somatic cells) do age, and some cells (e.g., stem cells) appear to be intermediate between germ and somatic cells in their aging changes.

When we look within cells, we need to account for a wild assortment of age-related changes in the cells that age, while accounting for the fact that other cells may show no such changes, even in the same species and the same organism. In cells that age – cells that senesce – we need to account for telomere shortening, changes in gene expression, methylation (and other epigenetic changes), a decline in DNA repair (including all four “families” of repair enzymes), mitochondrial changes (including the efficacy of aerobic metabolism enzymes deriving from the nucleus, leakier mitochondrial lipid membranes, increases in ROS production per unit of ATP, etc.), decreased turnover of proteins (enzymatic, structural, and other proteins), decreased turnover of other intracellular and extracellular molecules (lipids, sugars, proteins, and mixed types of molecules, such as glycoproteins, etc.), increased accumulation of denatured molecules, etc. The list is almost innumerable and still growing annually.

If we are truly to understand aging, we cannot look merely at aging humans and a few aging mammals, then close our minds and wave our hands about “wear and tear”. If we are to understand aging accurately and with sophistication, then we must not only look at a broader picture, but the entire picture. In short, to understand aging, we must stand back all the way in both time and space, and look at all of biology.

To understand aging, we must understand life.

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.


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.

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