Michael Fossel Michael is President of Telocyte

December 13, 2016

Telomeres: The Purloined Letter of Aging

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

                                                Edgar Allen Poe

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

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

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

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

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

There is a parallel in understanding aging.

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

 

November 22, 2016

Teaching Cells to Fish

Aging is the slowing down of active molecular turnover, not the passive accumulation of damage. Damage certainly accumulates, but only because turnover is no longer keeping up with that damage.

It’s much like asking why one car falls apart, when another car looks like it just came out of the showroom. It’s not so much a matter of damage (although if you live up north and the road salt eats away at your undercarriage, that’s another matter), as it is a matter of how well a car is cared for. I’ve see an 80-year-old Duesenberg that looks a lot better than my 4-year-old SUV. It’s not how well either car was made, nor how long either car has been around, but how well each car was cared for. If I don’t care for my SUV, my SUV rusts; if a car collector gives weekly (even daily) care to a Duesenberg, then that Duesenberg may well last forever.

The parallel is apt. The reason that “old cells” fall apart isn’t that they’ve been around a long time, nor even that they are continually being exposed to various insults. The reason “old cells” fall apart is that their maintenance functions slow noticeably and that maintenance fails to keep up with the quotidian damage occurring within living cells. If we look at knees, for example, the reason that our chondrocytes fail isn’t a matter of how many years you’ve been on the planet, nor even a matter of how many miles a day you spend walking around. The reason chondrocytes fail is because their maintenance functions slow down and stop keeping up with the daily damage. As it turns out, that deceleration in maintenance occurs because of changes in gene expression, which occur because telomeres shorten, which occur because cells divide. And, not at all surprisingly, the number of those cell divisions is related to how long you’ve been on the planet (how old you are) and how many miles you walk (or if you play basketball). In short, osteoarthritis is distantly related to your age and to the “mileage” you incur, but not directly so. The problem is not really the age nor is it the mileage; the problem is the failure to repair the routine damage and THAT failure is directly controlled by changes in gene expression.

So what?

The telomeres and gene expression may play a central role, but if your age and the “mileage” is distantly causing all those changes in cell division, telomere lengths, gene expression, and failing cell maintenance, then what’s the difference? Why bother with all the complexity? Why not accept that age and your “mileage” are the cause of aging diseases and stop fussing? Why not simply accept age-related disease?

Because we can change it.

The question isn’t “why does this happen?” so much as “what can we do about it?” We can’t change your age and it’s hard to avoid a certain amount of “mileage” in your daily life, but we CAN change telomeres, gene expression, and cell maintenance. In fact, we can reset the entire process and end up with cells that keep up with damage, just as your cells did when you were younger.

Until now, everyone who has tried to deal with only the damage (or the damaged cells) failed because they focused on damage rather than focusing on repair. For example, if you focus only on cell damage (as most big pharma and biotech companies do when they go after beta amyloid or tau proteins in trying to cure Alzheimer’s disease), then any clinical effect is transient and the disease continues to progress – which is why companies like Eli Lily, Biogen, TauRx, and dozens of other companies are frustrated. And small wonder. Or if you focus only on the damaged cells (and try removing them), then the clinical effect is not only transient, but will end up accelerating deterioration (as discussed in last week’s blog, see figure below) – which is why companies like Unity will be frustrated. Their approaches fail not because they don’t address the damage, but because they fail to understand the deceleration of dynamic cell maintenance that occurs with age – and fail to understand the most effective single clinical target. The key target is not damage, nor damaged cells, but the changes in gene expression that permit that damage, and those damaged cells, to lead to pathology. We can’t cure Alzheimer’s or osteoarthritis by removing senescent cells, but we can cure them by resetting those same cells.

Why you shouldn't kill senescent cells.

Why you shouldn’t kill senescent cells.

In the cases of removing senescent cells (an approach Unity advocates), wouldn’t it be better to remove the damaged cells and then reset the telomeres of those that remain? But why remove the damaged cells if you can reset them as well, with the result that they can now deal with the damage and remove it – as well as young cells do?

Why remove senescent cells at all?

While you could first remove senescent cells, then add telomerase so that the remaining cells could divide without significant degradation of function, why would you bother? You could much more easily, more simply, and more effectively treat all the cells in an aging tissue, reset their aging process and have no need to ever remove senescent cells in the first place. Instead of removing them, you simply turn them into “younger” and more functional cells. For an analogy, imagine that we have a therapy that could turn cancer cells into normal cells. If that were true, why would anyone first surgically remove a tumor? If you could really “reset” cancer cells into normal cells, there would be no need to do a surgical removal in the first place. While there is no such therapy for cancer cells, the analogy is still useful. Removing senescent cells is not only counter-productive, but (if we reset gene expression) entirely unnecessary.

Removal is unnecessary (both as to cost and pathology), risky, and medically contraindicated. You’d be performing a completely unnecessary procedure when a more cost-effective and reliable procedure was available. It would be exactly like removing your tonsils if you already had overwhelming data showing that an antibiotic was reliable, cheap, and without risk.

A cell with full telomere lengths – regardless of prior history – is already superior. The accumulated damage is not a static phenomenon, but a dynamic one. Reset cells can clean up damage. This is not merely theory, but supported well in fact, based on both human cells and whole animal studies. We shouldn’t think of damage as something that merely accumulates passively. All molecules are continually being recycled. The reason some molecular pools show increased damage isn’t because molecules denature, but because the rate of turnover slows, thereby allowing denatured molecules (damage) to increase within the pool.

Try this analogy: we have two buildings. One is run by a company that invests heavily in maintenance costs, the other is run by a company that cut its maintenance budget by 50%. The first building is clean and well-kept, the second building is dirty and poorly-kept. Would you rather raze the second building and then rebuild it or would you rather increase the maintenance budget back to a full maintenance schedule and end up with a clean building? This is precisely the case with young versus old cells: the problem is not the dirt that accumulates, the problem is that no one is paying for routine maintenance. There are cells that are “too senescent” to save, but almost all the cells in human age-related disease can be reset with good clinical outcome. There is no reason to remove senescent cells any more than (in the case of a dirty building), we need to send in the dynamite and bulldozers.

Too often, we try to approach the damage rather than looking at the longer view. Instead of addressing the process, we address the outcome. It’s like the problem that often occurs in global philanthropy, where we see famine and think we can solve the problem with food alone. While the approach is necessary – as a stopgap – many are surprised to find that simply providing free food for one year, results in bankrupt farmers and recurrent famines in the following years. Or we provide free medical care in a poor nation, then wonder why there is a dearth of medical practitioners in years to come, without realizing we have put them out of business and accidentally encouraged them to emigrate to someplace they can make a living and feed their families. We intend well, but we perpetuate the problem we are desperately trying to solve. Treating famine or medical problems, like treating the fundamental causes of age-related disease, is not simple and cannot be effectively addressed with band aids and superficial interventions, such as addressing damage alone or removing senescent cells. Effective clinical intervention – like effective interventions in famine or global healthcare – require a sophisticated understanding of the complexity of cell function, an understanding of the dynamic changes that underlie age-related pathology.

An adage (variously attributed to dozens of sources) about fish and fishing provides a useful analogy here:

Give a man a fish, and you feed him for a day.

Teach a man to fish, and you feed him for a lifetime.

If we want to intervene effectively in age-related diseases – whether Alzheimer’s, osteoarthritis, or myriad other problems of aging – we shouldn’t throw fish at medical problems.

We should teach our cells to fish.

 

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