Critiquing "The Way We Age"

Molecular biologist Derya Unutmaz (who maintains Biosingularity, and who was interviewed not so long ago by Attila Chordash of Pimm) made a few comments via the Gerontology Research Group mailing list on the topic of the recent New Yorker piece "The Way We Age":

There are several misconceptions early in the article in my opinion, see my comments below, which are mostly meant for discussion purposes.
These findings notwithstanding, scientists do not believe that our life spans are actually programmed into us.

I am wondering who are these scientists why they do not believe that our life spans are actually programmed in us?

After all, for most of our hundred-thousand-year existence­ - all but the past couple of hundred years ­- the average life span of human beings has been thirty years or less. (Research suggests that subjects of the Roman Empire had an average life expectancy of twenty-eight years.) Today, the average life span in developed countries is almost eighty years. If human life spans depend on our genetics, then medicine has got the upper hand. We are, in a way, freaks living well beyond our appointed time.

This is gross misconception. The reason why the average life span was so low was because most of the deaths occurred during childhood and through infections during adulthood. If one corrects for the infection survival and looks at life expectancy at older age, there has only been about 6-8 years increase in overall life extension in the last 100 years. Thus, the data strongly argues for biological program of aging, and that at current time we are not yet freaks living much beyond our appointed time, just that many more of us reaching the near maximal set program.

So when we study aging what we are trying to understand is not so much a natural process as an unnatural one. Inheritance has surprisingly little influence on longevity. James Vaupel, of the Max Planck Institute for Demographic Research, in Rostock, Germany, notes that only six per cent of how long you'll live....

This is not correct. The most comprehensive Danish twins study found that the genetic factors account for about 25% of longevity, which I think again greatly underestimates the biological genetic program because the life styles vary greatly even between identical twins. If genetically identical twins have the exact life styles, they appear to live remarkably to about the same age, again arguing for biological program.

If our genes explain less than we imagined, the wear-and-tear model may explain more than we knew. Leonid Gavrilov, a researcher at the University of Chicago, argues that human beings fail the way all complex systems fail: randomly and gradually. As engineers have long recognized, many simple devices do not age. They function reliably until a critical component fails, and the whole thing dies instantly. A windup toy works smoothly until a gear rusts or a spring breaks, and then it doesn't work at all. But complex systems­ - power plants, say­ - have to survive and function despite having thousands of critical components.

Again I would argue that wear-and-tear model is gross oversimplification. If the simple wear-and-tear model was true for complex biological organisms then one would not expect wild differences in lifespan of equally complex organisms such a mouse (2 years), human (100 years), Bowhead whales and turtles (200 years), or some plants/trees (1000s of years). This also contradicts with an earlier paragraph in the article.

While the engineering analogies made by some appear intuitive or attractive, they forget the biological systems are autonomous in that they have built in repair and control mechanisms and far more flexibility then material systems. When a gear of a car breaks down or rusts, that car can not repair itself or install a new gear, whereas our bodies perform these operations every day both on the cellular and organismal level. This is a fundamental distinction.

Engineers therefore design these machines with multiple layers of redundancy: with backup systems, and backup systems for the backup systems. The backups may not be as efficient as the first-line components, but they allow the machine to keep going even as damage accumulates. Gavrilov argues that, within the parameters established by our genes, that's exactly how human beings appear to work. We have an extra kidney, an extra lung, an extra gonad, extra teeth.

Mice and humans have exactly the same number of organs and appear to have the same backup systems, why is it that there is a 50 fold difference in their lifespan?

It happens in a bewildering array of ways. Hair grows gray, for instance, simply because we run out of the pigment cells that give hair its color. The natural life cycle of the scalp's pigment cells is just a few years. We rely on stem cells under the surface to migrate in and replace them. Gradually, however, the stem-cell reservoir is used up. By the age of fifty, as a result, half of the average person's hairs have gone gray.

So what if our stem-cell reservoir was never used up? Can we have non-gray and full hairs indefinitely or much much longer? That is to say if the code was written such that stem cells continued renewal for 200 years instead of 50.

Inside skin cells, the mechanisms that clear out waste products slowly break down and the muck coalesces into a clot of gooey yellow-brown pigment known as lipofuscin. These are the age spots we see in skin. When lipofuscin accumulates in sweat glands, the sweat glands cannot function, which helps explain why we become so susceptible to heat stroke and heat exhaustion in old age.

What if the mechanisms that clear out the waste products don't break down or rather stop working? That is if the genetic code was such that garbage collectors continued to do their job.

The eyes go for different reasons. The lens is made of crystallin proteins that are tremendously durable, but they change chemically in ways that diminish their elasticity over time­hence the farsightedness that most people develop beginning in their fourth decade. The process also gradually yellows the lens. Even without cataracts (the whitish clouding of the lens caused by excessive ultraviolet exposure, high cholesterol, diabetes, cigarette smoking, and other unhelpful conditions), the amount of light reaching the retina of a healthy sixty-year-old is one-third that of a twenty-year-old.

This could be one of those conditions that really is due to wear-and-tear, and needs to be regenerated or replaced completely.

I spoke to Felix Silverstone, who for twenty-four years was the senior geriatrician at the Parker Jewish Institute, in New York, and has published more than a hundred studies on aging. There is, he said, "no single, common cellular mechanism to the aging process." Our bodies accumulate lipofuscin and oxygen free-radical damage and random DNA mutations and numerous other microcellular problems. The process is gradual and unrelenting. "We just fall apart," he said.

I would say "it's the genetic program stupid" :)

I think there are gray areas where structure and process as defined by our genes ends and wear and tear picks up; I would present the whole as a case of wear and tear acting on a self-repairing system with certain defined characteristics. The end result is complex, highly varying between individual circumstances, but much more consistent over statistically significant (i.e. large) groupings of similar genes and lifestyles.

One of the fundamental and most important debates amongst those working on the development of longevity medicine is this: do we give priority to changing our program of operation (by, say, manipulating gene expression, altering our genes, or otherwise shifting the activity of proteins in our body), or do we attempt to fix up the wear and tear in the present program of operation. Discussion of the sort Unutmaz engages in above are far from academic: research, development, fundraising and education is taking place today. The foundation of the next decade of research is being laid right now - the effectiveness of that research will mean the difference between life and death for uncounted millions.

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Comments

The New Yorker article was utterly stupid. Of course, what can you expect from a lifestyle and culture magazine such as the New Yorker?

Derya hit the nail on the head with the comment about biological systems being inherently dynamic with built-in self-repair and regeneration, as opposed to a manufactured static product like a house or car. This crucial difference is overlooked, not only by the journalists like those of the New Yorker, but also by M.D.s who are supposed to know better. The reason? Because almost all M.D. (not to mention anyone else in the medical field) are of liberal arts background. They do not understand technical issues and are, therefor, incapable of understanding biochemistry and molecular biology.

Much of conventional medicine is a fraud. The medical schools do not teach the fundamentals of bio-chemistry and molecular biology. Rather, they teach medical conditions on the basis of rote memorization, much like learning the kanji when studying Japanese or Chinese language. It is no wonder why progress in medicine is essentially non-existant.

Especting people to practice medicine without knowing the fundamentals of biochemistry and molecular biology is as stupid as expecting people to design airplanes without knowing the principles of aerodynamics or fabbing semiconductor chips without understanding the material science and chemistry that goes into them.

Posted by: Kurt9 at April 26th, 2007 9:37 AM

"There are several misconceptions early in the article in my opinion, see my comments below, which are mostly meant for discussion purposes."

I think the misconceptions are mainly yours.

"I am wondering who are these scientists why they do not believe that our life spans are actually programmed in us?"

The answer is very simple. If you look at any animal *in nature* (not at the protecting environment of the laboratory/zoo/home), you see that lifespan curves are exponential, i.e the rate of death does not increase over time (a critical characteristic of aging). The reason for this is simple, animals in nature don't die of aging, almost all of them die because of extrinsic forces (predation, starvation, infectious diseases, accidents, cold weather...). If you understand this, then you understand why there is no need for genes that limit lifespan, there is no selective force to select such genes, because almost all animals in fact die at their prime health.

"This is gross misconception. The reason why the average life span was so low was because most of the deaths occurred during childhood and through infections during adulthood. If one corrects for the infection survival and looks at life expectancy at older age, there has only been about 6-8 years increase in overall life extension in the last 100 years. Thus, the data strongly argues for biological program of aging, and that at current time we are not yet freaks living much beyond our appointed time, just that many more of us reaching the near maximal set program."

Again, all animals in nature die *not* of aging, rather by extrinsic factors. There is no reason to believe things were any different for us humans, maybe not in the last couple of hundred years, but definitely before that.

Just a reminder, the changes to our genome in the last couple of hundred years, those that affect lifespan, are meaningless in comparison to the changes that happened before that, and by this I want to say that if you look for a genetic program for aging, you need to look in the hundreds of thousands of years before our current time, but in this period, a genetic program of lifespan could not have evolved if we died of extrinsic factors.

"This is not correct. The most comprehensive Danish twins study found that the genetic factors account for about 25% of longevity, which I think again greatly underestimates the biological genetic program because the life styles vary greatly even between identical twins. If genetically identical twins have the exact life styles, they appear to live remarkably to about the same age, again arguing for biological program."

Yes, genetics do have a role in human aging, but not the role you are thinking about. there is no "biological program of aging", rather, there isn't a "biological program for not aging", hence aging happens. in the far past, we didn't have to have a biological program for not aging, because we did not die of aging, rather by extrinsic forces. Our genome is perfectly capable of carrying us to our 30's in prime health, but because we didn't have a need for more than that in most of the period when our genome evolved, our genes do not support for good health over the 30's, and this is why aging happens after that.

"Again I would argue that wear-and-tear model is gross oversimplification. If the simple wear-and-tear model was true for complex biological organisms then one would not expect wild differences in lifespan of equally complex organisms such a mouse (2 years), human (100 years), Bowhead whales and turtles (200 years), or some plants/trees (1000s of years)."

You are wrong in my opinion.

First of all, mice in nature live around 1 year, humans supposedly lived 30 years up to several hundred yeasts ago (died before aging had a chance to influence) and galapagos turtles live several hundred years. Why is this so ?, again, because extrinsic factors govern the lifepan of the animal, and each animal in nature is differently equipped to handle those extrinsic factors at its natural habitant.

Humans are much more immune to extrinsic dangers than mice, it is not hard to see why, and this is the reason we live much longer. Galapagos turtles with their huge armor are more immune than humans were (in the fat past) to extrinsic danger factors, and this is why they live more.

Think about the following mechanism: let's talk about the ancestor of the bat, before he had wings, let's assume that his average lifespan was 1 year in nature (similar to mice) and he did not die of aging, as all animals in naure. Now (and this is of course simplification), let's take this wingless bat ancestor, and now give him wings. The result of this will be that now he will be able to be much more resistant to extrinsic dangers, so he will be able to live more years before extrinsic factors get him, but the result will be that he will now age (similar to what happens when you take animals from the wild, and put them in a more protected environment, they start to age). What will happen now is that we'll see a community of bats that die of aging, but during the next seveal hundred thousand years, those bats that do not age (or age less) will be selected by natural selection, because they can bring more descendants. So, at the end what we'll get is a group of bats that again don't age, but live more than the wingless ancestor.

Posted by: Noam at April 26th, 2007 1:00 PM

Kurt9,
I don't agree with you. Derya hit nothing on its head with his comment. Among those who really understand aging, he is in a minority with his opinion.

Yes, biological systems have self repair, but like Reason said, part of the damage that happen in aging, is in those self repair mechanisms themselves. Not to mention that these self repair mechanisms can't repair everything, and aren't suppose to.

You have to understand a simple notion: In nature it is rate to find an animal that dies of aging, they don't, rather they die of extrinsic forces that kill when the animal (at least according to its genome) should be in prime health.

Now, if 95% of the population of a certain animal in nature, don't live more than age 30 (for example), because they die of extrinsic forces (again: predation, starvation, infectcious disease, accidents etc.), then genes that confer healthy life beyond age 30, will not be selected for this certain animal, there is no selective pressure to select such genes.

So, what you're getting is an animal that has repair mechanisms that keep the level of molecular damages under a certain threshold up to age 30, but those repair mechanisms do not operate strong enough, nor handle enough type of damages to confer healthy life beyond age 30, and why ?, because it is a waste of energy for the animal's body to confer resistance to a period in time it has a 95% chance not to be living anymore.

If we have 30,000 genes in our genomes, non of them were selected to operate well beyond age 30, and this is why we start to slowly fall apart beyond that age. There is no genetic plan for aging, there is a lack of plan for staying alive forever, becuase up to several hundreds years ago, we didn't need such genetic plan, and several hundred years are not nearly enough to develop such genetic plan.

Posted by: Noam at April 27th, 2007 2:41 AM

Noam,

This is a response to your comments to my comments.

Me: "I am wondering who are these scientists why they do not believe that our life spans are actually programmed in us?"

Noam: The answer is very simple. If you look at any animal *in nature* (not at the protecting environment of the laboratory/zoo/home), you see that lifespan curves are exponential, i.e the rate of death does not increase over time (a critical characteristic of aging). The reason for this is simple, animals in nature don't die of aging, almost all of them die because of extrinsic forces (predation, starvation, infectious diseases, accidents, cold weather...). If you understand this, then you understand why there is no need for genes that limit lifespan, there is no selective force to select such genes, because almost all animals in fact die at their prime health.

Me: It seems to me that you are trying to explain why we have the current biological program that limits our lifespan, or rather don't have program that was selected for us to live indefinitely, through evolutionary biology. I didn't ask why we have the biological program we have, it is obvious that it was not selected for for the evolutionary reasons you state above. If you read my question again, I asked why some scientists, quoted vaguely in the article (we still don't know who they are except one), do not believe in this biological program. If you remove all environmental factors, the biological program will not allow you to live beyond a set point. You are stating why this is the case, which I agree.

Me: "This is gross misconception. The reason why the average life span was so low was because most of the deaths occurred during childhood and through infections during adulthood. If one corrects for the infection survival and looks at life expectancy at older age, there has only been about 6-8 years increase in overall life extension in the last 100 years. Thus, the data strongly argues for biological program of aging, and that at current time we are not yet freaks living much beyond our appointed time, just that many more of us reaching the near maximal set program."

Noam: Again, all animals in nature die *not* of aging, rather by extrinsic factors. There is no reason to believe things were any different for us humans, maybe not in the last couple of hundred years, but definitely before that.

Mel: Please reread my point. I am really not sure what you are responding to. I specifically said the increase in average human lifespan was because of elimination of extrinsic factors you point out. As this chart http://www.infoplease.com/ipa/A0005140.html clearly shows, if you made it to age 70 in 1850 your life expectancy was about 10 years. After more than 150 years that has only increased about 4 years! Whereas life expectancy at birth has doubled from 38 to 76. It seems we are saying the same thing, if you correct for the extrinsic factors, biological program of humans does not allow you to pass beyond a set point. In fact you are also correct that this set point probably have not changed during the last thousands of years.

Me: "This is not correct. The most comprehensive Danish twins study found that the genetic factors account for about 25% of longevity, which I think again greatly underestimates the biological genetic program because the life styles vary greatly even between identical twins. If genetically identical twins have the exact life styles, they appear to live remarkably to about the same age, again arguing for biological program."

Noam: Yes, genetics do have a role in human aging, but not the role you are thinking about. there is no "biological program of aging", rather, there isn't a "biological program for not aging", hence aging happens. in the far past, we didn't have to have a biological program for not aging, because we did not die of aging, rather by extrinsic forces. Our genome is perfectly capable of carrying us to our 30's in prime health, but because we didn't have a need for more than that in most of the period when our genome evolved, our genes do not support for good health over the 30's, and this is why aging happens after that.

Me: I am really puzzled by response again. I didn't say there is a biological program of aging, did I? I said there is a biological program, that program was not selected for us to survive beyond a certain age. Again you are explaining why our biological program is the way it is now, whereas I was simply responding to the article argueing that it is all about the biological program. If you do NOT change the program, no matter how much you stop the wear and tear, extrinsic factors, you will still age and die, maybe few laters but that's all.

Me: "Again I would argue that wear-and-tear model is gross oversimplification. If the simple wear-and-tear model was true for complex biological organisms then one would not expect wild differences in lifespan of equally complex organisms such a mouse (2 years), human (100 years), Bowhead whales and turtles (200 years), or some plants/trees (1000s of years)."

Noam: You are wrong in my opinion.

First of all, mice in nature live around 1 year, humans supposedly lived 30 years up to several hundred yeasts ago (died before aging had a chance to influence) and galapagos turtles live several hundred years. Why is this so ?, again, because extrinsic factors govern the lifepan of the animal, and each animal in nature is differently equipped to handle those extrinsic factors at its natural habitant.

Me: Nope I am not wrong. I was pointing out the maximum lifespans of different biological organisms, not their average lifespans. My point is, humans, turtles and bowhead whales, have been selected to have a biological program that allows them to live much much greater maximum lifespan compared to mice. Again, I didn't ask why is this so. Of course natural selection favored for genes of turtles that allows them to live longer selected because they can protect themselves from extrinsic factors through their huge armor. This means it is possible to change the biological program to live much much longer IF there was sufficient selective pressure. This in turn argues against simple wear and tear model, and also suggest that if we could genetically modify human biological program, we can extend our lifespan indefinitely, because we would be doing what natural selection would need millions of years.

In summary your arguments are evolutionary reasons of our current biological program, which I don't think any credible scientist would question. It seems you completley misunderstood my comments.

My summary "it's the genetic program stupid" remains the same. You just explained why that's the way it is because of natural selection.

Posted by: Derya at April 28th, 2007 11:02 AM

Hi Derya,

Yes I seemed to have some misunderstanding regarding what you were trying to claim.

You said:

1. "Thus, the data strongly argues for biological program of aging".

2."This means it is possible to change the biological program to live much much longer IF there was sufficient selective pressure. This in turn argues against simple wear and tear model, and also suggest that if we could genetically modify human biological program, we can extend our lifespan indefinitely, because we would be doing what natural selection would need millions of years."

We seem to agree that humans didn't have a selective pressure to select for genes that confer healthy lives beyond the 30's (or so), because in the past extrinsic factors killed most of us before that.

If we agree on this, we should also agree that potentially all of our 30,000 genes limit our lifespan beyond the 30's (because none of them has been through a pressure not to).

Yes, it is true that we have repair mechanisms that might extend our lives a bit if we'll get them to work harder, but there is no reason to believe we have any repair mechnisms for damages that do no influence within the first 30 years of our lives or so, if not repaired (never was a selective pressure to get such repair mechanisms).

So, if we agree on all this, then maybe you could see why I had trouble accepting your wording that we have a "biological program of aging", and that if we'll modify it, we could live indefinitely.

Purely theoretically speaking, you are correct (except that we won't live indefinitely, just won't age), but practically, saying we have a "biological program of aging", and that if we'll modify it we won't age, to me sounded like you are saying it is *practically* amendable for artificial change. It seemed to me that by using the word "program", you are saying there is some order in the way we age, and by understanding this order, and learning to amend it, we could change it successfully.

But the trouble is, there is no order in the process of aging, we have 30,000 genes, and trillions of interactions between those genes products and other molecules, and most of them if not all of them, lead in a parallel way toward aging. There is total chaos in the process of aging, and this is why I had trouble grasping your wording of "program of aging" as what aging really is. I gave the evolutionary explanation just because from it you can confer just how un-orderly and "un-programmed" the process of aging really is.

I think saying that aging happens because we "don't have a biological program of not-aging", is much better wording, and describe the phenomena of aging and what we have to deal with if we want to amend it, much more accurately, than saying that aging is caused by a biological genetic program. It could be semantics, but in my opinion those semantics are important.

Regarding how we *can* amend the "program of aging" toward not aging, well, nature does it by trial and error, over a period of millions of years, this is a straightforward way that requires no thinking.

If we want to achive it artificially using our logic, we have to take into account how our 30,000 genes, simultaneously, affect trillions of intracellular and extracellular molecule interactions and reactions, and make sure not a single one of them will eventually lead to some sort of accumulated damage that we have no enzyme that could repair. I think most will agree this is impossibe task, even if our reasoning will be aided by computers.

In my eyes, the only thing that could work is to artificially mimic how nature does it, by using supercomputers. Someday in the distant future, when we'll have a computer fast enough (and software accurate enough) to model the entire human body, we could ask this computer to use trial and error to find the right sequence of nucleotides that should build our genome, in order not to age, we'll simply be using the computer to simulate natural selection toward non-aging for our bodies, and then take the result of the calculation and apply it by gene therapy to amend all of our cells.

Because it is hard to say just how many years will take to achieve this sort of technology (if ever), I think the battle against aging should concentrate on constantly fixing the damages of aging, without tinkering with metabolism at all, ala De Grey's SENS. This is in my opinion the only thing that might work practically in this century.

Posted by: Noam at April 29th, 2007 12:33 PM

Noam,

I think we agree on most things but let me clarify my point again regarding the "biological program". Clearly there is a biological program that prevents us from aging at least until the ages of 30-40, I think you agree on that correct? This program is the massive repair and regeneration process coupled with efficient cleaning of extracellular junk and senescent cells.

Now, as you explained for evolutionary reasons this program has not been selected to maintain itself beyond the lifespan of the organisms. BUT, my key point in my critique was that this biological program, or lackof, of aging can be modulated as the nature has shown us, in organisms that have wildly different lifespans. The basic repair and regeneration machinary in mice, turtles, or humans are not very different. They are even evolutionarily conserved in extremely short lived organisms like flies or worms. However, we do know that the nature has selected for fine differences in this program that allows for humans to live about 50 times longer than mice, of thousand times longer than flies.

What this is teaching us is that, it is possible to tweak the program it is not set in the stone. My point was that we can accelerate these changes by interferring at the regulation of this program both on metabolic and genetic level. If you extrapolate that reasoning, one can see that it is in theory possible to have indefinite life extension, whether or not that will happen, we will see.

I pretty much agree with everything else you wrote, it seems we are saying the same things, perhaps looking from different perspectives.

One thing I want to comment on is this statement you made:

" If we want to achive it artificially using our logic, we have to take into account how our 30,000 genes, simultaneously, affect trillions of intracellular and extracellular molecule interactions and reactions, and make sure not a single one of them will eventually lead to some sort of accumulated damage that we have no enzyme that could repair. I think most will agree this is impossibe task, even if our reasoning will be aided by computers. "

Overall, I agree that the complexity is simply not possible to simulate unless we have billions of fold faster computers and until the time we have precise understanding of how all these interactions result in the biological outcomes. However, as you noted in the next paragraph, we can learn from the nature. Until the time we have those technologies to completely simulate the biological program, we can already improve on what our program is already doing by simply making sure it works longer than intended. In some ways we are beginning to do this in primitive ways of replacing organs or tricking the program to think everything is ok by drugs or supplements or restricting calories.

Finally, I would argue that we should be both fixing the damage of aging AND continue to tinker with the metabolism. For example, giving insulin to a diabetic is tinkering with the metabolism in a crude way, without which many would die very early. Supplements such as resveratrol and many compounds in foods we eat also tinker with the metabolism. Obviously we need to do this within the rules of science by first testing in the lab, then animal models then move on to humans. As we learn more and more about the precise regulation of metabolic pathways, prediction will also be easier.

The road to indefinite life extension is going to be very hard and painful, but I think we have to do this in stages, until the final stage when we can directly alter and redesign the program.

Posted by: Derya at April 29th, 2007 6:13 PM

Hi Derya,

Yes, Basically we seem to agree on most things.

I'm just skeptical regarding how practical it would be now to tinker with metabolism (genetics) in order to slow aging.

Take the Baker's yeast, for example (S.cerevisae), one of our best eukaryotic model organism, on which many of the characteristics of eukaryotic metabolic behaviour have been found first. It is arguably one of the most simple eukaryoes known to us, many orders of magnitude less complex than the simplest mammal. The yest is just a single cell organism, with about 6000 genes. We know about the yeast more than we know about any other eukaryote. I'm not sure how many decades will pass before we'll know even the mice like we know the yeast (metabolically speaking).

With all this knowledge, the most we could elongate the baker's yeast lifespan, is by about 30-40%. And that's an organism that lives for just several days (or 30-40 replications).

We have turtles living centuries, and they share basic repair mechanisms with the yeast, yet we can't elongate the life of the simple yeast more than several more replications (days).

The metabolic complexity of yeast aging is frightening the best labs, the most funded labs in the world. Yet again, it's the most basic, simple, eukaryotic model organism we have.

My point is that if scientists today don't have a first clue about how to tinker genes in order to elongate the yeast lifespan for more than 30-40% (they are trying for years now, to no avail), how can we even imagine we can do anything for organisms orders of magnitude more complex ?.

Posted by: Noam at April 30th, 2007 2:05 PM

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