A Little mTOR Triumphalism

It's always good to listen to viewpoints that you happen to disagree with. This is why I pay attention to research strategies and researchers informed by programmed aging theories such as the hyperfunction hypothesis that builds on antagonistic pleiotropy. In this view aging is the consequence of various developmental processes running off the rails, colliding, and fighting one another along the way, producing dysregulation and damage. This is programmed in the sense that it is an inevitable consequence of the way in which the many biological systems evolved to perform in early life. Thus evolved programs cause accumulations of cellular and molecular damage, which goes on to create further harm.

This is exactly backwards from the more mainstream view in the research community, and how I myself see the balance of evidence, which is that cellular and molecular damage accumulates through the normal operation of metabolism. That damage causes increasingly large reactions in evolved biological systems, few of them good, as their operating parameters and local environment become ever more dysfunctional. Damage causes more damage, and the process accelerates rapidly in later life, just as in any complicated machine. One of the most fascinating things about aging research at the present time is that biology is so fantastically complex that there is room enough yet to argue over whether damage causes change or change causes damage. There is so much left unknown and fuzzy still at this stage, despite the mountains of knowledge accumulated, that researchers still have great latitude to theorize and rearrange the chunks of what is known.

The end result is a lot of theorizing, as is always the case in any territory where much is left to be mapped. This will continue until enough proof arrives to settle the debate. In the case of the most important debate in aging research, which is between programmed aging and aging as damage, the most rapid and cost-effective way to settle this would be to implement initial prototypes of the SENS proposals for rejuvenation treatments. These are based entirely on the view of aging as damage accumulation, and involve the repair of specific forms of cellular and molecular damage thought to be fundamental, caused by the ordinary operation of metabolism rather than by some other form of damage. If aging is programmed then SENS will not work well at all, producing only fleeting benefits before the programs assert themselves to create more damage. If aging is damage, then SENS prototypes will greatly extend healthy life spans in laboratory animals such as mice. The cost of producing these prototypes is probably in the vicinity of $1-2 billion and 10-20 years, which is less than the cost for a Big Pharma entity to develop a single drug these days.

One of the originators of the hyperfunction theory of aging is very much in favor of manipulating mTOR, mechanistic target of rapamycin as a way to treat aging. He is a prolific author on this topic, and feels that work on rapamycin - and related drug candidates such as everolimus - in recent years goes a long way towards bolstering his case for mTOR as a master regulator of the aging process. If you are an adherent of the programmed aging viewpoint then altering metabolic operation, such as by dialing up or dialing down circulating levels of specific proteins, is exactly the approach that should be taken to treat aging. Restore something that looks more like youthful metabolism and damage will be repaired to at least some degree, depending on how far things have gone. If you follow the aging as damage viewpoint, on the other hand, then altering metabolic operation is a matter of rearranging deckchairs on the Titanic: it fails to address the underlying cause of frailty, degeneration, and disease, and therefore can only produce poor or fleeting benefits.

I think you'll find this an interesting piece, being almost exactly reversed in many of its viewpoints from much of the research I point out. All groups have their triumphalism, and one can appreciate a well conducted expression of that urge even when fairly certain that the author is wrong in his or her big picture view of the science:

Rejuvenating immunity: "anti-aging drug today" eight years later

Until recently, aging was believed to be a functional decline caused by accumulation of random molecular damage, which cannot be prevented. Breaking this dogma, hyperfunction theory described aging as a continuation of growth, driven by signaling pathways such as TOR (Target of Rapamycin). TOR-centric model predicts that rapamycin (and other rapalogs) can be used in humans to treat aging and prevent diseases. In proper doses and schedules, rapamycin and other rapalogs not only can but also must extend healthy life-span in humans. This theory was ridiculed by opponents and anonymous peer-reviewers. Yet, it was predicted in 2008 that "five years from now, current opponents will take the TOR-centric model for granted". And this prediction has been fulfilled.

Currently, humans and animals (in protected environment) die from age-related diseases, which are manifestation of aging. By slowing aging, rapamycin and calorie restriction can delay age-related diseases including cancer. They extend life span. Yet, the causes of death seem to be the same. Or not? Why is this important? Consider an analogy. 300 years ago in London, 75% of people died from external causes (infections, trauma, starvation) before they reached the age of 26. So only a few died from mTOR-driven aging. Only when most external causes have been eliminated, people now die from mTOR-driven age-related diseases. Similarly, if TOR-driven aging would be eliminated by a rational combination of anti-aging drugs, even then we still would not be immortal. There will be new, currently unknown causes of death. I call this post-aging syndrome. We do not know what it is. But we know that accumulation of molecular damage or telomere shortening (as examples) eventually would cause post-aging syndrome.

Even in the ancient world, when most people died from "external causes", symptoms of mTOR-driven aging were well known. In contrast, we do not know symptoms of post-aging syndrome. Aging is quasi-programmed and is not accidental. Although its rate varies among individuals, the chances to outlive aging and to die from post-aging syndrome are very low. Still, we may identify these symptoms in humans over 110 years old and especially in animals treated with rapamycin (and other anti-aging modalities). Inhibition of mTOR may extend life span, thus revealing post-aging syndrome. How will we know that we observe post-aging syndrome? There are potential criteria: Animals and humans die from either unknown diseases, unusual variants of known-disease and rare diseases. Or at least, the range of age-related diseases is dramatically changed. As discussed in 2006, causes of post-aging syndrome may include accumulation of random molecular damage, telomere shortening, selfish mitochondria and so on.

While gerontologists were studying free radicals and anti-oxidants, the TOR-centric (hyperfunction) theory revealed anti-aging drugs such as rapamycin and metformin. There are several potential anti-aging drugs in clinical use. Combining drugs and modalities, selecting doses and schedules in clinical trial will ensure the maximal lifespan extension. Simultaneously, medical progress improves aging-tolerance. Aging tolerance is the ability to survive despite aging. For example, bypass surgery allows patients with coronary disease to live, despite aging-associated atherosclerosis. Gerontologists do not need to catch the train that has already departed. No need to study rapamycin, which already entered the clinic. This is now a merely medical task. Gerontologists may continue to study free radicals and accumulation of random molecular damage as a potential cause of post-aging syndrome (not aging). It is important to study post-aging syndrome, to be ready to fight it, when medical progress with rapamycin will allow us to reach post-aging age: perhaps 50 years from now.

Comments

Saying that "aging is caused by programmed things going haywire over time" is in opposition to "aging is caused by the accumulation of damage" is a whole lot like the blind men and the elephant.

Posted by: Slicer at April 17th, 2015 6:26 PM

I took Rapamycin off label in an attempt to tame my severe allergies once. It reactivated some latent cold sore virus and instead of normal cold sore I got these incredibly painful ones. Life is not worth living levels of pain. It didn't help my allergies or chronic sinusitis unfortunately.

Posted by: jim at April 18th, 2015 7:52 AM

Hmm those side effects seem pretty miserable... But maybe you just were unlucky with it, like some people are with other drugs. How long were you taking it?

Posted by: H at April 18th, 2015 7:57 AM

Side effects would appear after a day or two. I did trying different dosing regimes, all to no avail.

Yes this is just a single person anecdote, but I wouldn't try that stuff again if you paid me.

Personally Rapamycin occupies the same space in my mind as those people who are practicing caloric restriction. It would probably add 2-3 years to your life, but nothing much over just being a healthy weight anyway, and definitely wouldn't be worth it. Rapamycin does have strong immuno suppressive effects (it is used to prevent the rejection of organ transplants after all).

I think Reason brings it up as people are forever taking things that extend life in mice and extrapolating to humans, without any thought as to whether mice are a good model of humans in the particular case.

Posted by: Jim at April 19th, 2015 6:58 AM

Ah, well depending on the side effects I experienced, I feel like if it would add 2-3 years, I'd probably take it, in hopes of that snowballing with something else, since I'm not expecting comprehensive rejuvenation therapy to roll out all at once. I guess I'm looking at it as just trying to make it long enough to see the full SENS suite. On a side note about rapamycin, I am interested in the clinical trials they're doing on dogs with it.

Posted by: H at April 19th, 2015 8:07 AM

Jim,

If scientists use mice as a reference point for medical discoveries (if it works for mice, it may work for humans) you would think that MOST of the time, it work work for humans.

Robert C.

Posted by: Robert Church at April 19th, 2015 9:03 PM

"Consider an analogy. 300 years ago in London, 75% of people died from external causes (infections, trauma, starvation) before they reached the age of 26". So the author is claiming that life expectancy was 15 or so? This isn't true, which casts doubt on the rest of the article.

Posted by: Barbara T. at April 20th, 2015 4:45 AM

@Adrian Look on the bright side Mice will be immortal in about ten years time. Makes me wonder if Hitchikers guide to the galaxy was right and the lab mice are in fact really experimenting on us :)

Joking aside mice studies dont have a great record of translating to Humans but I guess its a case of them being the best alternative to testing in us. Things like ATHENA are being developed and on chip organs too which I believe could be a better analogue to messing about with mice so lets hope that helps speed up research.

Posted by: Steve H at April 20th, 2015 6:31 AM

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