The Long Road Ahead to Exercise Mimetics

Today I'll point out a couple of recent research publications on the topic of the molecular mechanisms of exercise: how it might work to improve health, how it extends healthy life span but not maximum life span in animal studies, and how the response to exercise might be safely improved or otherwise manipulated. Researchers nowadays tend to comment on future directions for drug discovery based on their investigations of exercise, and in that this slice of the field is becoming much like calorie restriction research ten to fifteen years ago.

Take a moment to think about how much work and funding has gone into investigations of calorie restriction and the search for drug candidates that can mimic even just a fraction of the beneficial metabolic alterations and extension of healthy life spans that occur in response to calorie restriction: probably a few billion dollars and year after year of dedicated investigations by hundreds of scientists in the past decade alone. Yet at the end of all that, and after the collection of enormous amounts of data, there is only a small number of drug candidates, few of which are anything other than marginal in animal studies, none of which can reproduce all of the beneficial changes observed in calorie restriction, and there is still no comprehensive accounting of how calorie restriction works under the hood, just an outline of ever-growing complexity.

It has taken fifteen years to get that far. Processes like the reaction to restricted calorie intake and exercise are enormously complex. They impact near every aspect of metabolism and cellular biology, and the quest to understand them well enough to manipulate them is more or less the same thing as the quest to understand cellular biology completely. This and the past history of calorie restriction mimetic drug research is why I'm not holding my breath waiting on exercise mimetic drugs. Researchers will talk about this as a goal, just as they have talked about calorie restriction mimetic drugs, but the reality is that the inherent complexity involved makes this is a very long-term project, one that tends to produce marginal outcomes at great expense. Exercise mimetics and calorie restriction mimetics that are safe and reliable would be a pleasant thing to have around, to be sure, but it seems to me that at the present time there are better and more cost-effective approaches to the treatment of aging as a medical condition.

Exercise Pills: At the Starting Line

Excessive caloric intake and limited physical activity contribute to the current explosion of 'modern' chronic diseases such as obesity, type 2 diabetes, muscle atrophy, and cardiovascular diseases. By contrast, regular physical exercise maintains glucose homeostasis and induces physiological adaptations that effectively prevent, and often reverse, these diseases. Recognizing the human and economic burdens these diseases cause, and taking into account the health benefits of exercise, have led many exercise scientists to suggest that physical exercise may be the preferred method in the treatment and prevention of these 'modern' chronic diseases.

Unfortunately, exercise compliance levels are almost universally low, especially for people using home-based exercise programs. A variety of factors including poor physical condition, weakness, sickness, lack of time, and poor motivation contribute to low exercise compliance. The much publicized poor compliance begs the question: is there an alternative approach that both induces the health benefits of physical exercise and overcomes the problem of low compliance rate? Regular physical exercise activates a number of molecular pathways in whole organ systems and reduces the risk of developing numerous chronic diseases. Although nothing can fully substitute for physical exercise, candidate exercise pills that have emerged in recent years may be an attractive alternative.

Exercise in a bottle could become a reality

Researchers exposed a thousand molecular changes that occur in our muscles when we exercise, providing the world's first comprehensive exercise blueprint. "Exercise is the most powerful therapy for many human diseases, including type 2 diabetes, cardiovascular disease and neurological disorders. However, for many people, exercise isn't a viable treatment option. This means it is essential we find ways of developing drugs that mimic the benefits of exercise." The researchers analysed human skeletal muscle biopsies from four untrained, healthy males following 10 minutes of high intensity exercise. Using a technique known as mass spectrometry to study a process called protein phosphorylation, they discovered that short, intensive exercise triggers more than 1000 changes.

"Exercise produces an extremely complex, cascading set of responses within human muscle. It plays an essential role in controlling energy metabolism and insulin sensitivity. While scientists have long suspected that exercise causes a complicated series of changes to human muscle, this is the first time we have been able to map exactly what happens. This is a major breakthrough, as it allows scientists to use this information to design a drug that mimics the true beneficial changes caused by exercise. Most traditional drugs target individual molecules. With this exercise blueprint we have proven that any drug that mimics exercise will need to target multiple molecules and possibly even pathways, which are a combination of molecules working together. We believe this is the key to unlocking the riddle of drug treatments to mimic exercise."

Comments

For all the risks pharmaceutical companies take on nonsense things like Sinclairs sirtris, and mimetics, you would think one of them would be willing to take a gamble on the SENS type treatments. I know it's easy to say this now when talking about spending someone else's money, but it's disheartening to see all the things that they pour billions into, for sometimes minimal or no results at all.

Posted by: Ham at October 6th, 2015 5:00 PM

@Ham - Dave Sinclair's sirtins do have repeatable results in mice. None of the 5 underfunded SENS technologies have this. Senescent cells only have one published paper in a mouse model with a shortened lifespan. The use of enzymes to clear oxidised LDL from the lysozome has only been demonstrated in a dish (although Jason hope has put his money behind this to some unknown degree). Mitosens has only been demonstrated in the dish except for one gene (ND4). And breaking gluscospane has not even been demonstrated yet.

Demonstrate one of the above in a decent mouse model a few times with a health o lifespan benefit and a biotech or pharma may come knocking.

Posted by: Jim at October 6th, 2015 6:56 PM

Jim, thanks for the dose of realism.

Posted by: Seth at October 7th, 2015 2:00 AM

Exercise mimetics are not a costly, incremental anti-aging idea.

They could be the magic bullet for the obesity (and overweight) epidemic, giving users better quality-of-life along with an improved healthspan (and life expectancy).

I'm not aware of which SENS strategy explicitly targets obesity. Without going into the moralizing of "everyone needs to eat better and exercise more!", in a practical sense this is a necessary area of research.

Posted by: John at October 7th, 2015 9:20 AM

@Seth - I'm just a layman going off past conversations on here, but I do think the distance to some decent funding may not be that far for some of the proposed SENS technologies.

Posted by: Jim at October 7th, 2015 9:27 AM

Jim - "It works in mice" isn't a very good qualifier here, because the metabolic differences between humans and mice often involve longevity. Sirtuins could simply be getting these mice up to the human level. Turns out that it's really, really easy to increase the lifespan of a fruit fly and somewhat easy to increase the lifespan of a mouse. Wake me up when someone manages to actually rejuvenate one.

John - Forget morality for a moment; let's talk medicine. Regular exercise is the standard of care here, and I'd get plenty of it laughing if the FDA said "less effective than the current standard of care" while rejecting these mimetics. The problem's right in the name; they're trying to sell a mimic of something that people can get for cheap or for less than free. Want a perfect exercise mimetic, right now? Don't go to a pharmacy, go to a sporting goods store. Want to have a guaranteed 100% effective calorie restriction mimetic? Put down the fork.

For people who are so physically broken that they can't exercise enough or at all, the solution is to regenerate their tissues so they can again, and I'm thankful that research in that direction is progressing.

A lot of these proteins do have obviously beneficial effects, but they still can't make the cells burn fuel. (Some of these proteins are linked to fuel burning- but, if it's not actually being used, where does the energy go?) They might be useful in certain situations, such as part of stem cell therapy, but that kind of therapy goes beyond mimicry.

The SENS approach to the obesity epidemic is the same as its approach to the heroin epidemic and the [faster methods of] suicide epidemic. It's not in the business of stopping people from ending themselves, whether they use guns, needles, or cheeseburgers.

The reason this thing is treated with such contempt is because it's contemptible. Millions upon millions of dollars and who knows how many researcher man-hours spent on an imperfect treatment for easily preventable conditions, while treatments for things we can't currently prevent languish by the wayside. Here's an idea, how about trying to extend the lives of people not killing themselves?

Posted by: Slicer at October 7th, 2015 1:35 PM

Slicer -- there are plenty of people who are not killing themselves, but could still benefit from additional hours of mimicked exercise.

>Some of these proteins are linked to fuel burning- but, if it's not >actually being used, where does the energy go?

Heat. And probably a little for active repairs.

Posted by: John at October 8th, 2015 11:45 PM

All:

Posted by: Jim at October 6, 2015 6:56 PM: None of the 5 underfunded SENS technologies have [repeatable results in mice]. Senescent cells only have one published paper in a mouse model with a shortened lifespan. The use of enzymes to clear oxidised LDL from the lysozome has only been demonstrated in a dish (although Jason hope has put his money behind this to some unknown degree). Mitosens has only been demonstrated in the dish except for one gene (ND4). And breaking gluscospane has not even been demonstrated yet.

Hang on ... By "None of the 5 underfunded SENS technologies," I take it that you mean everything except cell therapy and extracellular aggregate clearance. Those two are indeed substantially better-funded than the other planks in the platform, but there is relevant work in rodents for several of the other planks.

First, you've yourself already mentioned the proof-of-concept clearance of senescent cells from aging tissues of hypomorphic BubR1 mice. You're right to call out that this is a quite artificial model, but I'll remind you that the field was jumpstarted by that work rather than ending with it. I'll remind you that Julie Anderson from the Buck Institute presented thrilling results using Judith Campisi's unpublished system (nothing of direct human translatability) in a Parkinson's disease mouse model at SENS Research Foundation's Rejuvenation Biotechnology 2014 conference, and the system has now been shown to prevent or reverse a range of diseases of aging modeled in transgenic mice. Additionally, as you know, Kirkland and van Deursen have demonstrated that ablation of senescent cells improves aging phenotypes in wild-type mice.

Alagebrium appears to provide quite multiple in vivo proofs-of-concept for rejuvenating tissues by breaking AGE crosslinks: it reversed age-related increases in myocardial stiffness in dogs, and reduced vascular stiffness and improved left ventricle function in nonhuman primates, and did multiple wonders in diabetic rodents. Its mechanism of action remains unclear, and its direct human translatability is demonstrably zero, but it almost certainly involves glycation and is widely thought to break medically-important crosslinks in these species.

As you parenthetically allude, bit more than 5 years ago, just prior to the formal institutional division, SRF/MF funded research on rendering mitochondrial mutations harmless reversed blindness induced by allotopic mitochondrial DNA mutations in rats. Yes, it's only one gene, and yes, it's rescue of an AE-induced harm, so it's neither as exciting nor as conclusive a demonstration of as we would all like. But it ain't mechanically-disaggregated hepatocytes ;) .

As regards intracellular aggregates: while we usually associate vaccine-based therapies with clearance of extracellular aggregates, several vaccines targeting beta-amyloid protein clearly clear intracellular aggregate in the process, and some of the tau-targeting vaccines do the same.

And while it's a highly incomplete solution (because it's limited to delivering more of an existing lysosomal enzyme rather than giving the lysosome a novel, engineered enzymatic capacity to degrade intracellular aggregates, we discuss an early proof-of-concept for prevention of atherosclerosis through enhancing the macrophage lysosome in mice in Ending Aging.

The examples start to get less impressive or direct after that, but let's remember that the "damage-repair" heuristic of SENS has undergone substantial in vivo validation already.

Posted by: Slicer at October 7, 2015 1:35 PMJim - "It works in mice" isn't a very good qualifier here, because the metabolic differences between humans and mice often involve longevity. Sirtuins could simply be getting these mice up to the human level. Turns out that it's really, really easy to increase the lifespan of a fruit fly and somewhat easy to increase the lifespan of a mouse.

I don't think the analogy holds: the main issue with invertebrate models is that they have entirely different body plans and life histories than mammals, and age in a dramatically different way. C. elegans' mature bodies are composed entirely of cells that don't divide, so they don't develop cancer; they don't have hearts or circulatory systems as they occur in mammals and thus don't suffer heart disease or atherosclerosis; they don't live long enough to accumulate mitochondrial DNA deletions, or several other key forms of molecular and cellular damage that contribute to aging in mammals; some investigators believe that they almost always die of starvation due to failure of the muscles in their pharynx; and they have the capacity to enter into the "dauer state," a kind of deep suspended animation, when challenged with food withdrawal or a range of other stressors, which likely confounds any data on extended fasting periods that (my esteemed mentor to the contrary) is really not analogous to rodent or human CR.

Many, many small molecules extend lifespan in these organisms by activating stress pathways or quenching free radicals; so far, none of these chemicals do so in normal, healthy mice. True, even studies in mice don't always translate directly to humans -- look at all the failed cancer drugs that cure the disease in mice -- but they're a much better start!

Posted by: Slicer at October 7, 2015 1:35 PMThe SENS approach to the obesity epidemic is the same as its approach to the heroin epidemic and the [faster methods of] suicide epidemic. It's not in the business of stopping people from ending themselves, whether they use guns, needles, or cheeseburgers.

Of course, we aren't and won't be in the literal suicide prevention business (and have no intention of attempting to mandate that people accept rejuvenation therapies, but people who become obese aren't suicidal, nor resigned to premature sickness and death. And while it won't address the purely aesthetic aspects of obesity, rejuvenation biotechnologies will certainly prevent, arrest, and reverse the diseases and debilities that are caused by the metabolic derangements of obesity, which are (after all) only earlier-onset, selective exacerbation of the byproducts of normal metabolism that drive the disease and debility of aging.

In addition to repair, removal, replacement, and rendering harmless aging damage directly induced or accelerated most directly by excessive visceral adiposity (notably, ablation of excessive visceral adipose tissue macrophages and senescent preadipocytes, to reduce systemic inflammation and restore hepatic insulin sensitivity), the same rejuvenation biotechnologies that will eradicate atherosclerosis, clear out senescent cells, repair damaged joints, replace pancreatic beta-cells destroyed or rendered dysfunctional late in type II diabetes, replace or patch failing kidneys, repopulate failing hearts with functional cardiomyocytes while eliminating the hypertension that drives hypertrophy and dysfunction, etc.

And yes: we're going to make people's bodies invulnerable to cancer, whether a woman is on a course toward breast cancer comes from being made obese during her developmental window, or because she worked shift work as a nurse caring for people when aging ravages their bodies, or because she struggled with alcohol, or for no discernible reason other than the normal operation of the machinery of a body always balancing development and tissue renewal against the risk of out-of-control cell growth.

The SENS approach to the obesity epidemic is thus the same as it is for the aging epidemic. The metabolic drivers don't matter: repairing the damage matters.

Posted by: Michael at October 9th, 2015 3:50 PM

Ah, I'm sorry I forgot about the mouse extracellular rejuvenation through alagebrium, but that's also just getting mice (and other animals) to the human level; it's breaking crosslinks that humans don't suffer from, and it wouldn't surprise me in the slightest if humans have evolved to produce an equivalent (the reason why we don't suffer from it). And of course there's the senolytic discoveries, which also constitute (slight, partial) rejuvenation.

(Serious question time, typed while eating quercetin-rich foods: Is there any way to get a hold of dasatinib from a trustworthy source without having bone cancer and without paying laughably ridiculous prices? Are there any clinical trials for its use as a senolytic? Because if this stuff demonstratably works in humans and is safe for regular consumption, it ought to be sold over the counter, as we'd all rather not have senescent cells in our bone marrow.)

As to whether or not obesity is suicide, it's a philosophical difference; I consider it the equivalent of running towards the same slow-moving train that's going to cream all of us until there's a comprehensive suite of therapies that work in humans (and it's not noble self-sacrifice, as undergoing intense stress on behalf of other people may be). If the damage is the same, and you'll eventually fix all of it, that's great; but a lot of people are going to die of these things before you finally do it, and anyone who hastens them is playing Russian Roulette.

I'm really surprised that SENS is still talking about WILT, which is probably the least popular, most controversial thing it discusses (it's the main thing that got all the MIT gerontologists cheesed off). You might as well just leave off that part for a couple of decades; whether it could possibly work or not, you're the only ones talking about it, and you're not making any headway in that direction.

Posted by: Slicer at October 9th, 2015 5:19 PM

@Slicer: Re: WILT, that's arguably further along on the way to the mainstream now than some of the other SENS threads, though not in the block everything all the time mode. More a matter of turning it on in a targeted way for a short time, or for tumor tissue only. A number of labs only peripherally associated with the SENS folk are working on ways to block telomerase activity or otherwise sabotage lengthening of telomeres in cancers.

The positions taken by critics of SENS ten years past are looking ever more silly and short-sighted as time moves on.

Posted by: Reason at October 9th, 2015 5:29 PM

Then the therapies are just ILT, not WILT.

Posted by: Slicer at October 9th, 2015 5:41 PM

Strictly speaking, WILT doesn't involve blocking telomerase, but eliminating telomerase gene altogether. AFAIK, laboratories not related to SRF are only working on blocking it, not eliminating the gene. The problem is, of course, that cancer can adapt to this blocking and develop countermeasures. But, anyway, it would be better than current therapies. It can be a preliminary step before WILT is developed.

Posted by: Antonio at October 10th, 2015 4:58 AM

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