Fightaging’s post: The Long Road Ahead to Exercise Mimetics – Michael Rae’s Reply to my comment

The original post on fightaging.org

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.”

My Comment

@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.

Michael Rae’s reply to my comment:

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.

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