Even Where Exercise is Shown to Help, it is Challenging to Identify the Exact Biochemistry Responsible

Physical exercise is good for long term health, and thus the research community is interested in finding ways to recreate its benefits without the need for exertion. The prospect of exercise mimetic drugs should sound like a familiar sort of goal, and it is. This line of development almost exactly recapitulates earlier years of the long-running effort to find ways to recapture the beneficial response to calorie restriction via pharmaceuticals. Both are immensely challenging projects, consuming enormous effort and funding with little to show for it but incremental progress in mapping slices of cellular biochemistry. The search for calorie restriction mimetics is going on for two decades old at this point, and has cost something like a billion dollars to date. It remains the case that there is no credible drug in the clinic, and a lot more of the relevant portions of cellular metabolism are yet to mapped.

The same process of mapping and initial drug evaluation that has been underway for many years for calorie restriction has really only just started in earnest for exercise, despite a few threads of research stretching back just as far, so we shouldn't be holding our breath waiting for pharmaceuticals to enable cardiovascular fitness without the physical exertion. At the present pace, advanced rejuvenation therapies that can turn back aging by reversing its causes will be contemporary with methods of tinkering with the operation of metabolism to somewhat improve health. It makes you wonder why the effort - but the answer to that is probably the as yet incomplete detailed map of cellular biochemistry. The true scientific goal is knowledge, not application of knowledge. If you want application, technology, and consideration of which paths forward might be more effective than others when it comes to health, then the pure science community is probably not the right place to be looking.

The research here is illustrative of the point. Given an age-related condition where exercise has been shown to be helpful in specific ways, is it possible to chase down exactly why exercise helps? The answer is that, given a few years, a research group can make some inroads, and then come to a stage at which a lot more work will be needed to progress further. Cellular biochemistry is enormously complex, and exercise influences nearly every aspect of the way in which cells work. Chasing the relationships between regulators and actors and systems and cellular behaviors, all of this in an environment of great complexity, is laborious and time-consuming. In the long run there is no such thing as useless knowledge, and the scientific aim of complete knowledge is correct and noble, but other strategies are needed if we want to achieve sizable gains in human health and longevity in the near term.

Researchers shed light on why exercise slows Parkinson's

While vigorous exercise on a treadmill has been shown to slow the progression of Parkinson's disease in patients, the molecular reasons behind it have remained a mystery. Now, for the first time in a progressive, age-related mouse model of Parkinson's, researchers have shown that exercise on a running wheel can stop the accumulation of the neuronal protein alpha-synuclein in brain cells. Clumps of alpha-synuclein are believed to play a central role in the brain cell death associated with Parkinson's disease.

The mice in the study, like humans, started to get Parkinson's symptoms in mid-life. At 12 months of age, running wheels were put in their cages. "After three months the running animals showed much better movement and cognitive function compared to control transgenic animals, which had locked running wheels." Researchers found that in the running mice, exercise increased brain and muscle expression of a key protective gene called DJ-1. Those rare humans born with a mutation in their DJ-1 gene are guaranteed to get severe Parkinson's at a relatively young age. The researchers tested mice that were missing the DJ-1 gene and discovered that their ability to run had severely declined, suggesting that the DJ-1 protein is required for normal movement. "Our results indicate that exercise may slow the progression of Parkinson's disease by turning on the protective gene DJ-1 and thereby preventing abnormal protein accumulation in brain."

Running wheel exercise reduces α-synuclein aggregation and improves motor and cognitive function in a transgenic mouse model of Parkinson's disease

DJ-1 is one of the Parkinson-associated genes in which mutations lead to early-onset, autosomal recessive disease. Because the loss of gene expression causes disease, the DJ-1 gene can be seen as protecting nearly everyone from developing Parkinson's disease. DJ-1 or its homologs are present in all life forms that use oxygen including all animals, all plants that perform photosynthesis, and all aerobic bacteria. This critical gene protects cells by antioxidant mechanisms such as stabilizing Nrf2 (nuclear factor erythroid 2-related factor) and thereby upregulating a family of antioxidant response element (ARE) genes. DJ-1 is also involved in regulating HIF1 transcriptional activity under hypoxic conditions. We have shown that DJ-1 also protects cells from abnormal protein aggregation by upregulating Hsp70.

Because Parkinson's disease leads to disabling bradykinesia and rigidity, exercise and physical therapy are often prescribed by physicians. The hope has been that exercise will enhance mobility, preserve muscle tone, and prevent medical complications such as pneumonia that are associated with immobility. Several clinical trials have found that regular exercise or physical therapy may improve motor function in Parkinson patients. In acute, drug-induced animal models of Parkinson's disease, exercise can partially protect dopamine neurons from neurotoxicity.

We have discovered that a functional DJ-1 gene is required for normal, voluntary running wheel performance in mice. In young wild-type mice as well as in aging transgenic mice expressing mutant human α-synuclein in all neurons, running wheel exercise can increase DJ-1 protein levels in muscle, plasma, and brain. We have found that long term running wheel exercise has a neuroprotective effect in our transgenic mice. Exercise significantly improves motor and cognitive function while dramatically reducing α-synuclein oligomer accumulation in brain while increasing plasma concentrations of α-synuclein. The mechanism by which exercise leads to these beneficial effects appears to be related to upregulation of DJ-1 and other neuroprotective factors such as Hsp70 and BDNF in the brain.

Because exercise produces sweeping changes in all aspects of physiology from sensorimotor activity to lipid metabolism in muscle, it is difficult to define a hierarchy of beneficial effects on brain function. Since mice which lack the DJ-1 gene cannot perform on running wheels with the same intensity as wild-type animals, DJ-1 appears to be essential for dealing with the physiological stress created in muscle by sustained motor activity. Because DJ-1 knockout animals have the same cognitive performance as wild-type mice, the DJ-1 deficit does not appear to influence cognition nor low intensity motor activity. To precisely define the role of muscle verse brain derived DJ-1, organ-specific DJ-1 knockouts would have to be developed.

Our study gives insight into the mechanism by which exercise prevents α-synuclein oligomer accumulation in brain. While oligomer formation was reduced in brains of mice with access to running wheels, the same animals showed increased plasma concentrations of α-synuclein monomers and dimers. α-Synuclein is known to be present in plasma of humans and other mammals, but the exact source of plasma α-synuclein remains uncertain. While it is possible that red blood cells may release α-synuclein into plasma, the protein may come from central and peripheral neurons.

In summary, we have found that voluntary exercise on a running wheel can upregulate DJ-1 in muscle and brain of a transgenic mouse model of Parkinson's disease and can prevent the age-related decline of motor and cognitive abilities normally seen in this transgenic strain. Since we have described similar beneficial effects with the drug phenylbutyrate in these transgenic mice, we hypothesize that patients with Parkinson's disease might be able to slow or stop disease progression from either an intensive exercise program or treatment with the drug phenylbutyrate.


This is the old mode of action (MoA) versus mechanism of action (MOA) debate that has gone on in pharma for decades

We don't really know MOA for most drugs on the market - many physician product inserts clearly state MOA - "Unknown"

If something works, and works safely, does it really matter?

Posted by: Ira S. Pastor at December 28th, 2017 7:10 AM

PGC-1a is the master regulator of mitochondria biogenesis, and is found mainly in skeletal muscle and the heart. It is activated by SIRT1, cold temperatures and exercise. When it is activated it increases mitochondrial activity and count in muscles, and can turn white muscle to brown muscle (high density of mitochondria), and can switch fast twitch muscle fibers to slow twitch muscle fibers with exercise. Frequent exercise results in storage of certain energy related compounds in the muscles, that are used during extended exercise periods. If you don't exercise regularily, these stored compounds have a negative effect on metabolism and the muscles, which is why exercise mimectics probably will not fully compensate for regular exercise. A good reference is Summermatter & Handschin, 2012, PGC-1a and exercise in the control of body weight, International Journal of Obesity.

Posted by: Biotechy at December 28th, 2017 8:46 AM

Since years researchers are trying to find exercise mimetics, sometimes called exercise in a pill. So far, the attempts failed. There are substances that can mimic some effects of exercise, but regular exercise also drives adaptations that can become maladaptive when the person stops training and obviously also when people are using exercise mimetics. It's true, the work from
Summermatter and Handschin. PGC1a and exercise in the control of body weight is the most comprehensive review explaining the different relationships. Exercise mimetics can be very usueful, but need to be prescribed only from MDs that really understand the context

Posted by: Physiologist at May 28th, 2019 4:34 PM
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