Despite the very promising progress in aging research that has taken place since the turn of the century, it remains the case that exercise and calorie restriction are still the most reliable and beneficial methods of improving long-term health and life expectancy. That should cease to be true a few years from now when the first senolytic drug candidates are better categorized and more easily available, but for today the oldest of free methodologies have a better expectation value than anything you might consider paying for. Precisely because these effects are reliable, and to a lesser degree because present medical approaches to treating age-related disease are expensive and marginal, the research community is interested in reverse engineering the changes in metabolism brought on by exercise and calorie restriction. The goal is to find ways to induce at least some of these changes independently of lifestyle choices, as a therapy.
The pharmaceutical development of calorie restriction mimetics has been ongoing in earnest for more than a decade, but there isn't yet much to show for it when it comes to practical treatments. The biochemistry is enormously tangled and complex, since calorie restriction changes just about everything in cellular metabolism that looks like it might be relevant to health and aging. Exercise is only marginally less challenging to investigate, but less work has gone into that end of the field to date, and so it lags further behind. Still, some general conclusions can be drawn from the evidence to date, one of which is that increased autophagy is an important component of the benefits.
Autophagy is a collection of processes responsible for clearing out debris and damaged inside cells: broken proteins, unwanted chemicals, and damaged cell structures. These are tagged, sometimes encapsulated in a membrane, and then hauled off for disassembly. It is clearly the case that more autophagy is good, based on the small mountain of evidence that exists to back up that claim, and this is presumably the case because more aggressive autophagy results in less damage present in cells at any given moment in time. Less damage means less of a chance for that damage to produce other, lasting consequences. Many of the scores of methods that modestly slow aging in laboratory species result in individuals that exhibit increased autophagy. Calorie restriction fails to produce its benefits when autophagy is selectively disabled. And so on. There is a portion of the field somewhat related to calorie restriction and exercise research in which boosted autophagy is investigated as a potential basis for therapies - though just like the development of calorie restriction and exercise mimetics, there is very little of practical use to show for the past ten years of work.
The research results noted here can be added to the long list of those that point towards autophagy as an important component in the way in which exercise produces improvements in long-term health. This is particulary true of autophagy that targets damaged mitochondria. The consensus in the research community is that mitochondrial damage plays an important role in the progression of aging, though there is considerable debate over the details. Anything that can cut back on the pace at which cells become taken over by dysfunctional mitochondria should as a consequence slow down aging.
Better autophagy is nowhere near as good as the sort of rejuvenation biotechnology solutions proposed by the SENS Research Foundation and others - any level of autophagy will still be subverted by suitably broken mitochondria to some degree - but it is better than nothing. The bounds of the possible for increased autophagy are amply demonstrated by the difference between people who take care of themselves and people who don't. You gain a few years in health life expectancy. You can't reliably exercise your way into living in good health until 100, and you'll still be frail and diminished even if you are one of the few who makes it that far. Exercise mimetics are unlikely to produce radically larger results. Only future repair therapies after the SENS model, those that can target and remove a large fraction of the damage that causes aging, such as every last dysfunctional mitochondrion, can possibly provide significantly more than just a slight slowing of aging.
Regular exercise is now considered an important form of treatment for heart failure, a condition in which the heart is unable to pump enough blood to meet the body's needs. The benefits of exercise range from prevention of cachexia - severe loss of weight and muscle mass - and control of arterial blood pressure to improved cardiac function, postponing a degenerative process that causes progressive heart cell death. About 70% of heart failure patients die from the condition within five years. A recent study helps to elucidate part of the mechanism whereby aerobic exercise protects the sick heart.
"Basically, we discovered that aerobic training facilitates the removal of dysfunctional mitochondria from heart cells. The removal of dysfunctional mitochondria increases the supply of ATP, the molecule that stores energy for the cell, and reduces the production of toxic molecules, such as oxygen free radicals and reactive aldehydes, an excess of which damages the cell structure." The long-term aim of the research is to identify intracellular targets that can be modulated by drugs to produce at least some of the cardiac benefits obtained by means of physical exercise. "Evidently, we don't aim to create an exercise pill, which would be impossible because exercise acts at many levels and throughout the organism, but it might be feasible for a drug to mimic or maximize the positive effect of physical activity on the heart."
In a previous study the group showed through experiments with rats that aerobic training reactivates the proteasome, an intracellular complex responsible for cleansing cells of damaged proteins. The results also showed that proteasome activity in the heart of a patient with heart failure decreases by more than 50% and that, as a result, highly reactive proteins build up in the cytoplasm, where they interact with other structures and cause heart cell death. In the recently published article the group showed that exercise also regulates the activity of another cellular cleansing mechanism, known as autophagy. "Instead of degrading isolated proteins, this system creates a vesicle, an autophagosome, around dysfunctional organelles and transports all this material at once to the lysosome, a sort of incinerator. The lysosome contains enzymes that destroy cell waste. However, we observed that autophagic flux is interrupted in the heart of a rat with heart failure and that there's a buildup of dysfunctional mitochondria."
The mitochondria may even divide to isolate the damaged part and facilitate its removal. The researchers were able to observe this by analyzing the activity of proteins related to the process of mitochondrial division. However, the system that should transport the rejects to the lysosome is unable to complete the task. When the researchers analyzed heart tissue from a rat model of heart failure, they found that the cells contained large clusters of small fragmented mitochondria. This was not observed in the group of healthy rats. These mitochondria were placed in an apparatus that measured oxygen consumption and hence assessed mitochondrial metabolism. The test confirmed that the mitochondrial respiration was not functioning properly.
"The images showed that membranes were trying to form around these small mitochondria, but the autophagosome failed to surround them completely. We concluded that they were accumulating because the removal system wasn't working. The rats were placed on the treadmill, and the dysfunctional mitochondria disappeared. The exercise restored the process of dysfunctional cardiac mitochondria removal. The benefits of exercise were abolished when we blocked autophagy pharmaceutically or genetically. Our hypothesis is that physical training modulates the expression and/or activity of one or more key proteins involved in mitophagy, or mitochondrial autophagy, thereby restoring its activity. We're now trying to confirm this hypothesis."
We previously reported that facilitating the clearance of damaged mitochondria through macroautophagy/autophagy protects against acute myocardial infarction. Here we characterized the impact of exercise, a safe strategy against cardiovascular disease, on cardiac autophagy and its contribution to mitochondrial quality control, bioenergetics and oxidative damage in a post-myocardial infarction-induced heart failure animal model.
We found that failing hearts displayed reduced autophagic flux depicted by accumulation of autophagy-related markers and loss of responsiveness to chloroquine treatment at 4 and 12 weeks after myocardial infarction. These changes were accompanied by accumulation of fragmented mitochondria with reduced O2 consumption, elevated H2O2 release and increased Ca2+-induced mitochondrial permeability transition pore opening. Of interest, disruption of autophagic flux was sufficient to decrease cardiac mitochondrial function in sham-treated animals and increase cardiomyocyte toxicity upon mitochondrial stress.
Importantly, 8 weeks of exercise training, starting 4 weeks after myocardial infarction at a time when autophagy and mitochondrial oxidative capacity were already impaired, improved cardiac autophagic flux. These changes were followed by reduced mitochondrial number:size ratio, increased mitochondrial bioenergetics and better cardiac function. Moreover, exercise training increased cardiac mitochondrial number, size and oxidative capacity without affecting autophagic flux in sham-treated animals.
Further supporting an autophagy mechanism for exercise-induced improvements of mitochondrial bioenergetics in heart failure, acute in vivo inhibition of autophagic flux was sufficient to mitigate the increased mitochondrial oxidative capacity triggered by exercise in failing hearts. Collectively, our findings uncover the potential contribution of exercise in restoring cardiac autophagy flux in heart failure, which is associated with better mitochondrial quality control, bioenergetics and cardiac function.