Cure your Aging Synapses with this New Diet and Exercise Regimen!

The title for this one comes from those stupid "1 tip for a flat belly!" and "The thing moms know about whitening teeth!" ads that keep popping up for me. You know the ones. Well, now, screw that. WHAT'S more important than getting a flat belly or whitening your teeth?! CURING YOUR AGING NEUROMUSCULAR JUNCTIONS!!!

Scientists have been searching for the fountain of youth for ages. Not an actual fountain, or a cure for aging, but the REASON behind the declines and changing that come along with age. A few years ago, scientists found that exercise and a low calorie diet (VERY low calorie, not something that is maintained easily), can reduce the effects of aging and dramatically extend lifespan in rodents. The question is, though, HOW this happens. Valdez, et al. "Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise" PNAS, 2010.

One of the things that is known to change as you age are your synapses, the connections between neurons, and the connections between neurons and other tissue, that keep things humming along at speed.

Above you can see a neuromuscular junction. This is the synapse that exists wherever a neuron targets a muscle. As you can imagine, you have a lot of them. You can see towards the top of the picture there's the neuron, with the little bubbly vesicles full of chemical neurotransmitters. The very top of the neuron is wrapped in myelin sheaths that allow signals to jump along and be conducted faster. When the neuron is stimulated, the stimulation travels down, and triggers the release of the vesicles ("RELEASE THE VESICLES!!!"), which move to the membrane, and release their chemicals into the space between the neuron and the muscle. The chemical (often it's acetylcholine, but there are lots of other options) travels across the teensy space, and hits the receptors located on the other side in the motor end plate. The signaling molecules bind to the receptors, which are linked to channels, which then open, crazy potential changes happen, and the muscle is officially stimulated.

And the BEST thing about neuromuscular junctions in particular is that we can SEE them. These things are large. So large that you can actually see them with a good light microscope. This makes it especially easy to characterize changes that may happen to them as they AGE! So the authors of the study looked at neuromuscular junctions in mice as they age, and then looked to see how diet and exercise changed your neuromuscular junctions.

On the left we've got a young, sprightly mouse (1-3 months old). And on the right we have an old mouse (24-28 months old, which is OLD, and longer than a mouse probably would ever live in the wild). These mice all express yellow fluorescent protein in their motor neurons, and they also tagged the the receptors on the post-synaptic membrane (the muscle side) in red so they could be easily visualized. You can see that the mouse on the left (Jr) has a nice thick axon, and that each terminal labeled in yellow is matched up neatly with a muscular junction in red. The older mouse on the right (Sr) however, looks a bit different. Not all the reds and yellows match up, which suggests that some of the synapses are partially non-functional (which happens when there's not a perfect match up). Not only that, the red labeling is fainter, more spread out, and fragmented, meaning that the synapses themselves are misshapen. And you can clearly see that the axon is thin and wobbly.

The graphs up there show the tracking of all the changes I listed above as the mouse gets old. Along the bottom of each graph is the mouse's age in months, and each graph shows things like the % of fragmented junctions, the % of partially innervated junctions, the % of thin axons, and more. The changes clearly increase as the mice get older. Most stuff appears to be ok for the first 12 months or so, but after that things really take off.

So, we've got the changes (we've even got them glowing all pretty! Seriously, I'd put that junction series on the left up as a poster), what happens when we change the mice? They took a bunch of mice and restricted their diets by 40%. This would be the human equivalent of reducing your 2000 calorie diet to 1200 calories (apparently some humans ARE trying this to look at effects on aging. To Sci it does not sound fun. I may not live til I'm 100, but I WILL have my POP-TARTS!!!). They they took these skinny mice and looked at their neuromuscular junctions as they aged.

Will you look at THAT! On the left side of each of those pairs are your older normal mice. On the right are your skinny mice. The graphs to the right side of the figure show the same age-related changes. And you can see that the pictures on the right look MUCH more uniform than the pictures on the left. And the graphs show a MASSIVE decrease in the percent of damaged junctions (the sets of bars on the far right, as compared to the sets of bars in the middle, which are the normal aged mice). The dieting mice weren't as undamaged as the YOUNG mice, of course (those are the bars on the far left of the figures), but that's a pretty drastic change right there.

But what about exercise? For this section, they didn't diet the mice, instead they just gave them running wheels in their cages. Mice LOVE to run, and the old little dudes ran on average about 4k (2.4 miles or so) per day. I'm not sure what that equivalent would be in humans, it takes us a lot more effort to run, but it's probably a bit.

And the results were again pretty impressive. On the left you have your normal mice, and on the right your marathoner mice. The neuromuscular junction pictures don't look quite as fluffy as with the diet, but they look much better, and the decreases in damage (the bar sets on the far right) are less, but still really significant.

So it looks like both diet and exercise can REALLY decrease the effects of aging on your neuromuscular junctions. They did more specific experiments looking at specific muscles (ones not generally used in exercise), and neuron and axon death. It looks like diet decreases the loss of neuromuscular junctions, while exercise reverses some of the effects (though keep in mind the mice only exercised for one month, longer times might have bigger effects). And it looks like diet is better than exercise, because exercise only really helped the muscles that were being worked, while diet appeared to work regardless.

But this doesn't mean that you should immediately start running marathons and drop your diet to 1200 calories. There are some important things there. First, dieting mice are almost always MORE ACTIVE than non-dieting mice. So some of the major effects of the diet might also be due to the increased activity (you can run around a cage and wrestle with your buddies even if you don't have a running wheel). Not only that, the time courses of each thing were different. The diets were imposed on young mice who then got old, while the running wheels were given to already old mice. So it could be that exercise could have a much bigger effect if you were to start young. So hopefully the authors are going to look more at exerciser throughout the lifespan, as well as combinations of diet restriction (probably not as severe) and exercise, to see if the effects can combine.

And of course, the neuromuscular junction is only one part (though an important part) of the things that change as you age. Still, it's never a bad idea to get runnin!*

*Of course with the caveat that not everyone can run safely or because of injury or other problems, I'm just going at an active lifestyle here. And heck, I assure you I prefer the activity to eating 1200 calories a day. I gotta have my pop-tarts.

Valdez G, Tapia JC, Kang H, Clemenson GD Jr, Gage FH, Lichtman JW, & Sanes JR (2010). Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise. Proceedings of the National Academy of Sciences of the United States of America, 107 (33), 14863-8 PMID: 20679195

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