Newsletter #244

Hey friends! At last, here are our top five studies of the past year.

I’d love to say that I developed some kind of objective criteria to determine which should be at the top, like some kind of modeling based on effect size, or even just which ones got the most likes on Twitter…but no. This is 100% subjective.

I did try, generally, to choose research that I thought was highly actionable, and that seemed to provide useful lessons for building a healthy lifestyle.

Some relatively new research suggests that exercise might help fight cancer through transient shifts in various metabolites and signaling factors in the blood. These changes are fairly short-lived, usually returning to baseline within an hour or two following the exercise bout, but could add up over time through repeated exposure. One metabolite that rises dramatically during strenuous physical activity is lactate, which is also responsible for the “burn” you feel in your muscles when you’re working really hard. The concentration of blood lactate is usually 1-2 mmol/L at rest, but can rise to greater than 20 mmol/L during intense exertion. In a prior experiment, when mice were infused with sodium L-lactate at doses that resulted in plasma lactate levels close to what is seen during intense exercise, tumor growth was significantly attenuated. Interested in better understanding how exactly lactate could be beneficial, researchers injected either glucose or lactate directly into mice that had tumors transplanted into their bodies. Glucose, as expected, did not do anything, but the lactate suppressed tumor growth substantially. When the scientists extracted tumor tissue from rodents that had been treated with lactate, and compared them to controls, they observed that more cytotoxic T cells had infiltrated the tumors. When they looked a little closer at the types of T cells that were being boosted in these tumors, they noticed that the stem-like T cells were increasing the most. Stem-like T cells are, in effect, youthful, and still able to respond to stimulation to become highly specific cancer-fighting cells, so this is definitely a good thing. They also noted that lactate treatment increased expression of an important transcription factor (TCF1) that regulates the function of T cells, promoting proliferation and stemness. To put this into a medical perspective, TCF1 is considered to be a critical determinant of success in immunotherapy. Generally speaking, exercise seems to lead to beneficial shifts in the immune system, improving resistance to both infectious disease and cancer.

The Protein Leverage Hypothesis argues that the body prioritizes protein over other dietary components, due to its essential role as a building block for our tissues, and when the diet is “diluted” by fat and carbs, humans are prone to overeating in order to meet that protein target. To decipher whether and to what extent this hypothesis explains current prevalence of overweight and obesity, researchers at the University of Sydney analyzed data from a cross-sectional survey of nutrition and physical activity in 9341 Australian adults. They plotted energy intake and macronutrient distribution versus timing of consumption, and found that those who ate a higher proportion of energy from protein at the start of the day had lower energy intake over the course of the day. In contrast, those who ate less protein, relatively, for their first meal went on to increase their energy intake as the day went on, suggesting that they were trying to “catch up” on their protein need, much like the Protein Leverage Hypothesis suggests. Then, the researchers zoomed in on what specific foods the participants were eating that drove this "protein hunger." They found that those who consumed a lesser proportion of protein for their first meal consumed an overall poorer diet at each mealtime, with their percentage of energy from protein decreasing as their intake of ultra-processed foods went up. In other words, ultra-processed foods in the diet were leading to "protein dilution."Author David Raubenheimer said, "The results support an integrated ecological and mechanistic explanation for obesity, in which low-protein, highly processed foods lead to higher energy intake in response to a nutrient imbalance driven by a dominant appetite for protein...It supports a central role for protein in the obesity epidemic, with significant implications for global health."

Exercise is a natural activator of a class of enzymes known as sirtuins, and most notably of SIRT1. SIRT1 plays an important role in maintaining cellular homeostasis, potentially leading to better health and longevity, and it is thought that activation of SIRT1 is one of the reasons why exercise is good for us. To explore how antioxidant vitamins might affect this process, researchers recruited 32 middle-distance runners and split them into two groups. One group was assigned to take 240 mg of vitamin C and 15 mg of vitamin E every time that they trained. The other group didn’t take any antioxidants and just worked out like normal. The researchers also enrolled 14 sedentary volunteers, who were around the same age as the runners, as a control group. At the end of the study period, the researchers found that the runners who didn’t supplement had higher levels of SIRT1 mRNA expression and activity than either of the other two groups. The runners who took the antioxidant vitamins, in contrast, had similar levels of SIRT1 mRNA expression and activity as the control group - indicating that the beneficial effect of exercise on SIRT1 was lost. This finding echoes previous studies, showing that supplementation with antioxidants can impair adaptations to training, as well as prevent exercise from improving insulin sensitivity. Why? Well, oddly enough, emerging evidence suggests that we need small doses of free radicals to trigger many of the health benefits associated with exercise, and obliterating them could actually be counterproductive in the long term. (Check out this podcast to learn more about how that works.)

Numerous studies, including the lactate one described above, have suggested that exercise helps fight cancer, and intense exercise may offer some unique benefits due to its metabolic effects. Recently, researchers affiliated with Tel Aviv University analyzed data from a random sample of 2734 individuals from the Israeli general population who were free of cancer at baseline and were followed for 20 years. Overall, exercise was associated with a lower likelihood of developing cancer, but when the researchers zeroed in on cancer staging, the association became much stronger. Specifically, over the course of the study, subjects who reported regular participation in high-intensity exercise had a 73% reduced risk of metastatic cancer, compared to inactive participants. To gain some insight into underlying molecular mechanisms, the researchers put a group of mice on an exercise program and injected melanoma cells into some of them. Sure enough, the animals that exercised had fewer metastases. How come? When the team examined the internal organs of the exercising rodents, focusing upon the places where metastases typically are found, like the lungs and lymph nodes, they noticed that the cells of these organs had enhanced capacity for glucose uptake. It is already well established that intense exercise increases the rate of glucose consumption by skeletal muscle. The researchers suggest that the stress of exercise, over time, may reprogram the tissue of these organs to also take up more glucose in order to compete with the sugar demands of muscle. This, in effect, cuts the supply lines to cancer cells, leaving them without enough fuel to grow in the regions of the body where they’re most apt to proliferate.

To test that, they administered Lac-Phe to obese mice in metabolic chambers and found that the treatment led to a 50% reduction in their food intake, and chronic use resulted in weight loss. Conversely, mice that were rendered unable to synthesize Lac-Phe ate more and became obese. So, what about in humans? Well, these researchers did find that humans who exercised on a treadmill also showed increases in Lac-Phe, with sprinting being the most favorable mode of training for this effect. Prior human trials lend further support to this phenomenon. It has been shown, for instance, that intravenous lactate, as well as lactate induced by high-intensity exercise, both lead to significant decreases in food intake, by as much as 250-300 calories. This may be due to reductions in the hunger hormone ghrelin. This actually makes sense from a physiological and evolutionary standpoint. When you eat, blood flow must be directed to your digestive system to break down food and absorb nutrients. So, in order to block these competing blood flow demands, lactate suppresses appetite, enabling you to continue your strenuous activity.

Thanks, as always, for reading, and we'll see y'all next week!

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