Dietary Protein and Cancer: mTOR, IGF-1, and Tradeoffs (Part 2)

Dietary Protein and Cancer: Recent Cross-Sectional Evidence

In a highly-publicized study of more than 6,000 US adults aged 50 years plus, a group of researchers reported that among people aged 50 to 65 years, participants reporting the highest protein intakes had a 75 percent increase in mortality and a 4-fold increase in risk of death due to cancer over a period of 18 years. Whoa. Somewhat strangely, higher protein intakes were associated with reduced cancer and overall mortality in people aged over 65 though. Analyses suggested that consumption of proteins from animal but not plant sources contributed to associations with risk of mortality and cancer. The scientists concluded that low protein intakes are best in middle-age, but high protein intakes might be preferable in elderly people.

When the University published a press release for this study, the supposed adverse effects of higher protein diets were likened to smoking. I don’t know about you, but to me that sounds hyperbolic.

Dietary Protein and Cancer: Be Discerning, Think Critically!

As more people read the paper, many of the world’s foremost experts in dietary protein expressed reservations about the study. Curiously, the journal in which the study was published refused to publish some of these, including a letter by Stuart Phillips and several of his colleagues. Among others, they made the following points:

The dataset from which the data came contains information for almost 12,000 adults. The researchers eliminated almost half of the data but didn’t elaborate on why.

The scientists grouped people by protein intake in a bizarre way: People consuming less than 10 percent of their calorie intakes were classified having as low protein intakes, and those consuming 20 percent or more of their calories from protein were considered to have high intakes.

Based on the existing body of scientific evidence, what does the National Academy of Sciences consider to be an acceptable proportion of calories from protein? Anything from 10 to 35 percent of calories. As a result of these strange categories, there were only 437 people in the low protein group. That’s less than 7 percent of participants, and such a skewed distribution reduces the likelihood of making statistically valid inferences.

The researchers reported that “…the level of protein is … not associated with differences in all-cause, cancer, or cardiovascular disease mortality.” But cancer mortality was actually numerically about 10 percent higher in the low protein group than in the high protein group. This is very interesting when you consider that the scientists then did a series of experiments on mice and yeast to look at why they think dietary protein increases risk of cancer. That’s a head-scratcher.

Finally, this point is worth dwelling on: To arrive at their conclusions, the authors used a single 24-hour dietary recall to assess diet over the entire 18-year period. Think about what you ate yesterday. Is that likely to be representative of your typical diet in the coming 18 years? If the answer is yes, more power to you. You are a machine.

More than anything, I’m highlighting these limitations to emphasize how important it is to be discerning when interpreting information about health – even information in prestigious academic journals. And while I don’t want to cry foul of any misdemeanors, it is relevant that the senior author on the study has created a line of low-protein, plant-based, “fasting mimicking” products. My understanding is that he doesn’t profit from sales of these products. But the profits do fund his research. And he does profit from sales of his book on how to eat to live longer.

Again, I’m categorically not saying there has been any bad play. But there’s no harm in being skeptical and considering ties and incentives.

Dietary Protein and Cancer: How Might Protein Intake Affect Cancer Progression?

With all of that said, might high-protein diets predispose people to cancer? The first point to make is that cancers are stupendously heterogeneous. In the interest of brevity I need to paint with broad brush strokes in this blog, but please be aware of this.

Some amino acids are directly implicated in accelerating tumor growth in other animals. Leucine, for example, hastens pancreatic tumor growth in both lean and overweight mice. And restricting methionine intake tends to curtail prostate tumor growth in mice.

Overall, I think there is quite strong evidence that mTOR and IGF-I signaling is involved in tumor progression, and restricting protein intake might be a good idea for cancer patients, even if this speeds muscle loss. I’ll add that the in the journal article that I discussed above, the researchers followed up the cross-sectional study of humans with experiments on male mice injected with melanoma (a type of skin cancer) cells and female mice injected with breast cancer cells. They found that mice consuming higher protein diets had a higher incidence of tumors after the injections, as well as accelerated growth of these malignant growths. IGF-1 signaling was greater in the higher protein groups.

However, keep this in mind if you don’t have cancer: I’m aware of no data that show a causal role of protein per se in the development of cancer. And people with more muscle tend to be more likely to survive solid tumor cancers. One last comment though: Independent of amino acid composition, the sources of your protein intake are likely to affect your risk of some cancers (colorectal cancer, for example). But that’s a topic for another time.

Consider Your Human Condition

These studies on aging pathways are very intriguing. And important. And fun to think about. (Maybe that’s just me). As I reflect on them though, you can probably sense that I’m not drawn to the idea of a low-protein diet. I don’t really want to amble into the sunset skeletal and lethargic after years on a low calorie diet. I want years in my life and life in my years. And think about our ecological niches as humans. We aren’t yeast or roundworms in media. Nor are we mice in cages. We are bipedal, long-lived primates.

We live in rapidly changing environments that we aren’t necessarily well adapted to, the results of which include strong dispositions to chronic diseases. One of these is obesity, which particularly seems to instigate cascades of unfavorable consequences. What else? When we fall in old age, we fall hard. Especially if we are weak and pudgy.

So, I’m interested in staying strong and lean as the clock ticks on. My perspective is undeniably musculoskeletal system-centric, surely reflecting my background (I studied exercise science and sports nutrition before my PhD) and preferences (my independence is really important to me, and I care about how I look. How vain, I know). Another factor has been the recent loss of my granny. I miss her. She lived a long, rich life, but understandably became very frail near her end.

What you value will surely differ, and you should of course use your goals to inform your choices. Perhaps, for example, you limit your intake of animal foods for ethical reasons. If so, you’re a better person than I am. And who knows, you might be doing yourself some good in the process.

You might also want to consider variables such as your family medical history. Let’s say that several of your family members have had sarcopenia and osteopenia. In this case, it might be important to optimize your resistance training and protein intake. But if several relatives have had been physically strong but then succumbed to cancer then this might nudge you to focus on different behaviors.

Dietary Protein, Skeletal Muscle, Cancer, and Aging: A Perspective

With all of this said, what factors have shaped my viewpoint? Consider these:

First, although lean body mass is likely to be reduced by long-term calorie restriction, the ratio of lean body mass to fat mass will probably be enhanced by caloric restriction, and this is surely a good thing for metabolic health. To be clear, I definitely think that intermittent calorie restriction is smart. Most people invariably gain a little weight during holidays, so if nothing else then calorie restriction is necessary to shirk any fat gained during these periods.

Please note that calorie restriction needn’t entail counting calories – simply consuming something like the Simple Food Diet or FLASH diet that Dan and Stephan detail in the Ideal Weight Program (available here) generally results in people inadvertently consuming fewer calories than they burn. And I’d rather have periods of high energy intakes too to provide plenty of energy to support exercise that is strenuous enough to produce many of the health benefits that counter the changes typically evident during aging. (Being perpetually depleted by a calorie deficit isn’t conducive to lifting heavy objects, doing hard interval training, or warding off coughs and colds while doing so.)

Second, consuming protein tends to quickly and substantially raise satiety hormones and hence how full people feel. As a result, tightly-controlled experiments have consistently shown that people tend to lose more weight when they consume higher protein diets.

Higher protein intakes therefore make it much easier to sustain calorie restriction. Both calorie intake and protein intake affect signaling through all of the pathways I’ve discussed, and it’s plausible to me that during calorie restriction, higher protein intakes combined with resistance training might increase signaling where you want it (in skeletal muscle) but have different effects in other tissues. After all, a well-known consequence of resistance training is increased amino acid uptake by the trained muscles. So, might the amino acid and appropriate training stimuli increase IGF-1 and mTORC1 signaling in muscle, while caloric restriction ensures that activation of these pathways is constrained in other tissues?

Keith Baar and Megan Roberts (who is part of the Nourish Balance Thrive crew – we love those guys) coauthored an interesting paper recently, showing that a ketogenic diet affects mTOR signaling in tissue-specific ways in mice. What we really need are studies looking at the amplitudes and kinetics of activation patterns of pathways like mTOR in different tissues in different animals subjected to different stimuli. Should be easy, I know.

Third, higher protein diets not only lead to greater reductions in fat mass in elderly people, those consuming more protein also lose less lean body mass. It’s not only the signalling pathways I’ve discussed that affect lifespan and healthspan – carrying less body mass and fat mass should beneficially many other processes involved in longevity, such as regulation of blood pressure, blood sugar, and blood lipids.

Fourth, older adults are more resistant to the muscle building effects of dietary protein. This dulled responsiveness of elderly muscles to stimuli that boost muscle protein balance has been dubbed “anabolic resistance”. For this reason, the advice to consume a lower intake of lower quality (in terms of digestibility and amino acid composition), plant-based protein in later life makes little sense to me.

Fifth, during fasting, mTORC1 activity drops, and this fluctuating mTORC1 pathway activity is probably integral to good health. Good news: well-timed meal patterns seem to be good for all sorts of things, as I discussed in previous blogs on chrononutrition (1, 2, 3) as well as in the circadian course program. Jeff and Dan also spoke at length about this subject in the fasting course. (Note that our courses are available for Pro users.) Anyway, one way of accomplishing this is using time-restricted eating, which seems to improve mTOR pathway function in mice fed poor quality diets. I’ll add that a very rigorous study was published last year showing that when mice are fed calorie restricted diets, they voluntarily shorten their feeding periods too – they self-impose time restriction. This work was remarkably comprehensive and raises questions about whether it is actually time restriction that accounts for many of the benefits reported in studies of calorie restriction in other animals.

There are of course so many other things to consider that I haven’t mentioned too, and my perspective hasn’t been shaped by any systematic literature review or attempt at assessing all of the factors currently known to influence longevity, healthspan, and quality of life. (As an aside, you should check out this resource if you want to explore the most troublesome health challenges that people face worldwide.)

So, take my thoughts with a pinch of salt.

Nevertheless, synthesizing the above, if I was elderly and relatively healthy then I would prioritize resistance training and periodically restrict my calorie intake. I’d probably almost always restrict the period in which I consume calories each day too. But I’d still consume a relatively high protein diet. To be honest, I already do these things, but I’d tweak the specifics of my behaviors. I’ll add that there are many nuances regarding optimizing protein intake for different ends. I’ll be addressing these in the upcoming course on dietary protein.

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Dietary protein is important for muscle mass. But it also raises mTOR and IGF-1 signaling. Does this have implications for cancer and aging? @GDMPotter shares his thoughts. Click To Tweet

Summary

Well done for making it this far. This has all been percolating in my mind for a few years, so it’s been a pleasure to jot down some ideas. I’m very open to other views, so please share opposing ones. These blogs are less prescriptive than some of my other work, but I hope you see why this is the case. This is a really consequential subject, and I plan to keep up with the research on it in years to come.

Stay strong… and think for yourself!

Key Takeaways

We don’t know much about how protein intake affects risk of developing cancer.
There are good reasons to believe that people who already have cancer might benefit from low protein diets.
High protein diets generally make it easier to sustain calorie restriction.
For optimal musculoskeletal health, relative protein needs of elderly adults tend to be higher than their younger counterparts.
During aging, it may be preferable to try to sustain mTOR and IGF-1 signalling in certain tissues (muscle) but not others. However, research on this subject is nascent.