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

At humanOS, we’re interested in helping people feel, look, and perform as well as possible throughout their lives, so how to stay youthful is often at the forefront of our minds. Think about this: Your age is the primary risk factor for afflictions like cardiovascular diseases, type two diabetes, and Alzheimer’s disease. But can you defy these associations as the years go by?

Behind the curtains, one thing I’m working on is a course on how you can optimize your protein intake to turn heads at the beach and ensure your musculoskeletal system is healthy and robust throughout life. As I drafted the script, I anticipated an interesting question that will surely be raised in response: yeah, but what about protein and aging?

So, I’m addressing this query here. It’s an unavoidably complex topic, so please bear with me (this is the first of two relatively long blogs). It’s also a contentious subject, and I cradle my current perspective on it gently. I’m interested in your thoughts, and you should check out some of Dan’s here. Okay, with that long preamble, let’s begin.

When people think about protein, one of the first things that generally comes to mind is skeletal muscle. To make explicit how important this tissue is, consider the following:

In the light of the above, it makes sense to focus on activities that help you maintain a powerful musculoskeletal system. This of course begins with resistance training (lifting weights, for example) and is supported by diet – energy and protein, especially. But are the signals involved in constructing new muscle conducive to living a long, healthy life? We’ll get to this question, but let’s first consider the primary determinant of changes in muscle mass.

Changes in muscle mass depend on muscle protein balance. Simplistically, this is how much protein your muscles synthesize minus how much of your muscle protein is broken down.

Resistance exercise and dietary protein increase muscle protein synthesis in an additive way, but I’ll hone in on protein since it’s the focus of this blog. When you consume protein, it’s broken down into its amino acid constituents. The concentrations of these amino acids in your blood spike sharply about 30 minutes later and typically peak after about 2 hours.

There are 9 indispensable (“essential”) amino acids that you must get from your diet, one of which is called leucine. Leucine independently triggers protein synthesis within muscle cells when enough of it is consumed. Once muscle protein synthesis is triggered, other amino acids then act as raw materials for new tissue.

Think about this as if it were a construction site (your muscles) in a house (your body) undergoing renovation (warding off aging). On this site, a general contractor manages a team of laborers, telling them when to add new bricks to build an extension (new muscle tissue) for the house. Leucine acts like a phone call to the general contractor, and other amino acids function as the bricks. This means that while leucine alone can kick start the construction process, other amino acids are needed to sustain the addition of new bricks. But who is the general contractor managing the site?

Leucine triggers protein synthesis by binding to a sensor named sestrin2. Sestrin2 then activates a protein complex called mechanistic target of rapamycin complex 1 (mTORC1). In this instance, the role of this complex is basically to allow the blueprints for new muscle to be translated into new muscle. (Note other amino acids such as arginine can also activate mTORC1, but they don’t have this potent muscle building effect.)

Returning to the construction site analogy, mTORC1 is the general contractor. And this general contractor analogy (borrowed from David Sabatini, the preeminent authority on mTOR) is a useful one, for mTOR has what might be a uniquely large diversity of roles within cells. It’s no wonder that the TOR pathway is conserved in almost all eukaryotes (organisms comprising cells with nuclei that are housed within membranes).

Now, there are two mTOR complexes. Broadly, the role of mTORC1 is to coordinate cell growth and metabolism with prevailing conditions. mTORC2 is most involved in cell survival and balancing the formation of cells (cellular proliferation) with the loss of cells. mTORC1 is most salient to this blog, so let’s concentrate on it.

mTORC1 senses stimuli that should be considered when determining whether to build or break down structures. These include stress signals, oxygen concentration, DNA damage, amino acids, energy availability, and growth factors such as insulin-like growth factor 1 (IGF-1).

In conditions of plenty, mTORC1 promotes many energy-intensive processes, building new lipids and proteins, synthesizing nucleotides needed for DNA replication, constructing the organelles (ribosomes) in which new proteins are made, and shifting how organisms burn glucose (from a way that uses oxygen to a way that doesn’t), encouraging the storage of nutrients.

Increased mTORC1 signaling doesn’t only support the genesis of new cellular structures though, it also applies brakes to breaking them down. mTORC1 affects two key breakdown systems. One of these is called the ubiquitin-proteasome system, which is responsible for the majority of protein breakdown in your cells. The other system involves autophagy (literally “self-eating”). Autophagy is largely determined by the balance between the activity of mTORC1 (which promotes growth) and another energy sensor named AMP-activated protein kinase (AMPK), which aids the mobilization of energy stores when cellular energy is low.

Let’s return to Keith Barr’s sink analogy. As the sink is used each day, things like soap, hair, and toothpaste pass down the drain. But if you block the sink then this gunk accumulates. Nasty. Similarly, without periods of breaking down structures that have become damaged, dysfunctional tissue can accumulate. This is part of the reason that people are interested in targeting mTOR to prevent and treat cancer.

So, if you are a healthy person, when you have a calorie- and/or protein-rich meal, increased mTORC1 signaling will divert your cells’ resources towards building various structures… provided there are relatively typical levels of other growth-promoting signals (like IGF-1). This is an important point: Amino acids and growth signals like IGF-1 concurrently act on mTORC1 to aid growth of tissues like muscle.

It’s tempting to speculate that tonic mTORC1 activation might give you bulging biceps, right? It probably doesn’t. The result might actually be muscle dysfunction and premature death – intermittent dips in mTOR allow damaged tissue to be removed, which is important to muscle growth and health.

There are other instances of chronic changes in mTORC1 signaling associating with adverse outcomes. Unsurprisingly, mTORC1 is overactive in some human cancers. Now, mTOR is a protein, so there is a gene (MTOR – when you see capitalized, italicized text like this, it’s a human gene) with the blueprint for the mTOR protein. Sure enough, MTOR mutations are found in some types of cancer, again implicating aberrant mTOR signaling in the development of tumors.

Risk of cancer is positively associated with age, and you probably aren’t surprised that mTOR is implicated in aging (by which I really mean senescence). The first-generation drug rapamycin reduces mTOR signaling (more so at mTORC1 than mTORC2) and is perhaps the most effective drug there currently is at prolonging lifespan in the non-human animals that scientists typically study. It does have some adverse effects though, impairing the function of the energy-hungry immune system and interfering with blood sugar regulation.

Scientists are therefore trying to figure out the best dosing schedules for rapamycin, and second-generation drugs named rapalogs have been developed to try to address some limitations of their predecessor. But these drugs are expensive, we don’t know much about their long-term effects in humans, and you’d be hard pressed to get your hands on them.

Growth factors like IGF-1 also act in part through mTOR, and I’ll add that reducing signaling through the insulin/growth hormone/IGF-1 axis is also remarkably effective at prolonging lifespan and healthspan (healthy lifespan). So, what are widely-studied ways of reducing the activity of these pathways and others that are associated with aging?

IGF-1 and mTORC1 signaling wanes as cellular energy status declines. So, just restrict calories and you’re bound to benefit, right?

This is precisely what happens in many non-human animals – restrict calories, and IGF-1 and mTOR signaling fall, animals live longer, and development of a slew of age-related pathologies is reined in. Tantalizingly, this even seems to happen in non-human primates like rhesus monkeys. (Please note that calorie restriction affects many other pathways too, but these are beyond the scope of this blog.)

What’s really interesting is that some of these life-prolonging effects seem to be mediated by TOR signaling in creatures like flies – block TOR signaling and calorie restriction no longer prolongs lifespan. So, there are common pathways here, even if we don’t know exactly how reduced IGF-1 and mTORC1 signaling prolongs lifespan. Plausible mechanisms include reduced oxidative stress because of slowed production of new proteins, as well as enhanced clearance of old proteins and damaged organelles like mitochondria. (Check out this episode of humanOS Radio for more on this!)

What about humans though?

Obviously, it would be very demanding to ask a group of people to dramatically restrict their calorie intakes for years at a time. But some people voluntarily do this – there’s even a Calorie Restriction Society in which lean, like-minded people congregate to share dreams about fast food.

Comparing people who eat more typical “Western” diets (whatever that means) to members of this society who report having restricted their calorie intakes by roughly 30 percent for about 10 years, society members have markedly lower insulin/IGF-1 signaling in their skeletal muscle. This probably isn’t conducive to musculoskeletal mass and power, but these people do tend to have profiles of gene expression in their muscles that more closely resemble those of younger people.

There have also been numerous studies on other forms of calorie restriction (such as alternate-day fasting and prolonged fasting) in several clinical populations, and the results of these are generally not stunning but are quite encouraging. Such findings are interesting, but some of you probably balk at the thought of using your willpower to substantially curb your calorie intakes, especially for long periods. I know I do. So, are there any other alternatives?

Remember I said that amino acids like leucine and arginine have well-characterized stimulatory actions on mTORC1 activity? Well, this implies that another option is to restrict protein (and hence amino acid) intake without necessarily limiting your calorie intake. (Note that lower protein intakes also tend to reduce IGF-1 pathway signaling.)

Sure enough, cutting back on protein seems to account for some of the benefits of calorie restriction in other animals. And there is particular interest in capping intake of individual indispensable amino acids, for limiting methionine and tryptophan intake prolongs lifespan in some animals. We now know that a breakdown product (metabolite) of methionine (S-adenosyl methionine) may act on a protein called SAMTOR, then affecting mTOR signaling. Another relevant pathway involves general control nonderepressible-2 kinase, which is activated in the absence of amino acids and seems to be important to pro-longevity actions of methionine and tryptophan restriction in other animals.

Again, what about humans though?

This time, we really don’t know. There was a study published a couple of years ago that sought to answer this question. I’m going to explore it in more detail in the next blog because I am among many who have strong reservations about it.

That’s it for the first part of this blog. In the second and final part we’ll explore what all of this has to do with cancer, and I’ll synthesize what we’ve covered while summarizing my perspective.

Stay tuned!

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