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The Protein Tug-of-War: Does Eating Less Protein Really Switch On Autophagy? Wisdom Wednesdays · Hardiness with Dr Paul Taylor

• 0:03
  Speaker 1: Hey everybody, welcome to another edition of Wisdom Wednesdays. And
• 0:09
  Speaker 1: today I want to talk about a topic that is
• 0:11
  Speaker 1: one of the biggest tug-of-wars in the longevity world right now.
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  Speaker 2: And we're going to look at a brand.
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  Speaker 1: New Australian-run human trial that actually points the evidence in
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  Speaker 1: one direction, and some people won't be expecting it. Now,
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  Speaker 1: let's make the two camps, because if you've spent any
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  Speaker 1: time in the health podcast or Instagram world, You've heard
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  Speaker 1: both of them. And camp one is the muscle camp.
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  Speaker 1: And the argument goes like this. Muscle is your longevity organ.
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  Speaker 1: It's your glucose sink, your metabolic engine. It's your insurance
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  Speaker 1: policy against falls, frailty, and losing your independence. And the
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  Speaker 1: way to build and keep muscle is by switching on
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  Speaker 1: muscle protein synthesis. And the master switch for that is
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  Speaker 1: a protein complex called mTOR, which actually stands for mammalian
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  Speaker 1: target of rapamycin, which is why people call it mTOR.
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  Speaker 1: So the key from this camp is eat more protein,
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  Speaker 1: hit your leucine threshold. That's a particular amino acid that
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  Speaker 1: stimulates mTOR. Hit your threshold at each meal, lift heavy shit,
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  Speaker 1: and keep that switch firing. More protein means more muscle,
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  Speaker 1: more muscle myokines, longer and better life. And as you
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  Speaker 1: probably know, I'm in that camp. Now, the other camp
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  Speaker 1: is kind of the cleanup camp. Their argument is the
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  Speaker 1: mirror image almost. They say that mTOR is a growth signal,
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  Speaker 1: and it is, and that constant growth, they say, is
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  Speaker 1: what aging looks like at a cellular level. When mTOR
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  Speaker 1: is switched on, your cells stop doing their housekeeping. That's
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  Speaker 1: a process called autophagy, which literally means self-eating in Latin.
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  Speaker 1: That's where your cells gather up damaged proteins and worn
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  Speaker 1: out bits of machinery and recycle them. So their idea
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  Speaker 1: is eat less protein, dampen mTOR and let the cleanup
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  Speaker 1: crew in. Less protein means more autophagy and longer life.
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  Speaker 1: And they do cite studies from animals. Now, here's what's fascinating.
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  Speaker 1: Both camps... are standing on real science. The mechanism they're
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  Speaker 1: pointing to, both of them, is actually genuine. But as
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  Speaker 1: you've probably heard me say a lot on this show,
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  Speaker 1: mechanism is not result. And a plausible pathway should be
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  Speaker 1: the start of the question. It's the hypothesis generator for experiments.
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  Speaker 2: It's not the answer.
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  Speaker 1: And until recently, the cleanup crews claimed that cutting protein
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  Speaker 1: switches on autophagy in humans was had surprisingly little direct
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  Speaker 1: human evidence behind it. Most of it came from mice,
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  Speaker 1: worms and cells in a dish. So a team in
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  Speaker 1: Adelaide in Australia decided to actually test it and properly.
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  Speaker 1: So before we get into this study, let's quickly talk
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  Speaker 1: about the machinery because that really makes the result make sense.
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  Speaker 1: So I want you to think of mTOR as a
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  Speaker 1: seesaw inside every cell. On one end of the seesaw,
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  Speaker 1: that's where the building happens. When nutrients are plentiful, especially
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  Speaker 1: amino acids like leucine and also insulin as well, mTOR
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  Speaker 1: tips down that seesaw on the build side, make proteins grow,
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  Speaker 1: repair muscle, store energy. And then on the other end
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  Speaker 1: of the mTOR seesaw is the clean side. When nutrients
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  Speaker 1: are scarce, particularly things like fasting, mTOR eases off and
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  Speaker 1: that releases the brake on autophagy. The cell starts wrapping
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  Speaker 1: up its junk in little bubbles.
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  Speaker 2: Think of them as rubbish bags.
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  Speaker 1: And then it delivers them to a part of the
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  Speaker 1: cell called the lysosome, which is the cell's recycling plant,
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  Speaker 1: where it all gets broken down and reused.
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  Speaker 2: And it turns out our cells are frigging awesome at recycling. Really,
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  Speaker 2: really good.
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  Speaker 1: So the logic at Camp 2 is simple. take away
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  Speaker 1: some protein, take away some leucine particularly, and the seesaw
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  Speaker 1: tips towards clean.
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  Speaker 2: Now, that's a pretty neat theory.
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  Speaker 1: The question is whether your seesaw actually moves that way
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  Speaker 1: whenever you change what's on your plate. So here's what
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  Speaker 1: the researchers did in the study. And I really like
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  Speaker 1: the design. So it's worth walking through it. So they
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  Speaker 1: recruited a bunch of healthy adults in Adelaide, 74 people,
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  Speaker 1: and they were randomized and 63 completed the whole study.
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  Speaker 1: And it was a crossover design, right? Which is the
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  Speaker 1: gold standard for this type of question. It's not that
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  Speaker 1: one half do one thing and one half do the other.
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  Speaker 1: Each person did both sides, right? So that way they
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  Speaker 1: act as their own control. So we're not comparing your
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  Speaker 1: biology to someone else or group A's biology to group B's.
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  Speaker 1: we're comparing the people in group A to the people
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  Speaker 1: in group A and the people in group B, the
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  Speaker 1: people in group B.
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  Speaker 2: At different times, right?
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  Speaker 1: And each diet lasted four weeks with a four-week washout
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  Speaker 1: in between, right? Brilliant study design. So diet one had
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  Speaker 1: about 20% of calories from protein, roughly what a lot
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  Speaker 1: of people already eat. And for context, for a typical adult,
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  Speaker 1: that lands in the ballpark of the higher protein targets
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  Speaker 1: that Muscle Camp recommends. Not quite the level that some
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  Speaker 1: people recommend, but it's pretty significant. Diet two was about 10%
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  Speaker 1: calories from protein. So literally cut the protein in half,
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  Speaker 1: which for a typical adult is somewhere around the standard
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  Speaker 1: recommended daily intake, right? Which you've heard me criticize before
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  Speaker 1: is too low. And here's what I really like. The
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  Speaker 1: calories were kept the same. An isocaloric study. Most of
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  Speaker 1: the food was supplied by the study. And they even
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  Speaker 1: used identical unlabeled protein sachets so participants didn't know which
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  Speaker 1: diet they were on.
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  Speaker 2: So that isolates the protein. So it wasn't fasting.
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  Speaker 1: There was no weight loss, no calorie restrictions, just what
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  Speaker 1: happens if you half your protein. And they checked if
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  Speaker 1: it worked. The low protein phase showed lower levels of
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  Speaker 1: blood urea, which is the chemical fingerprint of eating less protein.
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  Speaker 1: So people genuinely did eat less of it. So this
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  Speaker 1: is the first human study of its kind. So how
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  Speaker 1: do we measure autophagy in human? Now, this is the
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  Speaker 1: tricky bit and it's the clever bit and it's why
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  Speaker 1: this study actually matters. So most previous human studies measured
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  Speaker 1: autophagy with a snapshot, which means they'd count the number
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  Speaker 1: of of those little rubbish bags in the cell at
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  Speaker 1: any one moment. And the problem is that snapshot is
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  Speaker 1: pretty ambiguous. So what this team did instead is they
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  Speaker 1: measured something called flux. They actually flow through the system.
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  Speaker 1: They took a blood sample, split it into two tubes,
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  Speaker 1: and in one tube they added a.
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  Speaker 2: Drug called chloroquine.
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  Speaker 1: And that drug temporarily blocks the recycling plant, the lysosome
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  Speaker 1: that we talked about earlier on, They then waited for
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  Speaker 1: an hour and they measured how much of an autophagy marker,
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  Speaker 1: something called LC3B, how much of that actually piled up.
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  Speaker 1: So basically what they did is they shut the doors
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  Speaker 1: and they counted the amount of stuff that was going
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  Speaker 1: through it. And that's a much more honest measure of
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  Speaker 1: how hard the cleanup crew is actually working inside the cells.
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  Speaker 1: And they did this in circulating immune cells. These are
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  Speaker 1: the white blood cells floating around in your bloodstream.
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  Speaker 2: So the result, did.
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  Speaker 1: Halving protein switch on autophagy? This is where the drum
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  Speaker 1: roll comes in. And the answer was no. There was
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  Speaker 1: no meaningful difference in autophagic flux between the two diets.
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  Speaker 1: And here's a detail that the social media summaries tend
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  Speaker 1: to skip. The small difference they did see actually pointed
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  Speaker 1: the wrong way for the cleanup crew. Slightly lower flux
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  Speaker 1: on the low protein diet, not higher. Now it wasn't
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  Speaker 1: statistically meaningful, so we're not gonna hang our hat on it,
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  Speaker 1: but it certainly wasn't a switch that was flicking on.
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  Speaker 1: And this is important. This wasn't a sloppy study that
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  Speaker 1: was too small to find anything. They calculated in advance
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  Speaker 1: how many people they'd need to detect a 15% change
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  Speaker 1: in autophagy, and they recruited more than.
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  Speaker 2: That, right?
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  Speaker 1: So that's the same process that we went through in
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  Speaker 1: my PhD studies. You calculate the statistical power that is required, right?
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  Speaker 1: How many people that you need to measure a significant
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  Speaker 1: statistical change, right? And so it's what scientists call an
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  Speaker 1: informative null. It's not we didn't look hard enough. It's
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  Speaker 1: more like we looked properly and the signal is not there,
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  Speaker 1: at least in that particular study. Now, there's two other
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  Speaker 1: things that are actually worth commenting on in this. Firstly,
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  Speaker 1: the same research group had previously shown that a big
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  Speaker 1: 35 gram protein hit did switch on mTOR signaling in
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  Speaker 1: the same immune cells. but didn't change autophagic flux. So
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  Speaker 1: basically mTOR went up and the cleanup crew kept working
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  Speaker 1: anyway when mTOR was up, which suggests that the seesaw
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  Speaker 1: in the human body is a lot more buffered or
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  Speaker 1: a lot more sophisticated than the simple diagram that we
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  Speaker 1: see on infographics, right? And second, and this one is,
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  Speaker 1: I guess, a strengthening the muscle camps idea, On the
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  Speaker 1: low protein diet, people lost a little body weight and
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  Speaker 1: a little muscle mass while fat mass didn't bulge. After
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  Speaker 1: only four weeks, right, there was just a small change.
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  Speaker 1: But it was measured with bioimpedance scales and total bulge.
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  Speaker 1: body water drop too. So that could likely be fluid
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  Speaker 1: rather than muscle loss. I don't know why they didn't
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  Speaker 1: use something a bit more sophisticated than bioimpedance scales like
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  Speaker 1: a DEXA. But anyway, the direction's worth noting. You cut
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  Speaker 1: the protein, you didn't get the cleanup bonus. And there
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  Speaker 1: was an early signal on muscle that went the wrong way, i.e.
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  Speaker 1: losing muscle, but without cellular benefits. Now, let's not oversell
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  Speaker 1: this study, and I'm not going to jump up and
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  Speaker 1: down and say, hey, this is nailed-on evidence for the
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  Speaker 1: muscle camp. There's a couple of things the paper doesn't
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  Speaker 1: tell us. So the first one is it measured blood,
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  Speaker 1: not your brain tissue or muscle tissue or liver tissue, right? Clearly,
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  Speaker 1: we don't want to be doing brain samples, but somebody
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  Speaker 1: could come along and repeat that with a muscle biopsy.
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  Speaker 1: So white blood cells are the only human tissue that
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  Speaker 1: we can currently measure flux in easily.
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  Speaker 2: That's why they used it.
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  Speaker 1: Autophagy in your liver or your brain might respond differently,
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  Speaker 1: but I ain't volunteering to be a participant in that study, right?
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  Speaker 1: And then the second thing is that four weeks is short.
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  Speaker 1: A year of protein restriction might be a different story.
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  Speaker 2: We don't know, right?
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  Speaker 1: And third, these were young, healthy people, average age of
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  Speaker 1: about 30. And they specifically excluded women who were peri
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  Speaker 1: or postmenopausal, right? And think about who's actually listening to
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  Speaker 1: longevity podcasts and worrying about mTOR. It's mostly people in
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  Speaker 1: their 40s maybe, but certainly 50s and beyond. So we
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  Speaker 1: do need to do this study in older adults and
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  Speaker 1: also include peri and postmenopausal women. The reason they don't
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  Speaker 1: do it is that hormones can mess with everything, right?
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  Speaker 1: But the fourth point is that the calories were held steady.
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  Speaker 1: So this doesn't tell us anything about fasting or calorie restriction,
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  Speaker 1: where the biology is generally different, right? In fact, the
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  Speaker 1: same group has previously found hints that time-restricted eating may
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  Speaker 1: increase flux. So this isn't autophagy can't be moved by diet.
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  Speaker 1: It's basically halving your protein or reducing your protein and
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  Speaker 1: having the same calories didn't move it in the blood, right?
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  Speaker 1: I think there might be different stuff that comes out
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  Speaker 1: with fasting and time-restricted feeding and all those sorts of things.
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  Speaker 1: And then the fifth thing that we need to think
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  Speaker 1: about here is they measured.
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  Speaker 2: The whole pool of immune cells.
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  Speaker 1: Their earlier work suggests one specific subtype of immune cell
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  Speaker 1: may respond to amino acid restriction, and a whole pool
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  Speaker 1: measurement could wash that out, right? So there might be
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  Speaker 1: some benefits in specific immune cells, which they didn't test
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  Speaker 1: or would have been sort of swallowed up by all
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  Speaker 1: of the data. And there's one little transparency thing. Two
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  Speaker 1: of the senior officers, they do have a patent on
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  Speaker 1: the autophagy measurement method they use, but that's pretty normal
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  Speaker 1: in lab science and certainly doesn't make the result wrong.
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  Speaker 1: And that didn't influence the result, I don't think. But
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  Speaker 1: I think it's always good to highlight those things. So
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  Speaker 1: here's the takeaway. So mechanism isn't measurement. When someone tells
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  Speaker 1: you that food switches on or switches off a pathway,
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  Speaker 1: ask the question, has this been measured in humans? Because
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  Speaker 1: in this case, when it finally was, the switch didn't flip. Second,
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  Speaker 1: muscle is an asset and it is a longevity asset.
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  Speaker 1: Having the protein didn't buy people any extra cellular cleanup
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  Speaker 1: and the signal on muscle mass went the wrong way.
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  Speaker 1: And you've heard me say over and over again, when
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  Speaker 1: you get into your 40s and especially into your 50s
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  Speaker 1: and beyond, protecting muscle is one of the best evidence
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  Speaker 1: longevity moves that you currently have. And I wouldn't be
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  Speaker 1: trading a proven asset for for a theoretical benefit. Muscle
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  Speaker 1: produces myokines and myokines are powerful signaling molecules for every
• 14:06
  Speaker 1: organ and organ system in your body. And muscle will
• 14:09
  Speaker 1: prevent falls, the fifth biggest killer of people in their seventies.
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  Speaker 2: And losing muscle has.
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  Speaker 1: Direct effects on your risk of cardiovascular disease, neurodegenerative diseases,
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  Speaker 1: and metabolic diseases, and potentially some influence on cancer as well.
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  Speaker 1: So I think that keeping muscle is definitely the best
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  Speaker 1: longevity move that you currently have. And then the third
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  Speaker 1: thing is move the seesaw, but don't nail it down.
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  Speaker 1: What I mean by that, mTOR was never meant to
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  Speaker 1: be stuck in one position. It's built to cycle. Build
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  Speaker 1: when you feed and train, clean when you're resting in
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  Speaker 1: between meals and potential when you're fasting. You don't need
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  Speaker 1: to live on either end of the seesaw. The question
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  Speaker 1: worth asking isn't high or low protein. It's am I
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  Speaker 1: giving my body both phases? My current strategy, which may
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  Speaker 1: change when there's more evidence coming, but my current strategy
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  Speaker 1: around this is to optimize my muscle protein synthesis by
• 15:14
  Speaker 1: taking in enough protein up to two grams a day
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  Speaker 1: because I'm in my 50s now.
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  Speaker 2: But every now and.
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  Speaker 1: Then, maybe once or twice a year, doing a five-day fast,
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  Speaker 1: which we know switches on system-wide autophagy. So that's my
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  Speaker 1: current strategy. If I come across another one, you'll be
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  Speaker 1: the first to know. So that's it for this week, folks.
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  Speaker 1: Hopefully you found that a little enlightening. Catch you next time.