Wisdom Wednesdays - Anti-aging strategies part 6: Countering deregulated nutrient sensing

drivers of aging. So in simple terms, to explain it, nutrient sensing refers to how our cells detect and respond to nutrients such as glucose, amino acids, and fats, and this process controls our energy balance, whether or not we're gaining or losing weight, but also cellular growth and our

longevity as well. But as we age, we know that our ability to properly regulate nutrients sensing declines, as to do many metabolic processes, and that leads to increased metabolic issues such as insulin resistance, obesity, type two diabetes, Alzheimer's disease, and accelerated aging. Now, the good news is that, like the rest of these hallmarks, exercise, diet and targeted interventions can have an impact, and we know that they can restore nutrients sensing and help to slow aging at a

cellular level. So let's dive in a little bit so ourselves, they rely on these key pathways to monitor and respond to nutrient levels. So think of them like biological fuel gauges. I think that's probably the best analogy. And they adjust metabolism based on our food availability. And there's four major pathways involved in nutrients sensing. So the first one is in sin and IGF one and that's a growth pathway, so inin and inchin like growth factor one, they regulate

regulate sorry our glucose uptake and our cell growth. And when they're overactivated, these pathways contribute to aging and increased disease risks, particularly of diabetes and obesity. And then the second pathway is m tour mammalian target of rapamycin, and that's a growth and anabolism pathway, so it's a building pathway. So are now this m tour promotes protein synthesis and

sell growth. Now, chronic overactivation of it due to excessive calories. Overall, being in a constant fed state is linked to obesity, cancer, and reduce longevity. But as I'll explain, later there's a lot of controversy in this topic. Then the third word pathway is AMPK and that's I think of this as

a real energy sensor. So when our energy is low, if we've been fasting or exercising, AMPK activates fat burning and mitochondrial function, and also autophogy the cellular cleanup where it recycles lots of damage parts of the cell to actually recreate energy, which is very very clever. And we know that higher activity of AMPK is linked to longer lifespan and better metabolic health. And then the fourth pathway are cerituons, and these are often referred to as longevity regulators.

And these certuons regulate our cell repair, our DNA stability, and mitochondrial function, and they're activated by and things such as fasting and calorie restriction. And then there's a lot of controversy about this. Certain plant compounds reds veratrol was touted as a real act the Vieta of turturns largely the work of David Sinclair, which has now been firmly debunked.

So I'm going to come back to res virtual in a little bit, but we can see that there's still a lot that we don't know about these different pathways, and we know more about some than others. Now, when we're young, all of these systems working harmony. But when we eage, this nutrient sensing becomes dysregulated, leading to metabolic dysfunction. And so what happens is insulin resistant develops. We become less responsive to insulin, and that leads to chronically high

blood sugar, increased diabetes risk, and dementia. You've heard me talk about dementia and particularly Alzheimer's diseases, type three diabetes

and the other thing. M tour can become overactivated, and that can contribute to chronic inflammation, excessive cell growth, reduced a toophogy, and accelerated aging, and then this AMPK that declines, and when that is lower, your body tends to store more fat, it burns less energy, struggles with cellular repair, and you put on weigh and start to fall apart,

and Thenswertwin's become suppressed. Particularly this is accentiated by poor that lacks of lack of exercise and excessive calorie intake, and that then impoers mitochondrial function and longevity. And the result of all of this, it's a higher risk of metabolic diseases, you get increased inflammation and faster biological aging. So let's now talk about the interventions. So again, first off, cab off the rank you'll not be surprised to hear

is exercise. We know that exercise increases insulin sensitivity. There's oodles and oodles of research around that both aerobic slash, high intensity interval training and strength training, and all of them enhance glucose uptake and lower our blood sugar, make it more stable and reduce our diabetes risk and our risk of Altimer's disease. Exercise also activates a MPK pathway and that promotes fat metabolism, reducing inflammation and enhances our

cellular cleanup. Exercise also balances M tour and this is the key thing. This M tour needs to be in balanced, this growth versus repair. And we know that that moderate to vigorous physical activity stimulate its M tour just enough

to build muscle while allowing proper cellular repair. We know that overeating without exercise leads to constant M tour activation, increasing disease risk, and some researchers think there's a significant difference between M tour being activated within the muscle cells and M tour being activated outside of the muscle cells. So the M tour pathway certainly is not crystal clear.

You know, some longevity components are proponents talk about that we should be doing fasting and long term calorie restriction, and that is probably not looking like it's the answer, particularly for primates and especially humans. And then the fourth way that exercise restores are the nutrients sensing. Is it boosts or tuns and these DNA repairer and longevity pathways

and improves mitochondrial function and reduces eating markers. So other things that we can do is following a balanced diet and making sure we're not constantly in a FAED state.

And so this is where I think we should be eating a diet, And it doesn't matter whether you're vegetarian, vegan, paleo, high fat, low carb, low fat, high carb, just reducing our amount of ultra processed foods, making sure that we're eating lots of real foods what I call low hi stuff, and making sure we're having lots of of fresh fruit and vegetables with have polyphenols and flavonoids that really help to support these cellular pathways. I think that's really key.

And then making sure that we're not in a constantly fed state. I think this whole idea that we should have three meals a day plus snacks is really not helpful because it particularly impacts on M tour and switches M tour on all of the time. I think we're much better to have two, if you like, but certainly three good solid meals that have enough protein and fat, and then you won't need the snacks in between, and

you won't constantly turn on that M tour pathway. So another promising mechanism to help with this is intermittent fasting or time restricted eating. So fasting naturally activates ampk and sertoons, and the thinking is certainly in mace and other animals that can reduce age will of the damage. There's still a little bit of debate about this with humans, but it would appear that periods of fasting, such as like a three or a five day water fast can really

help with cellular cleanup. And then fifth sixteen to eight fasting or or you know, pressing your your eating into a ten hour window or a worst case, a twelve r window, or certainly an eight our window. That is a simple way to reset nutrient sensing. But I would say it really depends here whether or not you're doing you should be doing intermittent fasting really depends on your life stage and your metabolic health. So I would say that if your metabolic health is not great, then give

intermittent fasting or time restricted feeding a crack. But if you're a bit older, certainly fifty plus, and you're in good metabolic health, right, you're pretty late. You've got no issue with your blood sugar or those sorts of things, and maybe doing constant time restricted feeding might not be useful because of its impact on muscle mass. So that still needs to be cleared up. So I'm one that kind of sits on the fence a little bit. I

used to do sixteen eight. I stopped doing it because I was losing muscle quickly, But I've since realized that that was probably to do with my congenital heart issue, and that the bicos but aotic valve that I had causes you to lose weight and particularly muscle, So I might revisit this. But it is certainly not a close case about fasting whether or not it is beneficial for everybody.

If you want to lose weight, time restricted eating can be very very effective, mostly because it reduces your calories. If you've got issues with your blood sugar, it can be really effective and it can help you with metabolic flexibility. And that's why I say you've got to look at what are your major health goals. Right. If you've got a reasonable amount of muscle, but you're not metabolically healthy,

then maybe give it a crack. Then the next thing around nutrition is to make sure you're optimizing your protein intake. So again this is controversial around M tour. Some people say we don't want to overstimulate M tour, so we should have a low protein diet. I think that the evidence for that in humans and primates is really really weak.

We know that one of the biggest issues for long term health is scarcopenia, that loss of muscle mass, and like I said earlier, M tour inside the muscle cells seems to be different than M tour outside of the muscle cells. So, especially as you get older, we want to be having one point six to two grams of protein per kilogram of body weight. Now, if you're significantly overweight, you would look at your target weight, and you would

do that that calculation the old recommended daily intakes. In fact they're still there is zero point eight grams per kilogram. There are many many researchers, myself included, who think that that is way too low. It was based on old nitrogen balanced studies and it was never meant to be optimal. It was meant to be the amount to prevent disease. And we think now that that is definitely too low.

So one point six to two grams spread over those three meals will make sure that you're getting enough protein, stimulating your muscle, and making sure you're not having lots of snacks so that you're not switching on m tour all of the time. Then when we get into the idea of supplements again a bit of controversy here. Now, Berberine is one that I would give a big tick. It has been shown to activate AMPK and improves insulin sensitivity. It can help people who have diabetes, and that's a

natural supparant called berbermine. Berberine. Sorry, res veratrol, there was a lot a lot of stuff around res viatrol. It has been well and truly debunked that it's been shown that it does not activate surtoons, it does not increase lifespan. It's been tested in the Interventions Testing program, it's been debunked, and Professor David Sinclair has been called a charlatan by his Harvard colleagues. So if you're spending your money on res viatrol, I would suggest that you spend it elsewhere.

And met Foreman is another one that showed a lot of promise because there was an early study showing that people who had diabetes who were taking met foreman actually outlived people who did not have diabetes and were not taken met forman. But since then and that created this whole stuff in the longevity space, and there was all

these people taking met forman. We know that met forman interferes with exercise, and another study then came out and showed that actually people on diabetes who had met forman didn't live any longer. And when they went and reanalyzed the data from the first paper, it showed that there

were a lot of methodo logical issues. So met forman is one that's kind of a yeah nah, But it is being tested in longevity research, so we may see that there are some benefits and one thing that has been consistently shown to extend lifespan, and this is just in MAE, but this is through the Interventions Testing program, which is the most rigorous assessments of molecules that could potentially extend lifespan is rapamycin and that has been shown

over and over again to consistently extend lifespan in mice, and it appears to do so through its impact on m tour amongst other things. It is now being tested on dogs and if that shows promise on dogs, then I think people will really start to get excited. And I know there's a lot of people who take rap of mice in off label as a longevity drug. If you live in Australia, you get no chance of getting it. If you live in the States, you can probably get

it from a doctor off label. So in closing this, disregulated or deregulated nutrient sensing is a major driver of aging and disease, but it is also highly controllable and through exercise, intermittent fasting, eating a whole food, low heat side diet, and potentially some targeted supplements, and by doing that we can restore our metabolic balance, we can improve our longevity and reduce our disease risk. So that's it for this week, folks. I'll catch you next time for episode seven.