>In one test, the team tapped into two well-known treatments for delaying aging: inhibiting insulin signaling and caloric restriction.

Does this mean that the newer diet medications like Semaglutide could be accelerating aging since they increase the secretion of insulin from the beta cells?

You can almost think of a cell "switching modes" in this way as it "booting into a different OS": the DNA of the cell gets re-phosphorylated, which means different sections of the DNA become active and begin being transcribed into proteins.

And it's this re-phosphorylization process during each cellular "mode switch" that is the primary contributor to the consumption of telomere end-caps on the ends of your DNA; and so is the primary driver of cellular senescence.

Which means that the more frequently you do things that make your cells switch modes, the sooner those cells will break down.

I'm not sure what-all set of "modes" cells switch between — it's probably different per specialized cell type.

But I would hypothesize that "glucose metabolism" vs "ketone metabolism" is a pretty universal mode switch for most cell types; which would, if true, neatly explain the life-extending benefits of intermittent fasting (your cells stay in the ketone mode for longer, rather than flapping constantly between the ketone and glucose modes); and also the negative impact of insulin (insulin being the signal observed by cells that causes them to trigger a mode-switch into the "glucose metabolism" mode, if they're not already in it.)

There are two related but distinct kinds of glucose metabolism:

1. a buffered glucose metabolism, where the cell stores glucose as glycogen and then can burn the glycogen at will later on; and

2. an unbuffered glucose metabolism, where the cell passes (phosphorylated) glucose molecules directly into the nucleus to catalyze the one of the rate-limiting steps of the Krebs cycle.

Note how this actually forms three (or maybe four) distinct sub-modes that a cell still has to switch between — buffering glucose into glycogen; consuming buffered glycogen; consuming glucose directly; and rejecting glucose altogether (if it has both too much ATP and too much glycogen.)

For a cell to not need to switch between these glucose-metabolic modes, the intercellular matrix would have to contain a perfect level of glucose at all times — and every cell would have to always need exactly the same amount of energy at all times (which would make things like mitosis impossible.)

Even animals that subsist entirely on glucose, and don't really convert glucose into fat (e.g. hummingbirds) go "long" (in intracellular terms) periods between eating, such that muscle cells still need to keep glycogen buffers to do their jobs as the blood depletes in glucose.

Also, specifically re: unbuffered glucose metabolism, note that "unbuffered" here really is "unbuffered" — the cell only has a boolean "open/close the direct path for phosphorylated glucose to enter the nucleus" mode-switch it can flip. Not a knob it can turn to vary the speed at which the phosphorylated glucose is passed into the cell; nor a knob to control the phosphorylization rate; nor a knob to control the number of open glucose pores. As long as the full "unbuffered" path is open, the nuclear Krebs-cycle reaction cranks as fast as glucose can enter (and be phosphorylated by) the cell. So if — or rather, when — a cell gets too much ATP from this process, it's going to respond by doing a mode-switch out of direct glucose metabolism; either over to glycogen-buffering metabolism, or to the "transition mode" that shunts around ions to cause all the cell-membrane glucose pores to squeeze shut.

Interestingly, we have invented substances you can put in your body that prevent this mode-switch out of direct glucose metabolism, e.g. 2,4-Dinitrophenol. Some people consider these substances to be "diet drugs." But I hope you can see why they're very bad for you — without the cell able to say "I have enough ATP, I don't need any more glucose, let's buffer it / stop phosphorylating it / stop letting it in", you just get an indefinite runaway Krebs cycle loop spitting out all the ATP it can make, flooding the cell with it; where most cellular organelles in turn perform their function every time they get enough ATP to be able to do so, so suddenly the whole cell is just Sorceror's Apprentice-ing along — overheating itself, depleting itself of other stored chemicals, building up wastes too fast to excrete them, and doing other minor mode-switches as fast as they can happen, such that the nuclear DNA will burn away its telomeres (and introduce copying errors) at record speed.

> 2,4-Dinitrophenol

Wow that stuff sounds extremely dangerous.

I got incredibly annoyed at this piece of writing, and the article as a whole, trying to make it "fun and exciting" to the detriment of being clear. In the case of this particular problem, the short of version is "as individuals grow older, transcription speeds up, which leads to increased error rates". There is no "twist" - the process does indeed go awry.

Cancer itself, then, is a constructive proof that DNA damage can disable DNA-transcription-time error-checking mechanisms.

The question in my mind, then, is whether those safety mechanisms are "blocking" / "synchronous" steps done during DNA transcription, such that disabling them would make DNA transcription occur faster. If they are, that would neatly explain the observed effect.

ctrl + shift + t should fix that for you

For more detail, Peter Attia's new book 'Outlive' is a good introduction to some of the more involved steps you can take (wear a CGM to fine tune your diet for metabolic health, do more exercise and target it more specifically).

Attia does have some recommendations on protein (eat a lot, eat meat) that conflict with other longevity researchers' suggestions ( https://www.valterlongo.com/daily-longevity-diet-for-adults/ ) so take that with a pinch of (metaphorical) salt.

Also, normal people (entirely correctly) call table sugar a carbohydrate. Why nerd snipe?

Also, that might be a distinction without a difference in most cases, but sucrose and fructose also may not produce identical glycemic response to simple carbohydrates.

The point is this is a very complex topic, and some of it is at the edge of what humans know about nutrition.

https://startingstrength.com/article/sugar

Do you think I should be aiming for more sleep?

When you feel tired, it means you are very tired right now.

People who are sleep deprived and rate themselves as not tired shows poorer intellectual performance in tests.

Of course this is subject to perturbation by complicating factors like hungry cats.

Lots of my family members are in their late 80's now and I really wouldn't want to exchange say a decade of their life with a decade of mine if that means I will only live to 75 instead of 85 or 90. The number of people in their 80's that I know that I would want to exchange with is vanishingly small, most of them are going from one health issue to another, whereas most people in their 70's that I know, even the ones that lived relatively unhealthy are still going quite strong.

I get that that is what you are saying is a part of the quality of sleep experience, but those qualities are not really about duration, you either have those privileges or you don't. If you are lucky enough to have a biological clock requiring less hours per night to enjoy them fully, that's ok.

I would agree though that to forgo those qualities intentionally over an extended timeframe is a curious choice.

I think some people, specially nowadays, live in a very conceptual world inside their minds, and anything that they don't understand or deem unrelated to it, they compartmentalize as disposable, where in reality they're being a bit childish in how narrow they view the world.

I find that the 16 hours I have after clocking 8 hours are infinitely more "awake" than the 19 hours I get when I only clock 5.

Which is basically what the sleep researchers say. The bottom line is that there's clearly a tipping point, not the same for everyone of course but averaging around 7 hours, below which "wakefulness" (and functioning metabolism in general) experienced throughout the rest of the day rapidly starts to tank.

I'm actually taking plain Nicotinamide (one form of Vitamin B3) in larger amounts (3g/day) and the benefits I feel from it are similar to those ascribed to NMN (the recommended dose of which is about 1g/day).

Admittedly, I got put on it because my blood work wasn't going in the right direction, but it has noticably increased my ability to lose weight. Not exactly scientific, but in my first 5 months of trying to lose, I was down 30 pounds, in the next 5 months after starting it, I lost about 50 and was less strict about my diet...

Now I'm down a full 100.

It's a bit tough for me at the moment as I WFH and $wifie is horrified by the idea of fasting, but well if I don't get fired over next two weeks I'll start going into the office.

I do a water fast on thursdays (~36 hrs). I find that to be much easier than intermittent fasting mentally somehow.

Will they just stop happening after awhile?

The experiments showing longevity benefits from extreme caloric restriction have been conducted with small animals living in safe lab environments where they are protected from injuries and infectious diseases. Out in the real world, sarcopenia is a real killer. Elderly people need adequate (but not excessive) caloric intake in order to maintain muscle strength and prevent falls.

Temporary fasting for a few days likely has some benefits, at least for younger people with good lean muscle mass. But that's different from what people usually refer to as caloric restriction.

https://news.ycombinator.com/item?id=18252469

https://www.nature.com/articles/s41586-023-05922-y