Part III
In order to understand the aging process in muscle and what to do about it, we need to examine a fundamental concept in aging that unfortunately is rarely accounted for by the vast majority of biohackers. That concept is that aging is not just deterioration, but it is adaptation.
I have previously posted several studies on this site showing that many aging related changes in (1) the immune system (2) the cardiovascular system (3) the microbiome are not just a deterioration but an adaptation to other global changes in the organisms. An older immune system is a system adapted in some respects to the conditions of the rest of the body, because it is an effort at homeostasis of the whole organism, where one system compensates for the deterioration of another. If you now attempt to “bring back” the older immune system to the metrics of a younger one, you don’t get a younger functioning overall system, you get a dramatically worse outcome. Let’s go back to the house plumbing analogy. Imagine that when faced with weaker water flow from the tap (the result of age accumulated mineral deposits) we actually boost the water pressure so that the water flow is as if the pipes are brand new (“young”) - it will give you a very short increase in the rate of the water flow and then burst the pipes. The slower water flow is an adaptation of the aging plumbing system. If you want to fix the plumbing system, you need to go upstream and fix a lot of other things first, remove the deposits, fix the corrosion and so on. It takes a lot to fix the plumbing, merely boosting water pressure so that the water flows as if the pipes are young will lead to disaster. The same situation if you try to “boost” the immune system as we’re incessantly urged to do - this can very well be counterproductive, unless you take a very holistic approach and try fixing problems much upstream. I posted a study to that effect in the immune system. I did the same for the cardiovascular system and the microbiome, studies showing how a surface intervention to “fix” some aspect (bring it to “young” levels) results in disaster. This btw. is why I’m very cautious about the Michael Lustgarten approach of trying to push all biomarkers to their “youthful” state - when are you actually rolling back the clock and when are you merely obviating the aging adaptation which is trying to deal with the problems and bring the whole body into homeostasis? This is a huge problem in the biohacking longevity space. We are constantly reading studies that show some intervention, drug, supplement etc. bringing something to a more “youthful” state and we don’t ask ourselves if this is the right approach and we’re not actually making things much worse by working against the body adaptation processes. There are some nods toward this concept when there’s a hamhanded attempt to “increase antioxidants” without asking if doing so in this case might not result in a worse outcome like in cancer or removal of exercise adaptations.This is true of all systems in the body, including the muscle. Surely we understand that on some level in the case of muscles, because we understand that while some increased muscle mass is good, doing so by injecting steroids is suboptimal.
We need a much more subtle approach - generally this is going to be by going upstream in the aging pathway and more global solutions. Not increasing muscle size by injecting steroids so to speak. That is why the higher upstream you go, the more preserved the anti-aging effect is going to be, as in affecting the mTOR protein. Note that mTOR inhibition results in a very global effect of slowing the rate of aging itself, not so much by addressing discrete pathologies as such. So we have the same set of age related morbidities and pathologies, just postponed in time because we slowed the aging process. This is true of all these mTOR inhibitor interventions, whether through CR/fasting or rapamycin - you are slowing down the whole aging process at a high level - this is an approach that gets around the “adaptation” of the body to age-related changes, because you are slowing the aging itself and therefore we avoid the need for adaptation. That’s a very fundamental concept.
Do we see something similar to that in muscle tissue, as we do for all those curves in SGLT2i/kidney health, hormonal levels etc.? Yes we do. Here’s an interesting study - you can read the study or at least you should read the pop sci article on that study, it’s a really important one addressing this concept squarely, so I would strongly urge you to read this article at least, if not the study itself.
In fact, this is such a good study that I’m going to make a separate thread about it.
Cellular Survivorship Bias as a Mechanistic Driver of Muscle Stem Cell Aging
And one of the pop sci articles I found about this study, worth reading:
Muscle recovery slows with age, but it may not be a bad thing
A few quotes:
"Aging rarely announces itself in dramatic ways. It arrives through small delays. A sore muscle lingers longer than expected or a minor strain lasts weeks instead of days.
Movements that once felt effortless now demand caution. Many people read this as decline. The body seems to be losing its edge. But recent research offers a different view. These changes may not signal failure. They may reflect a shift in priorities inside the body."
"Young cells sprint, old cells endure
“Think of it like a marathon runner versus a sprinter. The stem cells in young animals are hyper-functioning – really good at what they do, namely sprinting, but they’re not good for the long term,” said Dr. Thomas Rando from the Stanford University School of Medicine.
‘They can make it through the 100-yard dash, but they can’t make it even halfway through the marathon. By contrast, aged stem cells are like marathon runners – slower to respond, but better equipped for the long haul.’
‘However, what makes them so proficient over long distances is exactly what renders them poor at sprinting.’
This contrast highlights a key shift. Aging cells do not simply weaken. They adjust their strategy."
"As tissues age, their environment becomes more demanding. Oxidative stress increases. Damage accumulates. Not all cells can survive under these conditions.
The cells that remain are not the fastest or most efficient. They are the ones that endure."
"This balance between performance and survival is not unique to muscle cells. It appears across living systems.
During periods of scarcity, animals often reduce activity linked to growth or reproduction. Energy shifts toward survival. This response helps them endure difficult conditions. The same principle operates within aging tissues. “Species survive because they reproduce, but in times of deprivation, animals turn on their own resilience programs,” Rando said.
“There are a lot of examples in nature of allocating resources to survival under times of stress. It’s exactly aligned with what we’re seeing at the cellular level.”
Muscle stem cells follow this pattern. They slow down to preserve their long-term function."
[This is called - CR!]
“Any attempt to modify this system must weigh short-term gains against long-term consequences.”
"Slower recovery may not signal failure. It may represent a protective adjustment. The body chooses to preserve its resources instead of using them all at once.
“Some age-related changes that look detrimental – like slower tissue repair – may actually be necessary compromises that prevent something worse: the complete depletion of the stem cell pool,” said Dr. Rando.
This perspective shifts the narrative. Aging becomes a process of balance rather than simple decline."
So - here we can see the same idea for muscle aging as we see in CR and other mTOR affecting interventions like rapamycin. You slam on the brakes. In the SGLT2i/kidney terms, you prevent the “hyperfiltration”, the frenzy of incessant activation. The muscle like many other tissues gradually loses the ability to receive signals - it becomes resistant to protein, growth etc. It’s like the loss of sensitivity to insulin - when you are no longer insulin sensitive, merely boosting the levels of insulin, boosting the signal is like going into hyperfiltration mode of increased effort that works in the short term, but leads to disaster longer term (increasing insulin until diabetes and eventual pancreatic beta cell exhaustion and death). Instead, you want to go upstream and fix the problem of signal reception loss, like insulin resistance, so you are not merely boosting the signal - go upstream through mTOR inhibition (CR or rapamycin).
CR just as rapamycin is slamming the brakes on the aging process in muscles at the cost of short term blunting of exercise performance. Long term, we know what CR does for muscles and rapamycin works through the same master regulator mTOR. It fixes loss of signal reception like insulin resistance.
This is where Dr. Brad goes wrong. He has the wrong model of why muscle recovery and adaptation slows down with aging. The primary lever is not autophagy, and therefore the cycling of autophagy model cannot explain the result. If you have the wrong model in mind, then run an experiment that gives you negative results, it’s not because there is something wrong with the tested intervention, it’s that your expectation is wrong because you have the wrong model. In the house plumbing analogy, Brad thinks that the intervention of lowering the pressure valve (administering rapamycin) means that it doesn’t work, because it causes the water flow to weaken, whereas that simply says that his model of how the plumbing system works is wrong. Same when he administers rapamycin thinking that based on his autophagy model if the exercise performance drops it means that rapamycin doesn’t work as hoped for, instead of realizing that the effect is actually good, instead it’s his model that’s bad. As the study above shows - slower muscle recovery is an adaptation, and blunted exercise peformance is a way to get ahead of the aging process itself by affecting mTOR.
More in part IV.
