This article is everything. As someone who has been looking into getting into creatine from the fitness aspect, I too have thought “what exactly is creatine and why are all the fitness influencers telling me to take it?” Thus, I’ve always associated creatine with replenishing the body after intense workouts. Thanks for explaining the science behind creatine, it’s equally fascinating and important to understand the role it plays in our bodies!
And yes, you nailed it. The fitness world essentially hijacked creatine, and the rest of us never thought to ask whether it had anything to do with us.
Here is what I find most fascinating about all of this. Creatine is not a fitness supplement that happens to have some effects on the brain. It is a molecule your body makes and needs, and the fitness industry just noticed it first.
A few things I want to dig into more as this series goes on ... The cognitive load angle is underappreciated. Most of us are not athletes, but we are exhausted, and that exhaustion is as much neurological as it is physical. Creatine sits right at that intersection.
The dietary piece is something I keep coming back to. Lower meat intake means lower baseline creatine, and we genuinely do not know yet what that means for brain aging over decades. That gap in the research bothers me. I keep digging into vegan and vegetarian studies, and creatine might help fill some of the gaps in those diets.
And the brain bioavailability question is where I think the next few years of research will get really interesting ... and my main focus. We now have data showing that creatine measurably increases in the brain at higher doses, and cognitive improvements follow it ... this is good and bad because of the higher dose required. But science is trying to catch up on that angle too. More coming soon.
Harshi, I am very careful about ever taking any supplements -- unless a clear deficiency is identified through blood or tissue analysis.
BUT -- I also eat a balanced diet. As I've gotten older, I've noticed a clear need for protein, among other things. I eat a bowl of blueberries every morning, with the rest of my breakfast. I'm 70, in fairly good shape, except for a musculoskeletal autoimmune inflammatory disease I've had my entire adult life. I have no need for statins or any other meds.
Yes you raise amazing points that need to be addressed! It’s imperative that creatine should be talked about as more than just something athletes benefit from, especially the brain aspect as you mentioned (everyone has a brain). Keep up the work, can’t wait to read your next pieces.
First time I read about Creatine, I thought of an engine turbo charger. But the biological engineering doesn't make sense that way.
Later I was reading how fast glycolysis was compared to mitochondrial phosphorus oxidation... like 100 times faster. However if phosphorus creatine can take a ADP and quickly turn it back to ATP without a trip back to mitochondrial processing, that would speed the non-glycolysis ATP average cycle rate. And decrease the somewhat messy glycolysis pathway (and reduce lactate production). I suspect it also reduces mitochondrial reactive oxygen species "exhaust" which is useful in some ways but also dangerous. Also less heat since mitochondrial process is inefficient like any engine.
One puzzle is how phosphocreatine gets recharged after the ADP->ATP conversion. There has to be a rapid recycling process to avoid exhausting the process. What a hoot if the ATP utilization, which "consumes" a phosphate could be recycled into a phosphocreatine!!
You are thinking about this exactly right, and your intuition about the downstream effects is spot on.
On the recycling question … this is actually the cool part of the system. Phosphocreatine is recharged directly by the mitochondria during recovery periods. The creatine kinase enzyme works in both directions. During high demand, it converts phosphocreatine plus ADP into creatine plus ATP. During rest or lower demand, the mitochondrial form of creatine kinase runs the reaction in reverse, using ATP produced by oxidative phosphorylation to recharge creatine back into phosphocreatine. So the mitochondria are essentially the long-range recharging station, and phosphocreatine is the rapid-deployment buffer between them and the sites of ATP consumption. The two systems are not competing; they are layered.
Your point about lactate is valid, too. Because phosphocreatine can sustain ATP levels long enough to delay the point at which the cell tips into anaerobic glycolysis, you do see reduced lactate accumulation during moderate intensity effort. It is not that glycolysis is bypassed entirely, but the threshold at which it becomes the dominant pathway gets pushed further out. I see this as an important aspect for athletes and highly active people.
The reactive oxygen species angle is where it gets interesting and less settled. There is some evidence that creatine supplementation reduces oxidative stress markers, and your reasoning about mitochondrial load could be true and valid. But the direct mechanism is still being researched so we need to wait for that.
My favorite aspect of lactate is seen in red blood cells - which have no nucleus probably to have room for more hemoglobin. They depend on glycolysis, produce lactate, lactate into blood, liver takes in lactate, sort of runs gluconeogenisis backwards (or short circuits that process) and pushes the reconstituted glucose back into blood. I also seem to remember the brain can use lactate as fuel also.
This one was a "must read." I've been taking this stuff for a long time. I've been asked about it many times. I don't push it, but I do recommend it. Every five years or so I recheck the research, just to see what's new. I'm biased, but this was your best post so far. Cheers.
I started researching the Alzheimer’s and Parkinson’s spaces first. Then realized the misconceptions and misunderstandings around creatine. This needs to be addressed starting from the basics.
I realize most will know what i wrote today. But starting at the very beginning is never a bad idea. 😃
Harshi, I enjoyed reading this! I support your efforts to teach people about responsible use of any supplements, and the concept of simply not believing all the claims of anyone who has "financial motivations."
(It's a multi& billion dollar industry.)
And, I realize this was written for the "non-scientist," but I have a few "irks":
"Instantaneously" is a long way from "less than a second!" But that's okay. I realize most ppl operate in a "world of seconds."
As someone who did many histochemistry experiments (coupled with electrophysiology) on slices of muscle tissue, I can vouch for the fast that ATP does NOT last long! We used to mix it in solution to use in our preps, and it surely doesn't last long. It's so "energetic" and essentially unstable that it starts "coming apart" almost immediately.
That's another miracle of our bodies! The fact that these biochemical systems each have mechanisms to support each other. ATP (and ADP) give our cells instant energy, and to "keep the flow sustained," there are other mechanisms in place to keep all the "supplies" (precursors) handy through other molecules, cellular transport, etc.
Again, this was great reading!
Oh, one other thing:
As someone who had lived their entire adult life with a musculoskeletal inflammatory disease, I can assure you that muscles never get a "day off." Simply moving around -- and especially maintaining any posture -- makes muscles work constantly.
But, I get your point, and I'll let you 'off the hook' for that, lol.
Cheers! 👍
PS: to get easily understood neuroscience from a neuroscientist who 'lived the knowledge he understood,' here's my 'stacks:
This article is everything. As someone who has been looking into getting into creatine from the fitness aspect, I too have thought “what exactly is creatine and why are all the fitness influencers telling me to take it?” Thus, I’ve always associated creatine with replenishing the body after intense workouts. Thanks for explaining the science behind creatine, it’s equally fascinating and important to understand the role it plays in our bodies!
Thank you so much, this makes me happy to hear!😊
And yes, you nailed it. The fitness world essentially hijacked creatine, and the rest of us never thought to ask whether it had anything to do with us.
Here is what I find most fascinating about all of this. Creatine is not a fitness supplement that happens to have some effects on the brain. It is a molecule your body makes and needs, and the fitness industry just noticed it first.
A few things I want to dig into more as this series goes on ... The cognitive load angle is underappreciated. Most of us are not athletes, but we are exhausted, and that exhaustion is as much neurological as it is physical. Creatine sits right at that intersection.
The dietary piece is something I keep coming back to. Lower meat intake means lower baseline creatine, and we genuinely do not know yet what that means for brain aging over decades. That gap in the research bothers me. I keep digging into vegan and vegetarian studies, and creatine might help fill some of the gaps in those diets.
And the brain bioavailability question is where I think the next few years of research will get really interesting ... and my main focus. We now have data showing that creatine measurably increases in the brain at higher doses, and cognitive improvements follow it ... this is good and bad because of the higher dose required. But science is trying to catch up on that angle too. More coming soon.
Harshi, I am very careful about ever taking any supplements -- unless a clear deficiency is identified through blood or tissue analysis.
BUT -- I also eat a balanced diet. As I've gotten older, I've noticed a clear need for protein, among other things. I eat a bowl of blueberries every morning, with the rest of my breakfast. I'm 70, in fairly good shape, except for a musculoskeletal autoimmune inflammatory disease I've had my entire adult life. I have no need for statins or any other meds.
Great read! And, I support your mission!
Cheers! 👍
Yes you raise amazing points that need to be addressed! It’s imperative that creatine should be talked about as more than just something athletes benefit from, especially the brain aspect as you mentioned (everyone has a brain). Keep up the work, can’t wait to read your next pieces.
First time I read about Creatine, I thought of an engine turbo charger. But the biological engineering doesn't make sense that way.
Later I was reading how fast glycolysis was compared to mitochondrial phosphorus oxidation... like 100 times faster. However if phosphorus creatine can take a ADP and quickly turn it back to ATP without a trip back to mitochondrial processing, that would speed the non-glycolysis ATP average cycle rate. And decrease the somewhat messy glycolysis pathway (and reduce lactate production). I suspect it also reduces mitochondrial reactive oxygen species "exhaust" which is useful in some ways but also dangerous. Also less heat since mitochondrial process is inefficient like any engine.
One puzzle is how phosphocreatine gets recharged after the ADP->ATP conversion. There has to be a rapid recycling process to avoid exhausting the process. What a hoot if the ATP utilization, which "consumes" a phosphate could be recycled into a phosphocreatine!!
You are thinking about this exactly right, and your intuition about the downstream effects is spot on.
On the recycling question … this is actually the cool part of the system. Phosphocreatine is recharged directly by the mitochondria during recovery periods. The creatine kinase enzyme works in both directions. During high demand, it converts phosphocreatine plus ADP into creatine plus ATP. During rest or lower demand, the mitochondrial form of creatine kinase runs the reaction in reverse, using ATP produced by oxidative phosphorylation to recharge creatine back into phosphocreatine. So the mitochondria are essentially the long-range recharging station, and phosphocreatine is the rapid-deployment buffer between them and the sites of ATP consumption. The two systems are not competing; they are layered.
Your point about lactate is valid, too. Because phosphocreatine can sustain ATP levels long enough to delay the point at which the cell tips into anaerobic glycolysis, you do see reduced lactate accumulation during moderate intensity effort. It is not that glycolysis is bypassed entirely, but the threshold at which it becomes the dominant pathway gets pushed further out. I see this as an important aspect for athletes and highly active people.
The reactive oxygen species angle is where it gets interesting and less settled. There is some evidence that creatine supplementation reduces oxidative stress markers, and your reasoning about mitochondrial load could be true and valid. But the direct mechanism is still being researched so we need to wait for that.
My favorite aspect of lactate is seen in red blood cells - which have no nucleus probably to have room for more hemoglobin. They depend on glycolysis, produce lactate, lactate into blood, liver takes in lactate, sort of runs gluconeogenisis backwards (or short circuits that process) and pushes the reconstituted glucose back into blood. I also seem to remember the brain can use lactate as fuel also.
Whew!!!
This one was a "must read." I've been taking this stuff for a long time. I've been asked about it many times. I don't push it, but I do recommend it. Every five years or so I recheck the research, just to see what's new. I'm biased, but this was your best post so far. Cheers.
Thank you 😊
I started researching the Alzheimer’s and Parkinson’s spaces first. Then realized the misconceptions and misunderstandings around creatine. This needs to be addressed starting from the basics.
I realize most will know what i wrote today. But starting at the very beginning is never a bad idea. 😃
You know how humans are. They want the hype, until they get sick. Even after all these years, you’ve filled in some blanks.
Harshi, I enjoyed reading this! I support your efforts to teach people about responsible use of any supplements, and the concept of simply not believing all the claims of anyone who has "financial motivations."
(It's a multi& billion dollar industry.)
And, I realize this was written for the "non-scientist," but I have a few "irks":
"Instantaneously" is a long way from "less than a second!" But that's okay. I realize most ppl operate in a "world of seconds."
As someone who did many histochemistry experiments (coupled with electrophysiology) on slices of muscle tissue, I can vouch for the fast that ATP does NOT last long! We used to mix it in solution to use in our preps, and it surely doesn't last long. It's so "energetic" and essentially unstable that it starts "coming apart" almost immediately.
That's another miracle of our bodies! The fact that these biochemical systems each have mechanisms to support each other. ATP (and ADP) give our cells instant energy, and to "keep the flow sustained," there are other mechanisms in place to keep all the "supplies" (precursors) handy through other molecules, cellular transport, etc.
Again, this was great reading!
Oh, one other thing:
As someone who had lived their entire adult life with a musculoskeletal inflammatory disease, I can assure you that muscles never get a "day off." Simply moving around -- and especially maintaining any posture -- makes muscles work constantly.
But, I get your point, and I'll let you 'off the hook' for that, lol.
Cheers! 👍
PS: to get easily understood neuroscience from a neuroscientist who 'lived the knowledge he understood,' here's my 'stacks:
https://jeffro55.substack.com and https://BrainEngage.substack.com
I hope to see y'all there!