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Retinoic acid versus Regeneration
I’ve been suspecting that symptoms like eczema, hair loss, wrinkles, and joint pain are caused by retinoic acid.
These issues come down to failure of regeneration and wound healing. I only have eczema and hair loss where I’ve scratched my skin. I only get wrinkles on skin which folds from joint movement. I only have knee pain in my right knee, my dominant side. These are normal injuries, but something in my body is preventing the wounds from healing.
Some might call this aging, but I suspect toxins such as retinoic acid, since the eczema gets worse with higher vitamin A foods. Also, my hair loss comes along with loose sebaceous glands, which have a distinct yellow color. My blood vitamin A levels are still at 68 mcg/dL, so this is a natural guess.
I’m sure Grant and others have researched this topic already. But after a short dive, I found a few clues which were interesting enough for me to write up.
This paper finds a connection between wound healing and cellular stress:
The part of the cell being stressed is the endoplasmic reticulum (ER), which does things like fold proteins and store calcium.
But another important aspect of the ER is that it is the largest source of CYP450 in the cell. CYP450 is an enzyme which detoxes many things, including retinoic acid.
The first clue is that antioxidant therapy doesn’t help ER stress. Since CYP450 is oxidative, antioxidants would go oppositely to its functioning.
The second coincidence to note is that retinoic acid causes ER stress. In fact, this is its selling point for its use as a chemotherapy! Instead of quoting a paper, I will just list the first 6 entries on a google scholar search, and you can decide for yourself.
Now finally we come to the main results of the paper. After giving mice a toxin called Streptozotocin, the mice lost regenerative capacity. But giving them vitamin D restored their rate of wound healing to nearly normal levels.
How did vitamin D do this? The authors observed that vitamin D treated rats had lower markers of ER stress, especially the GRP78 expression, which is the ER pause-button and the main hallmark of its stress response.
How did vitamin D normalize the endoplasmic reticulum? The authors did not probe this question.
To me, the main observations here are that toxins can impact regeneration by causing ER stress, and that retinoic acid can cause ER stress, possibly because of its relation to its detox enzyme CYP450, which is located in the ER.
In fact, the paper itself is motivated by wound healing failure in diabetics, not aging. This connection might shed light on that particular issue.
It is my pet theory that most everyone eventually ends up VA-overloaded, given enough time. I suppose that is what your screen name is all about! I like to think of that old nursery rhyme, "there was a crooked man, who walked a crooked mile". (he also had an old crooked house, crooked cat, crooked mouse, etc). Getting crooked in old age is part of humanity.
Grant has said that diabetes is related to VA overload as well. My two grandparents who lived into their 90's never got high sugars. They also didn't get crooked until the very end. I remember looking around the table at the old age home and noticing that my grandmothers fingers weren't bent like some of the others.
Ourania and I have talked about a common symptom of old age: bunions. This is when the outer toes start pointing into the middle, and the knuckles bulge out the sides. This causes pain in the foot but also FALLS because now your feet have less width and stability and flexibility. Falls are the bane of old age. I would not be surprised if bunions are down to shortening and twisting of ligaments in the feet... because of VA overload. Similar to my bent pinky finger (the prayer sign) which is also linked to auto-immunity, which Grant has also said is often about VA.
Interesting: I've had toe bunions and bent fingers since my early 20's, around when I started losing my hair and getting permanent aches from normal exercise injuries.
I think various toxic accumulations are associated with most of the aging process. I'm still unclear whether all those accumulations are causal of the process, or whether the aging process itself allows and encourages those accumulations to grow.
This is super interesting. I haven't had a chance to read it fully through yet, but I have had similar experience. Dry skin/eczema where I've scratched my skin, hair loss w/ dry skin at a specific point on the back of head. I have been on low vitamin A for about 1.5 years and I feel quite good overall, and my hypothesis is that my body is detoxing vitamin A right now.
That's the first time I've seen someone else notice this, interesting confirmation.
I definitely think the aging process is not uniform. The body doesn't lose hair and get wrinkly skin at the same rate or times. I've been able to understand each and every bit of deterioration as it comes, and it's usually from a well defined, discrete source of damage, that just didn't heal right.
I've also noticed an underlying itching, sort of within the skin, that's necessary for this to happen. Like when I get cheek eczema from scratching, I only scratched because that section of cheek was itching. The other parts of my cheek don't itch at all, and they heal OK if I scratch them. The same issue happens on my scalp, and I get hair loss only when I scratch that part of the scalp that itches. Other parts I scratch don't lose hair.
Bizarrely, the right side of my head is much more bald than my left side, because my dominant hand is my right one, and is the one that scratches.
I believe this sort of itchy sensation matches with what Grant wrote about early on, so this alone convinced me that the vitamin A stuff might be real. I've only finished one year of lowering vitamin A, and still have a ways to go.
Sweating also seems connected here. I lost the ability to sweat on parts of my cheeks: the precise parts I have eczema on.
There was actually a warning sign of this from years ago. Whenever I'd stop exercising and resume, I'd notice really painful stinging in this cheek area as the sweating started. After a few days of exercise and this sweat stinging, the pain would disappear.
So it's natural to hypothesize that sweating releases some stored retinoic acid. After enough sweating, there's enough clearance, and the pain stops.
I eventually got too sick to exercise, at some point, so maybe that area accumulated too much toxicity. Then its ability to heal stops, so after scratching, I have eczema.
I've had very similar observations on my eyebrows, which have lost 60% of their thickness over the past two years of scratching them.
There’s a bit of research going on on wound healing and wearables
https://www.darpa.mil/news/2019/intelligent-healing-complex-wounds
https://www.darpa.mil/news/2025/wearable-tech-prevent-infection