The Pattern Is the Point: Tretinoin, Nickel, PEA, and What the Research Is Actually Showing

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Every once in a while, I put together a livestream where several seemingly unrelated research papers land in my lap at the same time.

Muscle weakness and ME/CFS.

Copper and zinc in aging.

Ferritin and biological aging.

Nickel hidden in a wetsuit.

Nickel interfering with DNA repair after radiation.

A new “Magic Vitamin A” skincare ingredient.

Tretinoin.

PEA.

At first glance, that looks like a scientific junk drawer.

It isn’t.

The pattern is the point.

Over and over, we see potentially harmful things accumulating or becoming increasingly problematic with age, while minerals that the body depends upon to function and defend itself—especially zinc and selenium—trend in the opposite direction.

Then we see nickel making other forms of damage worse.

Then we see a supposedly wonderful new vitamin A derivative causing cells to radically alter their metabolism, including increasing PEA…one of the very compounds I’ve recently been discussing for its anti-inflammatory and protective effects.

And finally, we get to tretinoin.

That’s where things get especially interesting.

First: The Mineral Pattern Keeps Showing Up

One of the papers I covered was a 2024 review titled Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence.

The authors focused on a recurring problem inside skeletal muscle: abnormal sodium and calcium accumulation.

Their earlier model proposed that impaired muscle perfusion and metabolism could produce excessive sodium and calcium loading, leading to mitochondrial damage.

The newer evidence supported that model.

They specifically reported increased intracellular sodium in skeletal muscle and an inverse relationship between intracellular sodium and hand-grip strength.

In other words:

More sodium stuck where it doesn’t belong = weaker muscle function.

The authors described:

“excessive sodium and calcium overload in skeletal muscles”

Now think about what I have been teaching people for years.

The issue is not simply “calcium good” or “sodium bad.”

That’s kindergarten-level nutrition.

The issue is where the minerals are, how much is there, what other minerals oppose them, and whether the cellular machinery controlling them is functioning correctly.

The sodium-potassium pump exists for a reason.

Magnesium opposes many of calcium’s actions for a reason.

I continually emphasize potassium and magnesium because these aren’t random supplement recommendations. They directly oppose a pattern that keeps showing up in dysfunctional tissue: too much sodium and calcium in the wrong places, with inadequate potassium and magnesium activity to properly regulate them.

Once you start looking for patterns instead of isolated lab values, the picture changes completely.

Aging: More Copper, Less Zinc, Worse Function

Now look at copper and zinc.

The study High serum Cu and Cu/Zn ratios correlate with impairments in bone density, physical performance and overall health in a population of elderly men with frailty characteristics examined 144 frail elderly men.

The opening sentence of the abstract alone should get your attention:

“Serum Cu levels rise with age”

At the same time, the researchers found that higher copper-to-zinc ratios correlated with poorer health across multiple systems.

Higher Cu/Zn ratios were associated with:

• lower femoral bone mineral density

• poorer speed and strength

• reduced muscle mass

• lower hematocrit

• greater dependence upon assistance for activities of daily living

Read that again.

More copper relative to zinc was associated with weaker bones, weaker muscles, lower muscle mass, worse blood markers, and needing more help simply to function.

The authors concluded that serum copper and the copper/zinc ratio could serve as predictive biomarkers for poor health in the elderly.

Yet people will still tell you that rising copper is somehow wonderful because you just need more “bioavailable copper.”

Okay.

How is that theory working out for the elderly men getting weaker while their copper-to-zinc ratio goes up?

The outcome matters.

Ferritin and Biological Aging

Next comes iron.

A 2025 study titled Association Between Body Iron Status and Biological Aging examined serum iron markers against DNA-methylation measures of biological aging.

Ferritin stood out.

The researchers reported positive associations between ferritin and several measures of accelerated biological aging.

Their conclusion included:

“positive association between serum ferritin and biological aging”

Ferritin is your major iron-storage protein.

More stored iron means more potential iron-driven oxidative chemistry.

This is not difficult chemistry to understand.

Iron rusts.

Copper oxidizes.

Nickel promotes oxidative stress.

Now imagine accumulating several pro-oxidant metals while simultaneously losing the minerals involved in maintaining normal cellular function and detoxification.

Maybe “aging” isn’t simply a magical clock inside your cells telling you that you’re old.

Maybe part of what we call aging is accumulated toxicity plus accumulated deficiency.

That’s been my argument for years.

Meanwhile, Zinc and Selenium Go DOWN

Now we flip the direction.

The study Serum concentrations of zinc and selenium in elderly people: results in healthy nonagenarians/centenarians compared people 91–110 years old with a younger elderly group aged 60–90.

They found:

“A significant decrease of Se and Zn values”

as age increased.

Here’s what was especially interesting.

Among the healthy people over 90, 84.4% still maintained zinc and selenium concentrations at or above the lowest values seen in the younger elderly group.

Only 3.3% showed deficiency in both.

That is an important distinction.

The age-related trend was downward.

But the healthier very-old people were largely avoiding the bottom of that decline.

Then another paper—the ZincAge study—looked at 1,090 healthy elderly people from five European countries.

What most strongly predicted falling plasma zinc?

Age.

What increased with age and inflammation?

The copper-to-zinc ratio.

The researchers reported:

“Plasma Zn decrement was most strongly predicted by age”

and found that Cu/Zn ratio was positively associated with both age and markers of systemic inflammation.

There it is again.

Copper-to-zinc goes UP.

Inflammation goes UP.

Zinc goes DOWN.

Combine that with the other findings:

Ferritin UP.

Copper UP.

Zinc DOWN.

Selenium DOWN.

Then add what I’ve already documented elsewhere regarding the accumulation of vitamin A and nickel.

Patterns, patterns, everywhere.

Nickel: It’s Not Just About How Much You Eat

One of the stranger papers from this episode involved a woman developing allergic contact dermatitis from a neoprene wetsuit.

The paper, Allergic contact dermatitis due to nickel in a neoprene wetsuit, described a 31-year-old woman who repeatedly developed eczema after wearing her wetsuit.

Nickel allergy testing was positive.

Then researchers actually analyzed the wetsuit.

Atomic absorption testing confirmed substantial nickel, with higher concentrations around the wristbands.

She switched to another neoprene wetsuit with thicker fabric between her skin and the neoprene.

No recurrence.

She later wore the old wetsuit again.

The dermatitis came back.

So now ask the obvious question:

Why is nickel in neoprene that spends hours pressed tightly against someone’s skin?

This is exactly why I keep telling people that nickel exposure is not merely a question of whether you ate oatmeal today.

Nickel can come from cookware.

Utensils.

Jewelry.

Dental work.

Occupational equipment.

Clothing hardware.

And apparently even neoprene.

You have to look at the total exposure.

Nickel Can Also Make OTHER Damage Worse

This next paper is even more important.

The study Toxicological interactions between nickel and radiation on chromosome damage and repair exposed human lymphocytes to nickel acetate before radiation.

Nickel by itself was not producing a dramatic conventional chromosome-aberration signal at the lower doses being studied.

But when nickel exposure came before radiation, chromosome translocations increased beyond what would have been expected simply by adding the separate effects together.

The researchers wrote:

“pretreatment with nickel interferes with the repair of radiation-induced DNA damage”

There it is.

Nickel didn’t merely contribute another isolated injury.

Nickel interfered with the repair of another injury.

This distinction is HUGE.

Imagine evaluating toxic exposures one at a time.

Nickel?

Radiation?

Vitamin A?

Copper?

Iron?

You could easily miss the real problem if one toxin makes the body less capable of repairing damage caused by another.

That’s why reductionist toxicology can be so misleading.

Living organisms are not spreadsheets.

Exposures interact and may even synergize.

Enter “Magic Vitamin A”

And now we arrive at one of my favorite papers of the week.

Not because it was good.

Because the story behind it was so revealing.

The 2025 paper The anti-aging potential of VA’S new derivatives through metabolomic profiling investigated a compound the authors actually call Magic Vitamin A, or MVA.

Yes.

Magic Vitamin A.

Apparently regular vitamin A wasn’t magical enough.

The study used HaCaT skin cells and examined how MVA changed cellular metabolism.

The authors reported that MVA:

“substantially alters the cellular metabolic state”

That sentence deserves more attention than it received.

Altering cellular metabolism is not automatically beneficial.

The QUESTION is what the cell is doing and WHY.

The researchers reported increased levels of several compounds following MVA treatment, including:

• 18-beta-glycyrrhetinic acid

• palmitoylethanolamide — PEA

• 17-AAG

• L-arginine

• DHEA

They interpreted these changes as evidence of anti-aging, anti-inflammatory and antioxidant activity.

I look at it differently.

Why Did “Magic Vitamin A” Make the Cells Increase PEA?

PEA has become an extremely important compound in my recent research.

We’ve discussed its effects on inflammation, pain, mast cells, skin, the gut, TRP channels, and multiple other systems.

So when I saw that exposing cells to this new vitamin A derivative dramatically altered their metabolism and increased PEA, my immediate question was:

Why?

If I expose the body to something and the cells start increasing their production of anti-inflammatory and protective compounds, does that automatically mean the thing I administered is anti-inflammatory?

Or could those molecules represent the cellular defense response to the thing I just administered?

Those are not remotely the same interpretation.

Imagine punching someone in the face and then measuring increased production of anti-inflammatory molecules.

Would we conclude that getting punched is an anti-inflammatory therapy?

Apparently metabolomics can become very magical indeed.

And the paper itself gives us another clue.

It acknowledges that retinoids can cause:

• erythema

• peeling

• dryness

• increased transepidermal water loss

• temporary disruption of the skin barrier

Interestingly enough, PEA is one of the compounds I have discussed specifically in relation to helping normalize inflammation and skin-barrier function.

So again:

Why did the cells increase PEA after MVA exposure?

I think that question deserves considerably more attention than simply labeling the resulting metabolite changes “anti-aging.”

Then There Is the Conflict-of-Interest Problem

This paper gets even better.

The paper states:

“MVA derivatives were designed and synthesized by Coachchem.”

Now go look at the authors.

Six of the fourteen listed authors are affiliated with Shanghai Coachchem Technology.

One of the two equally contributing first authors, Jiang Wu, is affiliated with Shanghai Coachchem Technology and is also a corresponding author.

His email?

johnnywu@coachchem.com

And yet down at the bottom:

“The authors declare no competing interests.”

Seriously?

Your company designed and synthesized the substance being investigated.

Multiple authors work for that company.

A corresponding author works for that company.

And there are “no competing interests”?

You don’t have to take my interpretation of MVA at face value.

You should simply know who made the compound and who wrote the paper praising it.

Then decide how much weight you want to give those conclusions.

What Is Vitamin A’s Active Form Again?

The same MVA paper provides another useful reminder.

It states that retinoic acid—tretinoin—is the metabolically active form of vitamin A.

Tretinoin is also sold as Retin-A.

And the paper itself acknowledges the “potent skin-irritating properties” of retinoic acid.

Why does it irritate skin?

Because biological activity and toxicity are not opposites.

They can be the same thing.

A chemical peel is extremely “biologically active.”

So is a burn.

In aesthetic medicine, tretinoin is called a “yellow peel” and is used to induce “controlled wounds” of the skin.

Inducing cellular turnover after damaging the surface does not magically prove that the original damage was health-promoting.

Which brings us to the Veterans Affairs tretinoin trial.

They Put Tretinoin on Veterans to Prevent Skin Cancer

The randomized Veterans Affairs study Tretinoin and the prevention of keratinocyte carcinoma involved 1,131 people receiving either 0.1% topical tretinoin or a vehicle-control cream for up to 5.5 years.

Researchers were trying to prevent new basal-cell and squamous-cell carcinomas.

Did it work?

No.

At five years:

• basal-cell carcinoma occurred in 53% of the tretinoin group and 54% of controls

• invasive squamous-cell carcinoma occurred in 28% of the tretinoin group and 31% of controls

Neither difference was statistically significant.

The researchers reported:

“No differences were observed in any cancer-related end points”

Even worse, the tretinoin group reported worse symptoms at 12 months.

The authors’ conclusion was straightforward:

“high-dose topical tretinoin is ineffective at reducing risk of KCs”

So it didn’t accomplish the major thing they were trying to accomplish.

But the story wasn’t over.

The Trial Was Stopped Early Because Too Many People Died

A separate analysis of this same trial was published as Topical tretinoin therapy and all-cause mortality.

Remember: 1,131 veterans.

Mean age: 71.

And the study had specifically excluded people believed to have a very high short-term risk of death.

Then this happened:

“terminated 6 months early because of an excessive number of deaths”

in the tretinoin-treated group.

After adjusting for differences in age, smoking and comorbidities, the mortality difference between the randomized groups remained statistically significant.

The researchers wrote:

“We observed an association of topical tretinoin therapy with death”

The randomized group receiving tretinoin experienced excess mortality large enough that the intervention was terminated six months early.

The same treatment failed to significantly prevent the cancers it was supposed to prevent.

And the tretinoin group had worse symptoms at 12 months.

Those are the actual observations.

You can decide whether rubbing tretinoin on your face sounds “anti-aging” to you.

Now Put the Whole Pattern Together

Look at everything we just covered.

As people age:

Copper rises.

The copper-to-zinc ratio rises.

Higher ferritin is associated with faster biological aging.

Zinc falls.

Selenium falls.

In dysfunctional skeletal muscle, sodium and calcium accumulate where they should not.

Nickel can appear in products you would never think to test.

Nickel can interfere with the body’s ability to correctly repair radiation-induced DNA damage.

Then we administer a new vitamin A derivative and the cells suddenly increase compounds including PEA, which the authors themselves identify with anti-inflammatory activity.

And tretinoin—the active retinoic-acid form of vitamin A—failed to prevent keratinocyte cancers in a large randomized trial while the treated group experienced significantly more deaths.

At what point are we allowed to stop looking at all of these findings as isolated curiosities?

The patterns are the entire point.

PEA Keeps Showing Up for a Reason

The MVA study caught my attention because of PEA for another reason.

I’ve been watching what happens in real people using PEA.

These are testimonials, not randomized controlled trials, and I keep the categories of evidence separate.

But observations matter.

One person reported longstanding bladder pain disappearing after the first PEA dose and remaining absent after two weeks of continued use.

Another family reported that their two-year-old daughter had experienced abnormal stools for most of her life, including previous episodes of blood and mucus. After they had already made other Love Your Liver and low-nickel changes, they added PEA. Within days they reported her first normal formed stool—and stated that normal stools continued afterward.

Another person described years of musculoskeletal, neurological and digestive problems improving through a combination of the Love Your Liver approach, zinc, fiber, diet, lactoferrin and eventually PEA. Their pain had reportedly fallen from around 8.5 at its worst to around 3 before PEA. Four days after starting PEA, they rated it a 1.

Again, these are observations, aka anecdotes, the very thing that scientific research is supposed to be borne from.

But when an experimental vitamin A derivative causes cells to increase PEA, while people using PEA directly keep reporting reduced inflammatory-type symptoms, I’m paying attention.

Because maybe PEA isn’t merely another “anti-inflammatory supplement.”

Maybe it is part of a much larger endogenous protection system that becomes increasingly important when the body is dealing with toxic stress.

That is one of the directions I am investigating now.

Stop Looking at One Thing at a Time

This is the larger lesson.

The body does not experience:

“a copper issue”

plus

“an iron issue”

plus

“a nickel issue”

plus

“a vitamin A issue”

plus

“a zinc deficiency.”

It experiences all of them at once.

If nickel interferes with DNA repair, then your nickel status changes how you respond to radiation.

If copper rises while zinc falls, the ratio changes dramatically even if somebody tells you that each individual number is technically “in range.”

If ferritin rises while antioxidant and detoxification systems deteriorate, the same ferritin level may not mean the same thing anymore.

If retinoids damage the skin barrier and cells respond by increasing anti-inflammatory protective molecules, measuring those protective molecules afterward does not automatically prove that the retinoid was beneficial.

This is systems biology whether people want to call it that or not.

It is also why I’ve never been interested in simply chasing symptoms.

Find the patterns.

Reduce the things interfering with normal physiology.

Restore what the body actually needs.

Then get out of its way enough to see what it can repair.

That approach keeps making more sense every time I open another research paper.

When you’re ready, find the help you need at NutritionDetective.com.