— May 28, 2026 · Active Forms, Reversible Biology, and Genotype-Tuned Minerals

This edition pulls together six May 2026 findings that, taken together, change — or at least put pressure on — how we think about vitamins, minerals, amino acids, and the biology of aging. The through-line is short and worth holding in mind while you read: the active form of a nutrient often matters more than the total amount in the blood, aging is increasingly being treated as biology that can be moved in either direction rather than a one-way ratchet, and mineral supplementation is shifting from a generic “replace what’s low” model toward genotype-aware protocols where the same dose has measurably different effects in different people. None of the six stories below is a finished translation into clinical practice. All six are signals the supplement-shelf framing is now too coarse for what the underlying science is starting to show.

1. D-Serine and Menin — A Brain-Aging Switch That May Be Reversible
2. IDOL Enzyme — A New Drug Target for Alzheimer's
3. “Normal” B12 May Not Be Enough — The Active-B12 Story
4. Vitamin D Before Surgery — Less Pain, Less Opioid
5. Zinc and Selenium — Toward Genotype-Personalized Immunity
6. Creatine Across the Lifespan — A Field Consensus Forms
Key Research Papers
PubMed Topic Searches
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1. D-Serine and Menin — A Brain-Aging Switch That May Be Reversible

The single most consequential paper this month came from Lige Leng’s team at Xiamen University, published in PLOS Biology in May 2026. The team focused on a protein most clinicians know only as a tumor-suppressor gene product — menin, encoded by MEN1, the same gene whose loss-of-function mutations cause multiple endocrine neoplasia type 1. Menin’s role in the ventromedial hypothalamus (VMH) of the aging brain, however, turns out to be entirely different from its endocrine-tumor role. And what the Xiamen group did with it is, in the mouse, dramatic.

They began with a simple observation: menin protein levels in the VMH decline with age. To test whether that decline mattered, they knocked menin down in young mice and watched what happened. The animals developed what the authors describe as a full geriatric phenotype within weeks: brain inflammation, deficits in spatial and recognition memory, bone loss, thinning of the skin, and a shortened lifespan. By the standard markers a geroscience lab uses, these young mice looked old.

Then they ran the experiment in the opposite direction. Taking aged mice that already exhibited the same constellation of changes, they restored menin in the VMH. Within 30 days, several of the aged phenotypes reversed — bone density rebounded, skin thickness recovered, and cognitive performance on memory tasks returned toward young-adult levels. This is the kind of finding that a decade ago would have been treated as too good to be true. In 2026 it is starting to feel like part of a pattern.

The mechanism the authors propose is what makes the paper translatable. Menin in the VMH controls expression of serine racemase, the enzyme that converts L-serine to D-serine — an unusual amino acid that serves as a co-agonist of the NMDA glutamate receptor. NMDA receptors are central to synaptic plasticity, learning, and memory; they require both glutamate and a co-agonist (either glycine or D-serine) to open. When menin falls, D-serine production falls, NMDA transmission weakens, and cognition declines. The team confirmed this by skipping the menin restoration entirely and simply giving aged mice supplemental D-serine. That alone — without touching menin — restored cognition in the aged animals.

D-serine is not a new molecule. It has been in schizophrenia research for two decades at doses of 30–120 mg/kg/day, and the safety story at moderate doses is reasonable, with the standard caveat of renal proximal tubule injury at high doses in rodents. What this paper does is reframe D-serine from a niche psychiatric tool into a candidate geroscience intervention with a clear molecular rationale.

Two cautions are worth stating clearly. This is a mouse study; the human VMH is anatomically and developmentally different from the mouse VMH, and the timescale of human aging dwarfs the mouse lifespan that defines the experiment. And menin activation is not therapeutically available in humans — the existing menin-targeting drugs in clinical trials (revumenib, SNDX-5613) are inhibitors developed for KMT2A-rearranged leukemia, mechanistically opposite to what the Xiamen paper suggests would help an aging brain. The translatable lever, today, is the downstream one: D-serine itself.

For deeper reading on the two sides of this finding, see the dedicated articles on D-serine and menin as the hypothalamic aging switch. The DOI for the Xiamen paper is 10.1371/journal.pbio.3002033.

2. IDOL Enzyme — A New Drug Target for Alzheimer's

A team led by Hande Karahan and Jungsu Kim at the Indiana University School of Medicine published in Alzheimer’s & Dementia (February 2026) what is, in our view, the most mechanistically distinct Alzheimer’s drug target to surface in the past five years. Removing a single neuronal enzyme called IDOL — inducible degrader of the LDL receptor, an E3 ubiquitin ligase — from neurons in mouse models reduced amyloid plaque burden and lowered brain APOE protein levels. The mechanism is what makes this exciting: IDOL tags the LDL receptor for destruction. With IDOL removed, more LDL receptor remains on the neuronal surface; the LDL receptor is the primary route by which neurons clear APOE-bound amyloid-β; and the result is better clearance, less seeding, and lower plaque load.

It is worth being precise about why this is different from the two recently approved monoclonal antibodies, lecanemab (Leqembi) and donanemab (Kisunla). Both of those agents work by binding existing plaque or proto-plaque species and recruiting immune clearance. They remove amyloid that has already formed. The IDOL approach is upstream: by raising the neuron’s native amyloid-clearance capacity through LDL-receptor recycling, it aims to keep amyloid from accumulating in the first place. In the language the Karahan–Kim group uses, this is a resilience mechanism, not a removal mechanism. The two are not mutually exclusive; a future regimen might combine an IDOL inhibitor for prevention with a monoclonal antibody for clearance, the way oncology routinely combines mechanistically distinct drugs.

The patients most likely to benefit are also the patients who currently have the worst odds: APOE4 carriers. APOE4 is the ε4 allele of apolipoprotein E, and one or two copies of it dramatically raise late-onset Alzheimer’s risk. The reason appears to be that the ε4 form is a less efficient amyloid clearer than the ε3 or ε2 forms. An IDOL inhibitor — by raising LDL receptor density on neurons and giving the system more chances to grab amyloid as it forms — theoretically gives APOE4 carriers the most absolute benefit.

The honest assessment is that this is preclinical-stage work. There is no IDOL inhibitor in human trials. Even in the optimistic case, IND-enabling toxicology takes a year, first-in-human Phase 1 takes another year to two, and a Phase 2 efficacy signal in a slow-moving disease like Alzheimer’s is at least 2–3 years away from the present. Two questions will dominate that runway: (1) IDOL is expressed in macrophages and liver as well as neurons, so what does whole-body IDOL inhibition do to lipoprotein metabolism and infection biology? and (2) does long-term LDLR upregulation in the brain have cardiovascular or vascular-cognitive consequences over decades?

For the deeper write-up, see our dedicated IDOL Enzyme article. The Indiana University news summary is at medicine.iu.edu/news/2026/02.

3. “Normal” B12 May Not Be Enough — The Active-B12 Story

The piece of work most likely to change how a primary care physician orders labs this year came out of the UC San Francisco Brain Aging Network for Cognitive Health (BrANCH). In a sample of 231 cognitively healthy older adults with a mean age of 71, the BrANCH investigators measured both total serum vitamin B12 and the active fraction — holotranscobalamin (holoTC), the form of B12 bound to transcobalamin II that cells actually take up. Total B12 in the cohort averaged 414.8 pmol/L, well above the conventional 148 pmol/L cutoff for deficiency. By the chart-review definition, none of these people had a B12 problem.

The MRI and cognitive testing told a different story. Lower active B12 — not lower total B12 — was associated with slower processing speed and a higher burden of white-matter lesions on brain MRI. Total B12 did not correlate with anything that mattered cognitively in this study. HoloTC did. That is the entire finding in one sentence, and it has been a long time coming.

The biology behind it is straightforward. Only about 20% of circulating B12 is bound to transcobalamin II; the other 80% is bound to haptocorrin, which delivers B12 nowhere useful for the brain. Haptocorrin levels shift with liver disease, with some myeloproliferative conditions, with several medications, and (most often invisibly) with age-related changes in inflammation. A patient whose total B12 looks reassuring may have haptocorrin doing most of the lifting while transcobalamin-bound delivery to neurons quietly fails. Total B12, in other words, is a measurement of the wrong pool.

The practical follow-through is to order a four-tier panel when you suspect B12 insufficiency in someone with cognitive symptoms but a “normal” total B12:

Total B12 — legacy reference, mostly useless if normal in this scenario.
Holotranscobalamin (holoTC) — the active fraction. Cutoffs vary by lab; below 35 pmol/L is consistent with deficiency, 35–50 pmol/L is a grey zone that should prompt the next two tests, ≥70 pmol/L is consistent with sufficiency.
Methylmalonic acid (MMA) — rises when cellular B12 is insufficient regardless of serum pool. MMA is the most cell-specific functional marker; upper limits of normal are typically around 270 nmol/L but vary.
Homocysteine — rises in both B12 and folate insufficiency, useful but non-specific.

HoloTC plus MMA is the high-yield pair when you actually want to know whether a patient’s cells are getting enough B12. Total B12 plus a normal MCV (mean corpuscular volume on the CBC) reassures only that the patient is not yet in megaloblastic anemia territory — a late, hematologic endpoint that says nothing about neurological reserve.

Who should be asking for this panel? At minimum: anyone over 60 with any cognitive complaint, strict vegans or vegetarians for more than a year or two, long-term PPI or metformin users, people who have had gastric bypass or sleeve gastrectomy, anyone with diagnosed atrophic gastritis or pernicious anemia, and anyone with a family member who developed B12-related neurological deficits late in life. For the full clinical write-up, including reference ranges, treatment thresholds, and the practical question of how to ask your physician for the test, see our Active B12 (Holotranscobalamin) Testing deep-dive. The UCSF source release is at ucsf.edu/news/2025/02/429491.

4. Vitamin D Before Surgery — Less Pain, Less Opioid

A study from Fayoum University Hospital in Egypt, published in Regional Anesthesia & Pain Medicine in 2026, enrolled 184 women undergoing unilateral modified radical mastectomy and measured preoperative 25-hydroxyvitamin D alongside postoperative pain scores and opioid use. The finding is precise enough to be operationally useful: patients with a preoperative 25(OH)D below 30 nmol/L (roughly 12 ng/mL) were three times more likely to experience moderate-to-severe postoperative pain and consumed significantly more opioids than patients in the sufficient range. The effect was independent of age, BMI, surgical duration, and known pain-modifying comorbidities.

The mechanism is not exotic. Vitamin D receptors are present on nociceptive neurons in the dorsal root ganglia and on every major immune cell type that contributes to the postoperative inflammatory milieu — macrophages, T cells, dendritic cells. Vitamin D deficiency tilts that milieu toward higher TNF-α, IL-6, and IL-1β signaling, which is the inflammatory soup that primary nociceptive afferents respond to during the first 48–72 hours after surgery. Restoring sufficiency before the surgical insult means the inflammatory amplifier is partially turned down before the wound is made.

The actionable detail is the timing window. Oral cholecalciferol (D3) at typical repletion doses of 5,000–10,000 IU/day with a fatty meal takes 6–8 weeks to move a deficient patient’s serum 25(OH)D into the sufficient range (≥75 nmol/L = ≥30 ng/mL). Testing 25(OH)D on the day before surgery is too late — you have the diagnostic information without the treatment runway. The Fayoum trial implies a simple checklist for any elective surgery: test 25(OH)D 8–12 weeks before the procedure, replete if low, recheck at week 6–8 to confirm sufficiency, and proceed.

This is not a finding limited to breast surgery. The same logic applies, with varying strengths of evidence, to orthopedic procedures (where postoperative falls and bone healing add additional vitamin D-dependent endpoints), cardiac surgery (where vasoplegia and post-bypass acute kidney injury have inflammatory components), and major abdominal surgery (where anastomotic healing depends in part on immune-cell function). The mastectomy paper is the cleanest current dataset; the principle is broader.

One important caveat: repletion is not the same as megadosing. Single boluses of 50,000–100,000 IU before surgery have been tried, with mixed safety and efficacy signals, and risk producing transient hypercalcemia in patients with undiagnosed primary hyperparathyroidism or sarcoidosis. The conservative protocol — daily 5,000–10,000 IU for 8 weeks with a recheck — is the one with the cleanest evidence base. Magnesium and vitamin K2 cofactors are reasonable additions; we cover them in the Surgical Recovery deep-dive. The Fayoum trial is registered at ClinicalTrials.gov NCT06551688.

5. Zinc and Selenium — Toward Genotype-Personalized Immunity

A Cureus review published in February 2026 synthesized the contemporary evidence on micronutrient support of immune function with a focus on the two minerals where the mechanistic case is strongest: zinc and selenium. The headline finding will feel familiar — zinc, selenium, and vitamin C remain the three nutrients with the most consistent immune-support evidence, especially for upper-respiratory infections. The novel and underappreciated angle is the one we want to highlight.

Both zinc and selenium reshape the gut microbiota, and the gut microbiota in turn trains and tunes systemic immunity. This is a feedback loop the older “mineral deficiency → immune deficit → replace the mineral” framing simply missed. Zinc supplementation in zinc-marginal individuals enriches the Faecalibacterium prausnitzii and Akkermansia muciniphila populations associated with intact gut-barrier function. Selenium does something similar through selenoprotein-dependent regulation of the mucosal immune compartment. A non-trivial fraction of what these minerals do for “immunity” happens not in the bone marrow or the spleen but in the gut, and is mediated by which bacteria the host is feeding.

The second novel angle is nutrigenomics. Different people respond to the same supplemental zinc or selenium dose differently, and the variation is now partly explained by genotype:

SLC30A8 (ZnT8) — a pancreatic zinc transporter whose common variant alters serum zinc and the postprandial insulin response. Carriers respond differently to oral zinc loading.
SLC39A8 (ZIP8) — a broader zinc/manganese transporter whose variants alter membrane-trafficking efficiency. Loss-of-function variants are associated with lower serum zinc and a constellation of inflammatory and neurological phenotypes.
GPX1 (glutathione peroxidase 1) — the principal selenium-dependent antioxidant enzyme. Common variants (notably Pro198Leu) change selenium incorporation efficiency and the antioxidant response per microgram of supplemental selenium.
SELENOP (selenoprotein P) — the major plasma selenium transporter; variants alter how much selenium reaches peripheral tissues and the brain at a given dietary intake.

None of this is reduced to clinical practice yet. A primary care physician cannot order a SLC39A8 genotype panel and dose zinc off the result; the labs do not exist at scale, the cutpoints are not validated, and insurance does not cover the testing. But the direction the field is moving is unambiguous. The next decade of mineral supplementation will look less like “everyone over 50 should take 15 mg of zinc” and more like “your variants in SLC30A8 and SELENOP suggest you respond well to zinc, modestly to selenium, and aggressively to copper-zinc balance.”

For now, the practical implications are conservative. Stay within the established upper limits (zinc tolerable upper intake is 40 mg/day for adults; selenium is 400 µg/day), maintain zinc-copper balance if you supplement zinc long-term (a frequent oversight; chronic zinc above ~25 mg/day depletes copper), and do not megadose selenium — the curve for selenium and immunity is sharply U-shaped, with both deficiency and excess producing measurable harm. Mineral nutrigenomics will change the dose tables eventually. It does not yet change them today.

6. Creatine Across the Lifespan — A Field Consensus Forms

The least surprising but most clinically useful story of the month is the formation of a clear field consensus on creatine monohydrate. A May 2026 consensus paper indexed in PMC, paired with an updated systematic review of cognition in older adults, converges on what creatine researchers have been saying carefully for a decade and confidently for the past three years: creatine monohydrate is safe and beneficial across the lifespan. The dose, the timing, the formulation, and the precaution list have all stabilized.

The newest evidence layer is cognitive. Multiple trials in adults over 65 have shown small but consistent improvements in working memory and processing speed, with the cleanest effects in two populations: people under sleep deprivation (where cerebral phosphocreatine reserves are most stressed) and people on vegetarian or vegan diets (who consume essentially no dietary creatine from meat). The effect sizes are modest — Cohen’s d of roughly 0.2–0.4 on working memory tasks in supplemented vs. unsupplemented vegetarians — but they are real, replicable, and visible without the heroic n-of-1000 trials that pharmaceutical effects of similar magnitude would require.

The dose is now boring, which is what good clinical evidence does to a supplement once it matures: 3–5 g/day of creatine monohydrate, taken at any time, with food, indefinitely. The classical 20 g/day × 5–7 day “loading phase” that older protocols recommended is unnecessary for any indication that is not a same-week strength competition; tissue saturation is reached in 3–4 weeks at the 3–5 g/day dose. Creatine monohydrate is the only formulation with a substantial evidence base; the more expensive creatine HCl, ethyl ester, and buffered forms have not demonstrated either superior efficacy or superior tolerability.

The safety story is now unusually clean for a supplement. Renal function does not deteriorate at the 3–5 g/day dose in repeated trials of people with normal baseline kidney function; the elevation in serum creatinine that creatine supplementation produces is a measurement artifact (the assay does not distinguish creatinine from creatine), not a sign of glomerular injury. Patients with established kidney disease should still discuss creatine with their nephrologist — not because creatine has been shown to harm them but because the creatinine-based eGFR estimate becomes harder to interpret. Hydration matters; creatine pulls water into muscle.

The interesting open question is whether creatine has a role in depression, where the early evidence base is intriguing but underpowered, and whether the cognitive benefit in older adults extends into people with mild cognitive impairment. Several Phase 2 trials are ongoing; we will report on them as they read out. The references for this section are the consensus paper at PMC12053822 and the systematic review at PMID 40971619.

Key Research Papers

Primary Studies This Edition Covers

Leng L, et al. Menin deficiency in the ventromedial hypothalamus drives brain aging; menin restoration and downstream D-serine signaling reverse cognitive decline in aged mice. PLOS Biology. May 2026. doi:10.1371/journal.pbio.3002033
Karahan H, Kim J, et al. Neuronal IDOL deletion reduces amyloid plaque burden and lowers APOE in mouse models of Alzheimer's disease. Alzheimer's & Dementia. February 2026. Indiana University School of Medicine summary: medicine.iu.edu/news/2026/02/alzheimers-drug-discovery-pathway-2026
UC San Francisco Brain Aging Network for Cognitive Health (BrANCH) study, n=231 cognitively healthy older adults: holotranscobalamin (active B12), not total B12, correlates with processing speed and white-matter lesion burden. ucsf.edu/news/2025/02/429491
Fayoum University Hospital trial, n=184 women undergoing unilateral modified radical mastectomy. Preoperative 25(OH)D below 30 nmol/L tripled the risk of moderate-to-severe postoperative pain and significantly increased opioid use. Regional Anesthesia & Pain Medicine. 2026. Registration: ClinicalTrials.gov NCT06551688
Zinc, selenium, and vitamin C in immune function — with new attention to gut microbiota reshaping and nutrigenomic variation in SLC30A8, SLC39A8, GPX1, and SELENOP. Cureus. February 2026. PubMed: zinc selenium immune nutrigenomics 2026
Creatine across the lifespan — consensus statement. PMC. May 2026. PMC12053822
Creatine and cognition in older adults — systematic review. PubMed. 2025. PMID 40971619

Supporting Literature

Mothet JP, et al. D-Serine is an endogenous ligand for the glycine site of the NMDA receptor. PNAS. 2000;97(9):4926–4931. PMID 10792051
Kantrowitz JT, et al. D-Serine for the Treatment of Schizophrenia: A Review. Schizophrenia Research. 2010. PMID 20709569
Madeira C, et al. D-Serine levels in Alzheimer's disease patients. Translational Psychiatry. 2015. PMID 25867926
Zelcer N, et al. LXR Regulates Cholesterol Uptake Through Idol-Dependent Ubiquitination of the LDL Receptor. Science. 2009. PMID 19608917
van Dyck CH, et al. Lecanemab in Early Alzheimer's Disease. NEJM. 2023;388:9–21. PMID 36449413
Sims JR, et al. Donanemab in Early Symptomatic Alzheimer Disease. JAMA. 2023;330(6):512–527. PMID 37460697
Refsum H, et al. Holotranscobalamin and total B12 for assessment of cobalamin status. Am J Clin Nutr. 2011. PMID 21795441
Stabler SP. Vitamin B12 Deficiency. NEJM. 2013;368:149–160. PMID 23323902
Smith AD, Refsum H. Vitamin B12 and Cognitive Decline. Annu Rev Nutr. 2018. PMID 29852087
Holick MF, et al. Evaluation, Treatment, and Prevention of Vitamin D Deficiency: Endocrine Society Clinical Practice Guideline. JCEM. 2011. PMID 21646368
Helde-Frankling M, Björkhem-Bergman L. Vitamin D in Pain Management. Int J Mol Sci. 2017. PMID 29036937
Bouillon R, et al. Skeletal and Extraskeletal Actions of Vitamin D. Endocr Rev. 2019. PMID 30192901
Rayman MP. Selenium and human health. Lancet. 2012;379(9822):1256–1268. PMID 22381456
Prasad AS. Zinc in human health: effect of zinc on immune cells. Mol Med. 2008;14(5-6):353–357. PMID 18385818
Kreider RB, et al. International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation. J Int Soc Sports Nutr. 2017. PMID 28615996
Avgerinos KI, et al. Effects of creatine supplementation on cognitive function of healthy individuals: A systematic review of randomized controlled trials. Exp Gerontol. 2018. PMID 29704637
Kennedy BK, et al. Geroscience: Linking Aging to Chronic Disease. Cell. 2014;159(4):709–713. PMID 25417146
Zhang G, et al. Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature. 2013;497:211–216. PMID 23685975

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