Menin and Hypothalamic Aging

Table of Contents

  1. Menin and Aging: Overview
  2. The 2023 Xiamen Mouse Study
  3. What Menin Does
  4. The Hypothalamus in Aging Research
  5. The D-Serine Downstream Story
  6. Mouse to Human: What Is and Is Not Known
  7. Where the Clinical Pipeline Stands
  8. What This Research Means Today
  9. Cautions and Open Questions
  10. Key Research Papers
  11. Featured Videos

Menin and Aging: Overview

Aging is the greatest risk factor for a majority of chronic diseases, and mammalian aging can be delayed in experiments with genetic, dietary and drug approaches; that is the starting point of the field known as geroscience (Kennedy and colleagues, 2014). One line of mouse research places the hypothalamus at the centre of whole-body aging: a 2013 study found that preventing an inflammatory signal (IKK-β/NF-κB) in the mouse hypothalamus slowed aging and extended lifespan.

In March 2023, a team at Xiamen University in China (first author Lige Leng, senior author Jie Zhang) published a mouse study in PLOS Biology that adds a protein called menin to this story. The study reported that menin in the ventromedial hypothalamus (VMH) falls with age in mice, that deleting it produced signs of premature aging, and that raising it in old mice extended lifespan and improved several aging markers within 30 days. The study linked menin to the brain's supply of D-serine, an amino acid that acts as a co-agonist at NMDA receptors.

Almost everything on this page comes from mouse and rat experiments. No human study has tested whether raising menin slows aging.

The 2023 Xiamen Mouse Study

The study was published in PLOS Biology in March 2023 (Leng and colleagues). The full citation and open-access link are in the Key Research Papers section below. All of the findings below are from mice, apart from one small measurement of D-serine in human blood.

What the researchers measured

Comparing seven brain regions of young (3-month-old) and old (20-month-old) mice, the team found that menin fell most with age in the hypothalamus, alongside increased hypothalamic inflammation. Within the VMH, the decline was seen in SF-1 neurons, not in astrocytes or microglia.

Deleting menin: signs of premature aging

The team deleted menin from VMH SF-1 neurons in two ways: in mice bred to lack it in those neurons from early life, and in adult mice by injecting a gene-transfer (AAV) vector at 9 months of age. The knockout mice showed:

Raising menin in old mice: changes within 30 days

In the opposite experiment, the team raised menin in the VMH of 20-month-old mice with an AAV vector. The treated mice lived longer than controls. Thirty days after the injection, the authors reported that:

Identifying the downstream messenger

Gene-expression and metabolite analysis pointed to the D-serine synthesis pathway. The team reported that menin binds the promoter of the Phgdh gene, which encodes PHGDH, the first rate-limiting enzyme of serine synthesis; when menin was deleted, PHGDH and D-serine fell, and when menin was raised in old mice, both rose. Hippocampal D-serine was also lower in the knockout mice, and long-term potentiation (a synaptic model of memory) was reduced. Giving D-serine in drinking water for 3 weeks (about 100 mg/kg body weight) rescued the cognitive deficits of the knockout mice and of 22-month-old mice. The authors noted that this rescue was limited to cognition: the peripheral aging changes were not reversed by D-serine.

Study DOI: 10.1371/journal.pbio.3002033

What Menin Does

Menin is the protein encoded by the MEN1 gene. Mutations in this tumor suppressor gene cause multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder characterized by tumors of the parathyroid glands, the pancreatic islets and the anterior pituitary, according to the Endocrine Society's 2012 clinical practice guidelines.

This tumor-suppressor role is the reason most clinical research on menin to date has been in endocrinology and oncology, and it is one of the open questions about any idea of raising menin activity (see Cautions below).

Menin and gene regulation

Menin contributes to epigenetic regulation of gene expression, partly through its association with the H3K4me3 histone mark, a modification linked to active genes (as summarized in the Leng study). The same study's authors had earlier reported that menin associates with p65, a subunit of NF-κB, to inhibit NF-κB activity.

Menin in the hypothalamus

In the Xiamen study, menin in hypothalamic SF-1 neurons controlled transcription of Phgdh, the first step of the serine-synthesis pathway. Further down that pathway, the enzyme serine racemase converts L-serine into D-serine, a co-agonist at NMDA receptors. The study did not report that menin controls serine racemase itself.

The chain the study proposes is: aging hypothalamus → menin decline → less PHGDH → less D-serine → impaired NMDA receptor-dependent signaling and memory, with menin's anti-inflammatory role as a second arm. The authors described this as one possible driver of aging, not the only one.

The Hypothalamus in Aging Research

The Xiamen authors describe the hypothalamus as the arbiter that orchestrates systemic aging through neuroinflammatory signaling. The VMH neurons they studied, which carry the marker SF-1, are known metabolic regulators that help maintain whole-body energy balance and respond to nutritional status.

Dongsheng Cai's NF-κB work (2013)

A 2013 Nature paper from Dongsheng Cai's group at Albert Einstein College of Medicine (Zhang and colleagues, PubMed PMID: 23636330) reported that the hypothalamus is important for whole-body aging in mice, through immune signaling by IKK-β and NF-κB and microglia-neuron crosstalk. Preventing aging-related IKK-β/NF-κB activation in the hypothalamus or brain slowed aging and extended lifespan in several mouse models. IKK-β and NF-κB suppressed the hormone GnRH, and GnRH treatment improved aging-impaired neurogenesis and slowed aging. The menin study builds on this: its authors propose that falling menin may contribute to the hypothalamic inflammation seen with age.

The D-Serine Downstream Story

D-serine is a D-amino acid (a mirror-image form). Its discovery in large amounts in the brain challenged the idea that only L-amino acids matter in animals; brain D-serine levels can reach as much as one-third of L-serine levels (Wolosker and Mori, 2012 review).

NMDA receptor co-agonism

NMDA receptors, a type of glutamate receptor involved in synaptic plasticity and memory, need both glutamate and a second co-agonist at the "glycine site" to work. A 2000 study (Mothet and colleagues) showed that removing D-serine with an enzyme greatly reduced NMDA receptor activity in brain cells and that adding D-serine back reversed this, establishing D-serine as an endogenous ligand that fully occupies this site at some synapses.

D-serine and aging

In aged rats, hippocampal D-serine and the expression of serine racemase, the enzyme that makes it, were significantly lower than in young rats, and the impaired long-term potentiation of old rats was restored by adding D-serine to brain slices (PubMed PMID: 16842499). A follow-up study found this decline in a rat strain with age-related memory impairment but not in a strain considered a model of healthy aging (PubMed PMID: 19800712), and a 2024 study found lower serine racemase in the prefrontal cortex and all hippocampal subfields of aged male and female rats (PubMed PMID: 38761177). In people, the Xiamen study measured lower D-serine in the blood serum of 5 adults aged 83–94 than in 5 aged 22–26.

Alzheimer's disease points the other way: a 2015 study (Madeira and colleagues) found higher D-serine in post-mortem hippocampus and cortex of Alzheimer's patients and in the cerebrospinal fluid of people with probable Alzheimer's than in comparison groups, and higher D-serine and serine racemase in animal models of the disease. Lower D-serine with normal aging in rats and higher D-serine in Alzheimer's disease are separate findings.

Supplementation in the mouse study

The Xiamen team's translational finding was that D-serine in drinking water rescued cognitive performance in menin-knockout and old mice without restoring menin, while the peripheral aging changes stayed. This suggests that, in mice, the memory arm of menin's effect runs through D-serine.

In people, D-serine has been studied mainly in schizophrenia, where it is tested as an NMDA receptor-based treatment. In a 4-week open-label trial of 42 patients taking antipsychotics, add-on D-serine at 30, 60 or 120 mg/kg/day was followed by significant improvement in symptoms and neuropsychological measures, with large effects at 60 mg/kg/day and above (Kantrowitz and colleagues, 2010). No trial has tested D-serine for age-related cognitive decline in the papers cited here.

Mouse to Human: What Is and Is Not Known

Where the mouse evidence is strong

The study used both loss-of-function (deleting menin) and gain-of-function (raising menin) designs in the same brain region, with effects in opposite directions. The aging markers measured spanned several systems: hypothalamic inflammation, cognition, metabolism, bone, skin, muscle and lifespan.

Limits of the evidence

What is likely to be tested next

The D-serine link is the part closest to human study, because D-serine has already been given to people in psychiatric trials, where plasma D-serine rose with dose (Kantrowitz 2010); in the mouse study, oral D-serine raised D-serine in the hypothalamus and hippocampus. Whether D-serine affects cognitive aging in older people has not been tested in the studies cited on this page.

The study raised menin by gene transfer; it did not test a drug that raises menin.

Where the Clinical Pipeline Stands

The menin drugs that have reached patients work in the opposite direction: they are menin inhibitors for leukemia.

Menin inhibitors in oncology

Menin inhibitors target acute leukemias with high HOXA gene expression, including those with KMT2A rearrangements and NPM1 mutations; these cancer-driving proteins depend on the KMT2A–menin interaction to maintain their gene expression program (Wenge and Armstrong, 2025 review). According to the U.S. Food and Drug Administration:

The FDA lists differentiation syndrome, QTc prolongation and embryo-fetal toxicity among the warnings for these drugs. The mouse aging study did not involve menin inhibitors, and its findings say nothing about their use in leukemia.

The translational gap

The aging study raised menin with a gene-transfer vector injected into one hypothalamic nucleus of each mouse. A treatment for people would need a way to raise menin selectively in hypothalamic neurons, tested first for safety; no such treatment appears in the papers cited here.

What This Research Means Today

The menin findings are from mice, and no menin-raising treatment exists for people. The research points to D-serine as the part of the pathway already studied in humans.

D-serine in human research

Human D-serine data come mostly from psychiatric trials. Kantrowitz and colleagues (2010) reported symptom and neuropsychological improvement in schizophrenia at 30–120 mg/kg/day for 4 weeks in an open-label trial, and supported further double-blind study at 60 mg/kg/day and above. No study cited here has tested D-serine for age-related cognitive decline, and the doses used in schizophrenia trials have not been studied for that purpose.

Kidney safety: a 2021 cross-species safety review (Meftah and colleagues) found that D-serine doses above 500 mg/kg in rats very commonly cause acute kidney tubular damage within hours, while kidney toxicity has not been reported in other species, including mice and rabbits. Across all published human studies, the review found one person with abnormal kidney values related to D-serine, which resolved within a few days of stopping. The reviewers concluded that D-serine appears safe at the maximal doses studied so far when current FDA-guided monitoring is used. The review's abstract does not address older adults or people with reduced kidney function. Decisions about supplements belong with a clinician.

Following the research

This is an early field. The PubMed topic searches in the Key Research Papers section below list new studies on menin, D-serine and hypothalamic aging as they appear.

Cautions and Open Questions

Menin and tumor risk

Menin is a tumor suppressor: loss-of-function mutations in MEN1 cause parathyroid, pancreatic islet and anterior pituitary tumors. In some leukemias, by contrast, cancer-driving proteins depend on menin's interaction with KMT2A, which is why menin inhibitors are used to treat them. Menin therefore has opposite roles in different tissues, and the aging study did not examine whether raising menin affects tumor risk.

Context-specificity of menin function

In the Xiamen study, the age-related fall in menin was seen in SF-1 neurons and not in astrocytes or microglia, and the effects came from raising or deleting menin only in the VMH. Whether raising menin throughout the body would have the same effects is unknown.

Replication

The menin–aging findings come from one published mouse study. Results in other strains, other species and people have not been reported in the papers cited here.

Long-term effects unknown

The rejuvenation measures were taken 30 days after menin was raised in old mice; lifespan was also followed. Long-term effects of raising menin in people are unknown.

D-serine and the kidney

As noted above, high doses of D-serine cause kidney tubular damage in rats, a finding that has limited human research at high doses; the 2021 safety review found that this toxicity has not been reported in other species and that only one human subject had a D-serine-related kidney abnormality, which resolved.

Key Research Papers

  1. Leng L, Yuan Z, Su X, et al. "Hypothalamic Menin regulates systemic aging and cognitive decline." PLOS Biology. 2023;21(3):e3002033. — The index study for this article (mouse study). Menin fell with age in the mouse VMH; deleting it accelerated aging, raising it in 20-month-old mice extended lifespan and improved aging markers; menin regulates D-serine synthesis through PHGDH, and oral D-serine rescued cognitive decline. — doi:10.1371/journal.pbio.3002033
  2. Zhang G, Li J, Purkayastha S, et al. "Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH." Nature. 2013;497(7448):211-6 — Mouse study: preventing hypothalamic IKK-β/NF-κB activation slowed aging and extended lifespan; GnRH treatment slowed aging. — PubMed PMID: 23636330
  3. Mothet JP, Parent AT, Wolosker H, et al. "D-Serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor." Proceedings of the National Academy of Sciences. 2000;97(9):4926-31 — Showed that degrading D-serine attenuates NMDA receptor transmission and that D-serine fully occupies the glycine site at some synapses. — PubMed PMID: 10781100
  4. Wolosker H, Mori H. "Serine racemase: an unconventional enzyme for an unconventional transmitter." Amino Acids. 2012;43(5):1895-904 — Review of D-serine synthesis by serine racemase and lessons from serine racemase knockout mice. — PubMed PMID: 22847782
  5. Madeira C, Lourenco MV, Vargas-Lopes C, et al. "D-Serine levels in Alzheimer's disease: implications for novel biomarker development." Translational Psychiatry. 2015;5:e561 — Found higher D-serine in post-mortem brain tissue and cerebrospinal fluid of Alzheimer's patients than in comparison groups. — PubMed PMID: 25942042
  6. Kantrowitz JT, Malhotra AK, Cornblatt B, et al. "High dose D-serine in the treatment of schizophrenia." Schizophrenia Research. 2010;121(1-3):125-30 — 4-week open-label trial in 42 patients of add-on D-serine at 30, 60 or 120 mg/kg/day; symptoms and neuropsychological measures improved. — PubMed PMID: 20541910
  7. Kennedy BK, Berger SL, Brunet A, et al. "Geroscience: linking aging to chronic disease." Cell. 2014. — Framework paper: aging is the greatest risk factor for a majority of chronic diseases, and mammalian aging can be delayed with genetic, dietary and pharmacologic approaches. — PubMed PMID: 25417146
  8. Mothet JP, Rouaud E, Sinet PM, et al. "A critical role for the glial-derived neuromodulator D-serine in the age-related deficits of cellular mechanisms of learning and memory." Aging Cell. 2006;5(3):267-74 — Rat study: hippocampal D-serine and serine racemase fall with age; exogenous D-serine rescued impaired LTP in old rats. — PubMed PMID: 16842499
  9. Turpin FR, Potier B, Dulong JR, et al. "Reduced serine racemase expression contributes to age-related deficits in hippocampal cognitive function." Neurobiology of Aging. 2011;32(8):1495-504 — Rat study: serine racemase and D-serine fell in the hippocampus of aged, cognitively impaired rats but not in a healthy-aging strain. — PubMed PMID: 19800712
  10. Bean L, Bose PK, Rani A, Kumar A. "Serine racemase expression profile in the prefrontal cortex and hippocampal subregions during aging in male and female rats." Aging (Albany NY). 2024;16(10):8402-8416 — Rat study: serine racemase was lower in the medial prefrontal cortex and all hippocampal subfields of aged rats, with no sex difference. — PubMed PMID: 38761177
  11. Meftah A, Hasegawa H, Kantrowitz JT. "D-Serine: A Cross Species Review of Safety." Frontiers in Psychiatry. 2021;12:726365 — Systematic review: kidney toxicity at doses above 500 mg/kg in rats, not reported in other species; one human subject with a D-serine-related kidney abnormality that resolved. — PubMed PMID: 34447324
  12. Thakker RV, Newey PJ, Walls GV, et al. "Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1)." Journal of Clinical Endocrinology and Metabolism. 2012;97(9):2990-3011 — Endocrine Society guideline: MEN1 is an autosomal dominant disorder caused by mutations in the tumor suppressor gene MEN1, which encodes menin. — PubMed PMID: 22723327
  13. Wenge DV, Armstrong SA. "Menin inhibition for the treatment of acute leukemia." Seminars in Hematology. 2025;62(3):187-195 — Review of how menin inhibitors act in leukemias that depend on the KMT2A–menin interaction, and of resistance and ongoing trials. — PubMed PMID: 40940237

PubMed Topic Searches

  1. PubMed: Menin hypothalamus aging
  2. PubMed: D-serine NMDA aging cognition
  3. PubMed: Serine racemase brain aging
  4. PubMed: Hypothalamus NF-kB systemic aging
  5. PubMed: MEN1 gene brain longevity
  6. PubMed: Ventromedial hypothalamus aging reversal

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