Loss of Menin helps drive the aging process, and D-Serine can reverse it in mice

Decline in the hypothalamic Menin may play a key role in aging, according to a new study publishing March 16th in the open access journal PLOS Biology by Lige Leng of Xiamen University, Xiamen, China, and colleagues. The findings reveal a previously unknown driver of physiological aging, and suggest that supplementation with a simple amino acid may mitigate some age-related changes.

The hypothalamus has been recognized as a key mediator of physiological aging, through an increase in the process of neuroinflammatory signaling over time. In turn, inflammation promotes multiple age-related processes, both in the brain and the periphery.

Recently, Leng and colleagues showed that Menin, a hypothalamic protein, is a key inhibitor of hypothalamic neuroinflammation, leading them to ask what role Menin may play in aging. Here, they observed that the level of Menin in the hypothalamus, but not astrocytes or microglia, declines with age. To explore this decline, they created conditional knockout mice, in which Menin activity could be inhibited. They found that reduction of Menin in younger mice led to an increase in hypothalamic neuroinflammation, aging-related phenotypes including reductions in bone mass and skin thickness, cognitive decline, and modestly reduced lifespan.

Another change induced by loss of Menin was a decline in levels of the amino acid D-serine, known to be a neurotransmitter and sometimes used as a dietary supplement found in soybeans, eggs, fish and nuts. The authors showed this decline was due to loss of activity of an enzyme involved in its synthesis (which was in turn regulated by Menin).

Could reversing age-related Menin loss reverse signs of physiological aging? To test that, the authors delivered the gene for Menin into the hypothalamus of elderly (20-month-old) mice. Thirty days later, they found improved skin thickness and bone mass, along with better learning, cognition, and balance, which correlated with an increase in D-serine within the hippocampus, a central brain region important for learning and memory. Remarkably, similar benefits on cognition, though not on the peripheral signs of aging, could be induced by three weeks of dietary supplementation with D-serine.

There is much left to be learned about Menin’s role in aging, including the upstream processes that lead to its decline, and there is much to learn about the potential for exploiting this pathway, including how much phenotypic aging can be slowed, and for how long, and whether supplementation with D-serine may trigger other changes, yet to be discovered.

Nonetheless, Leng said, “We speculate that the decline of Menin expression in the hypothalamus with age may be one of the driving factors of aging, and Menin may be the key protein connecting the genetic, inflammatory, and metabolic factors of aging. D-serine is a potentially promising therapeutic for cognitive decline.”

Leng adds, “Ventromedial hypothalamus (VMH) Menin signaling diminished in aged mice, which contributes to systemic aging phenotypes and cognitive deficits. The effects of Menin on aging are mediated by neuroinflammatory changes and metabolic pathway signaling, accompanied by serine deficiency in VMH, while restoration of Menin in VMH reversed aging-related phenotypes.”


Citation: Leng L, Yuan Z, Su X, Chen Z, Yang S, Chen M, et al. (2023) Hypothalamic Menin regulates systemic aging and cognitive decline. PLoS Biol 21(3): e3002033. Hypothalamic Menin regulates systemic aging and cognitive decline


Some caution is in order, since over supplementation with D-Serine might cause overactivation of NMDA receptors : Not only does it provide no benefit if your body already produces enough D-Serine, but it might result in Neuronal toxicity. In fact one Alzheimer’s drug, Memantine, acts by blocking NMDA receptors to avoid overactivation by D-Serine : Alzheimers and D-Serine

The only source of D-Serine supplements I could find is a Dutch website : ERGOMAX website. The body normally produces D-Serine by converting the Isomer L-Serine.


Yes - you have to be careful about excitotoxicity with D-serine. Too much of a good thing can be bad for you…

Related reading:


and as referenced by previous poster, from For Researchers | Cognitive Vitality | Alzheimer's Drug Discovery Foundation

D-serine-Cognitive-Vitality-For-Researchers.pdf (342.8 KB)

1 Like

Well, it may be a simple supplement but it is hard to find and much more expensive than L-serine. Fortunately, as previously posted D-serine is made in the body from L-serine which is a cheap supplement.


The mice received 100 mg/kg of D-serine in the paper (in water). This comes out to a human equivalent dose of about 500 mg for a 60 kg person using the Nair and Jacob paper. This seems reasonable, and lines up with the 500 mg dose of the Dutch D-Serine, and a few of the L-Serine on Amazon. There are, however, some whopping 2000 mg doses on Amazon of L-Serine.

1 Like

I wonder the percent of L-serine that gets converted to D-serine in the body? Anyone know?

Well, now that you mention it, it looks like it may be a 4 to 1 conversion, so maybe 2 g of L-Serine is the right amount for a 500 mg desired dose of D-Serine.

We observed that the decrease in L-serine was more pronounced than the total synthesis of D-serine, i.e., about 4 mol of L-serine are consumed for each mol of D-serine produced (Fig. 1C). This gap is not caused by degradation of produced D-serine by the cells, as HEK 293 cells do not possess significant amounts of D-amino acid oxidase.



The open question is whether the aging related loss of Menin also impairs the conversion of L-Serine to D-Serine : In that case supplementing L-Serine might not work, though it would be safer than overdosing on D-Serine.

The D-Serine NMDA receptor was originally called the Lycine receptor since Lycine binds to it (more weakly than D-Serine) : So another safer option would be to supplement with Lycine.

I confirm that I would use L-Serine instead of the D : L-Serine Conclusion? - Supplements - LONGECITY

Safer. Potentially our 3rd best amino acid for lifespan extension after glycine and taurine ?