Jie Zhang's team at Xiamen University finds that Menin deficiency accelerates aging, and that dietary supplementation with D-serine can delay aging and cognitive decline

Aging is a physiological and pathological process of systematic deterioration of the body's physiological functions that eventually leads to the end of life. Its development is closely related to a variety of age-related degenerative diseases, such as Alzheimer's disease and diabetes. Aging is a rather complex biological process and its regulatory mechanisms are not well understood. Therefore, exploring the genetic mechanisms of aging and finding interventions to slow down aging and reduce the occurrence of aging-related diseases are the primary scientific research goals to address aging and aging-related diseases.

On 16 March 2023, Professor Jie Zhang and Associate Professor Leng Lige published a research paper entitled: Hypothalamic Menin regulates systemic aging and cognitive decline in the journal PLOS Biology, Institute of Neuroscience, School of Medicine, Xiamen University.

The study found that the expression of Menin protein in the hypothalamus declines gradually with aging, which affects the metabolic homeostasis and D-Serine synthesis of the organism, leading to accelerated aging and cognitive decline.

The study also found that replenishing Menin protein in the hypothalamus or adding D-serine to the diet significantly improved the aging phenotype and cognitive deficits in aged mice.


The hypothalamus is the most prominent brain region that regulates organismal aging, and microinflammation exists in the hypothalamus during aging, which is mediated by IKKβ/NF-κB activation and further affects systemic aging and aging-associated cognitive dysfunction.

In a 2018 article published in Neuron, Prof Jie Zhang's team found that Menin was able to inhibit the activation of inflammatory pathways by suppressing the transcriptional activity of NF-κB-p65. In this new paper, Prof Jie Zhang's team first screened that mouse hypothalamus Menin expression is significantly reduced in aging, and Menin is in turn highly expressed in the VMH region of the hypothalamus.

Based on these foundations, the research team guessed that Menin in the hypothalamus may play an important role in combating aging. Therefore, the research team constructed Menin-specific knockout mice (ScKO) of hypothalamic SF-1 neurons. Knockout of Menin in hypothalamic SF-1 neurons resulted in mice that showed a shortened lifespan, systemic aging phenotypes throughout the body including reduced bone mass, muscle, tail tendon elasticity, and skin thickness, as well as cognitive dysfunction. At the same time, they also used AAV-assisted knockdown of Menin in the hypothalamus and similarly found that the mice produced a cognitive dysfunction phenotype, ruling out the effects of other glands on this experiment. In order to reverse the aging phenotype in mice, the team backfilled Menin in the hypothalamus of 20-month-old aging mice, successfully reversing the systemic aging phenotype and cognitive dysfunction in mice.

On the other hand, the research team found that hypothalamic Menin deficiency affected the metabolic homeostasis of the organism and influenced the transcription of PHGDH, the first step of the rate-limiting enzyme in the synthetic pathway of D-serine, through the role of epigenetic regulation, which affected the level of D-serine. In turn, D-serine is a co-agonist of the NMDA receptor and is critical for cognitive functions such as neuronal synaptic plasticity and learning memory. Foods such as soy, eggs, fish and nuts are rich in D-serine. The research team gave dietary supplements of D-serine to ScKO mice and older mice, significantly improving cognitive dysfunction in both.

Based on the results of these trials, the research team made the following important discoveries: for the first time, it was found that decreased Menin expression in the hypothalamus may be a driver of aging, leading to systemic aging phenotypes and cognitive dysfunction in the body. Menin may be a key protein linking genetic, inflammatory, and metabolic factors in aging, and may also regulate D-serine production through epigenetic mechanisms, while further studies identified D-serine as a potential metabolite candidate for the treatment of cognitive dysfunction.