A new study suggests that a key role in aging may be played by the decline of hypothalamic Menin.
Supplementing the amino acid D-serine helped to mitigate some of the age-related changes associated with a decline of the hypothalamic hormone Menin in mouse models.
The previously unknown driver of physiological aging has been revealed by our findings, suggesting that supplementation with a simple amino acid may help to mitigate some age-related changes.
The role of the hypothalamus as a key mediator of physiological aging has been recognized, as the process of neuroinflammatory signaling increases over time, leading to inflammation that promotes multiple age-related processes in both the brain and the periphery.
“In our recent study, we demonstrated that Menin, a hypothalamic protein, is a key inhibitor of hypothalamic neuroinflammation, which prompted us to investigate its role in aging. Our observations showed that the level of Menin in the hypothalamus declines with age, while it remains unchanged in astrocytes or microglia.
To investigate this decline, we created conditional knockout mice, in which Menin activity could be inhibited. Our findings revealed that a reduction of Menin in younger mice resulted in an increase in hypothalamic neuroinflammation and aging-related phenotypes, including reductions in bone mass and skin thickness, cognitive decline, and a modestly reduced lifespan.”
– Lige Leng of Xiamen University, Xiamen, China
Another change that was induced by the loss of Menin was a decline in levels of the amino acid D-serine, which is known to be a neurotransmitter and can be found in dietary supplements such as soybeans, eggs, fish, and nuts. The loss of activity of an enzyme involved in the synthesis of D-serine, which was regulated by Menin, was the reason for this decline, as demonstrated by the authors.
“To investigate whether reversing age-related Menin loss could reverse signs of physiological aging, the gene for Menin was delivered into the hypothalamus of elderly (20-month-old) mice by our team.
Thirty days later, we observed 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, our study found that three weeks of dietary supplementation with D-serine induced similar benefits on cognition, although it did not have the same effect on peripheral signs of aging.”
There is still much to be learned about the role of Menin in aging, including the upstream processes that lead to its decline, and the potential for exploiting this pathway, including how much phenotypic aging can be slowed, for how long, and whether supplementation with D-serine may trigger other changes yet to be discovered.
Nonetheless, it can be assumed 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.
As Leng noted,
“The signaling of Menin in the ventromedial hypothalamus (VMH) diminished in aged mice, contributing 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.”
Original Research: Open access.
“Hypothalamic Menin regulates systemic aging and cognitive decline” by Lige Leng et al. PLOS Biology
Aging is a systemic process, which is a risk factor for impaired physiological functions, and finally death. The molecular mechanisms driving aging process and the associated cognitive decline are not fully understood. The hypothalamus acts as the arbiter that orchestrates systemic aging through neuroinflammatory signaling. Our recent findings revealed that Menin plays important roles in neuroinflammation and brain development. Here, we found that the hypothalamic Menin signaling diminished in aged mice, which correlates with systemic aging and cognitive deficits. Restoring Menin expression in ventromedial nucleus of hypothalamus (VMH) of aged mice extended lifespan, improved learning and memory, and ameliorated aging biomarkers, while inhibiting Menin in VMH of middle-aged mice induced premature aging and accelerated cognitive decline. We further found that Menin epigenetically regulates neuroinflammatory and metabolic pathways, including D-serine metabolism. Aging-associated Menin reduction led to impaired D-serine release by VMH-hippocampus neural circuit, while D-serine supplement rescued cognitive decline in aged mice. Collectively, VMH Menin serves as a key regulator of systemic aging and aging-related cognitive decline.