The results of a study headed by researchers at Xiamen University has found that a hypothalamic protein called Menin may play a key role in aging. The findings, reported in PLOS Biology by Lige Leng, PhD, and colleagues, revealed what they describe as a previously unknown driver of physiological aging.
In vivo studies demonstrated that hypothalamic Menin signaling diminished in aging mice, and correlated with systemic aging and cognition-related deficits. Further experiments showed that restoring Menin expression in the ventromedial nucleus of the hypothalamus (VMH) extended lifespan in aged mice, improved learning and memory, and was associated with reduced biomarkers aging. Conversely, inhibiting Menin the VMH of middle-aged mice induced premature aging and speeded up cognitive decline. Through additional investigations the team also discovered that aging-related Menin reduction led to impaired D-serine release in the VMH-hippocampus neural circuit, and that administering D-serine to aged mice could help rescue cognitive decline.
Leng stated, “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.”
The researchers described their findings in a paper titled “Hypothalamic Menin regulates systemic aging and cognitive decline,” in which they concluded, “the results explored a novel role of Menin in regulating systemic aging and cognitive function … we have identified the importance of VMH Menin in orchestration of aging pace. Menin levels may indicate the aging status and serve as anti-aging target.”
Aging is characterized by the progressive and overall deterioration of physiological functions, eventually leading to death. While the molecular mechanisms that drive the aging process and associated cognitive decline are not fully understood, the hypothalamus has been identified as a key mediator of physiological aging, through an increase in the process of neuroinflammatory signaling over time, the authors noted. “The hypothalamus acts as the arbiter that orchestrates systemic aging through neuroinflammatory signaling.” In turn, this inflammation promotes multiple age-related processes, both in the brain and in the periphery.
Leng and colleagues recently showed that Menin, a hypothalamic protein, is a key inhibitor of hypothalamic neuroinflammation, prompting them to ask what role Menin might play in aging. “Our recent findings revealed that Menin plays important roles in neuroinflammation and brain development,” they further noted. “It is plausible that decreased Menin signaling contribute to the activated neuroinflammation in the hypothalamus.”
Their studies in young and old mice demonstrated that the level of Menin in the hypothalamus, but not in astrocytes or microglia, declines with age. “ … we first examined the trends of Menin in 7 brain regions of young and old mice, and found that the decrease of Menin in the hypothalamus was the most significant with age, which accompanies increased neuroinflammation in the hypothalamus,” they stated. “…we found that the expression of Menin decreased significantly only in VMH SF-1 [steroidogenic factor-1] neurons but not in astrocytes and microglia in aged mice brain.” They further pointed out, previous studies had implicated SF-1 neurons, which are exclusive to hypothalamic VMH, as important metabolic regulators.
To explore Menin decline in these neurons they created conditional knockout (ScKO) mice, in which Menin activity could be inhibited in the SF-1 neurons. 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, which acts as a neurotransmitter. The authors showed this decline was due to loss of activity of an enzyme, phosphoglycerate dehydrogenase (PHGDH) which is involved in its synthesis, and which is, in turn, regulated by Menin.
To test whether reversing age-related Menin loss could reverse signs of physiological aging the authors delivered the gene for Menin into the hypothalamus of elderly (20-month-old) mice. Thirty days later, they found that treated animals had improved skin thickness and bone mass, along with better learning, cognition, and balance, and that this correlated with an increase in D-serine within the hippocampus, a central brain region important for learning and memory. “Overall, up-regulating Menin in VMH of 20-month-old mice could successfully increase mouse lifespan without significant changes in body weight, brain weight, and neuron number in hypothalamus and hippocampus,” they stated. Similar benefits on cognition, though not on the peripheral signs of aging, could be induced by administering D-serine to aged mice through their diet, for three weeks. “These results suggest that D-serine reduction play a vital role in the cognition decline, and its complement can attenuate the cognition decline in ScKO mice and old mice,” the investigators concluded. “Our data indicates that the remission of aging phenotype by D-serine is limited to cognitive improvement, leaving peripheral systems aging phenotypes unchanged.”
The authors acknowledged that more research will be needed to better understand Menin’s role in aging, and to identify the upstream processes that lead to its decline. “Currently, the upstream regulators for Menin are unclear,” the authors stated. Further studies will also be required to investigate any potential to exploit the relevant pathway, including by how far phenotypic aging can be slowed, for how long, and what other effects D-serine administration may have.
Even so, the team concluded, “Manipulating Menin levels selectively in SF-1 neuron of VMH altered a variety of aging biomarkers in multiple systems and the aging process of whole body, through regulation of hypothalamic microinflammation and metabolic states (e.g., serine signaling). These results indicate Menin as a novel arbiter for systemic aging and the therapeutic potential for D-serine in treatment against cognitive decline.”
Leng further noted, “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.”