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.”
Source: https://www.eurekalert.org/news-releases/982100
Journal article: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3002033
Image CREDIT
Lige Leng, Ziqi Yuan and Jie Zhang, 2023, PLOS Biology, CC-BY 4.0 (https://creativecommons.org/licenses/by/4.0/)
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