Aging is a systemic process, a risk factor for reduced physiological functions and ultimately death. The molecular mechanisms driving the aging process and associated cognitive decline are not fully understood.
The hypothalamus has been identified as a crucial central regulator of aging processes in the brain and subbrain region. The hypothalamus acts as the arbiter orchestrating systemic aging through neuroinflammatory signaling.
Recently, a new study by Lige Leng of Xiamen University, Xiamen, China, and colleagues showed that Menin, a hypothalamic protein, is a crucial inhibitor of hypothalamic neuroinflammation. It leads them to wonder what role Menen might play in aging.
They found that the level of Menin in the hypothalamus, but not astrocytes or microglia, decreases with age. It suggests that the decline of the Menin hypothalamus may play a key role in aging.
They developed conditional knockout mice that could block Menin activity to study this decline. They found that lower levels of Menin in younger mice were associated with increased hypothalamic neuroinflammation, aging-related features such as decreased bone density and skin thickness, cognitive decline, and moderately shortened lifespan.
The amino acid D-serine, which is present in foods such as soybeans, eggs, fish and nuts and is known to be a neurotransmitter, also decreases due to the loss of Menin. The authors showed that an enzyme involved in its manufacture had lost activity, which was the cause of this drop.
Can physiological aging symptoms be reversed by reversing age-related Menin loss?
Scientists tested by inserting the gene for Menin into the hypothalamus of older (20-month-old) mice. After 30 days, the mice were found to have improved skin thickness and bone mass, along with better learning, cognition and balance, which correlated with an increase in D-serine in the hippocampus.
Remarkably, similar benefits on cognition, but not on the peripheral signs of aging, may be produced by three weeks of dietary supplementation with D-serine.
ling said, “We speculate that the decline of Menin expression in the hypothalamus with age may be one of the driving factors of aging. Menin may be the key protein linking the genetic, inflammatory and metabolic factors of aging. D-serine is a potential promising therapy for cognitive decline.”
Leng adds, “Ventromedial hypothalamic (VMH) Menin signaling decreased 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.”
- Leng L, Yuan Z, Su X, Chen Z, Yang S, Chen M, et al. (2023) Hypothalamus Menin regulates systemic aging and cognitive decline. PLoS Biol 21(3): e3002033. DOI: 10.1371/journal.pbio.3002033