Nature sub-issue: Yang Yuanjian's team from Jiangxi Mental Health Center found that the longevity factor Klotho may have antidepressant potential

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Klotho protein is the main part of the endocrine fibroblast growth factor (FGF) receptor complex and is highly expressed in the brain choroid, neurons and kidneys and other tissues
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By inhibiting the classical aging signaling pathway insulin/IGF-1, it inhibits the aging process and prolongs lifespan
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5-week-old Klotho knockout mice have increased levels of oxidative stress in the hippocampal brain region, causing cognitive dysfunction, loss of muscle and adipose tissue, and dysplasia and other premature aging
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Studies have shown that Klotho protein has an anti-aging effect.
After high expression of mouse Klotho protein, activation of the N-methyl-D-aspartate (NMDA) receptor GluN2B subunit can prolong lifespan and slow down age-related cognition.
Dysfunction
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Serum Klotho protein levels were reduced in women who experienced high-intensity chronic stress stimulation compared to those who experienced low-level stress, suggesting that the level of this protein expression may be related to stress
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On April 21, 2022, Yang Yuanjian's research team from Jiangxi Provincial Mental Health Center and Nanchang Key Laboratory of Biological Psychiatry published an article in the journal Neuropsychopharmacology, a sub-journal of Nature, revealing that the anti-aging protein Klotho is reduced in expression in the brain after chronic stress and is involved in regulation Depressive-like behavior disorder
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Figure 1: Chronic stress causes Klotho protein expression to decrease.
The researchers induced depression-like behavioral disorder in mice through chronic stress.
At the same time, Klotho protein was significantly decreased in the hippocampus and nucleus accumbens (NAc) brain regions, and the NAc brain region decreased more for obvious
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After specifically increasing the expression of Klotho protein in the NAc brain region by the viral vector tool, it can significantly improve the social impairment, anhedonia and other depression-like behaviors caused by chronic stress
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The virus reduced Klotho protein in the NAc brain region to cause depression-like behavior in normal mice
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The researchers found that chronic stress did not cause changes in the levels of the NMDA receptors GluN1 and GluN2A subunits, but significantly decreased GluN2B subunit protein levels, as well as the postsynaptic protein PSD95
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Interestingly, virus-reduced Klotho protein can also reduce the levels of GluN2B subunit and PSD95, while overexpression of Klotho protein can increase the levels of GluN2B subunit and PSD95, suggesting that Klotho may regulate synaptic function mediated by NMDA receptors.
Depression-like behavior
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Morphologically, chronic stress caused an increase in the density of dendritic spines in the NAc brain region of mice, and overexpression of Klotho protein reversed this structural disorder
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Functionally, chronic stress induces impairment of NMDA receptor-mediated long-term inhibition in the NAc brain region, and overexpression of Klotho protein can reverse this dysfunction
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These results suggest that Klotho protein mediates depression-like behavior by regulating synaptic plasticity
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Injecting a low-dose NMDAR blocker into the NAc brain region (the affinity for the GluN2B subunit is more than 3000 times that of other subunits) did not affect the exercise ability of mice, but it could block the antidepressant effect of Klotho protein overexpression
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Low levels of Klotho protein may be detrimental to the body: Klotho protein levels are reduced in various tumor tissues; serum Klotho protein levels are also reduced in hypertensive patients
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The Klotho protein in the brain of the depression animal model in this paper is also reduced, and the increase of its level can exert an antidepressant effect
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Collectively, we found that Klotho protein in the nucleus accumbens region mediates stress-induced depression-like behavior by regulating the function of the NMDAR subunit GluN2B
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【References】1.
Life extension factor klotho regulates behavioral responses to stress via modulation of GluN2B function in the nucleus accumbens https:// The pictures in the text are from the reference