In this open access paper, researchers report on use of a portion of the longevity-associated klotho protein to enhance cognitive function in mice. It works in both young and old mice, so is a fairly general mechanism, and may or may not be related to any of the possible roles klotho might play in the progression of aging.
α-Klotho (klotho) is a pleiotropic protein that circulates as a hormone following cleavage from its transmembrane form. It regulates insulin, Wnt, and fibroblast growth factor (FGF) signaling. Overexpression of klotho extends life in organisms, whereas lowering klotho shortens it. Elevated klotho levels in humans, resulting from genetic variation, also associate with lifespan in some populations. In model organisms and humans, levels of klotho decline with age, chronic stress, cognitive aging, neurodegenerative disease, and models of neurodegenerative disease.
We previously discovered that life-long, genetic overexpression of klotho causally enhances normal cognition and neural resilience independent of age and when broadly expressed in the mouse body and brain. It does so, at least in part, by directly or indirectly optimizing synaptic functions through NMDA receptor (NMDAR)-dependent mechanisms. Importantly, genetic, lifelong, and widespread klotho elevation also contributes to neural resilience in a human amyloid precursor protein (hAPP) model of neurodegenerative disease related to AD; that is, it effectively counters cognitive and synaptic deficits despite high levels of pathogenic proteins, including Aβ, tau, and phospho-tau. The relevance of klotho to brain health in humans is supported by the findings that elevated serum klotho, related to variation in the gene, are associated with better measures, including cognition, structural reserve of the prefrontal cortex in normal aging, connectivity between cortical regions, and physical performance in aging, and that diminished klotho levels are associated with worse brain measures.
Whether acute klotho elevation represents a strategy that can rapidly enhance cognition, motor functions, and/or induce brain resilience is a gap in our knowledge of its therapeutic potential. Here we show that αKL-F, a fragment of the α-klotho protein similar to its secreted form, can acutely improve cognitive and motor functions following peripheral administration. It does so despite apparent impermeability to the blood-brain barrier in mice. Further investigation of αKL-F-mediated molecular mechanisms revealed activation of glutamatergic signaling and enhancement of synaptic plasticity. Our findings highlight a role for αKL-F in promoting optimal synaptic functions in the normal brain and to boost "synaptic health" in aging and disease-states. Because synaptic health may confer resilience against the effects of aging and a myriad of aging-and non-aging related neurologic and psychiatric diseases, the potential to enhance it may be relevant to the human condition.