Exogenous Klotho as a Cognition Booster in Aging Primates

Snata Pandey, St. Xavier’s College, Autonomous, Kolkata

Introduction

Klotho, a protein closely linked to aging, comes in two forms: a transmembrane form and a secreted form. The secreted form plays roles in phosphate and vitamin D metabolisms, as well as various signalling pathways. As individuals age, the circulating levels of klotho protein decrease. This decrease correlates with cognitive abnormalities, phosphate toxicity, chronic kidney disease, and other age-related disorders. A study by Castner et. al. 2023 explored the efficacy of substituted klotho to treat ageing-related cognitive dysfunction in rhesus monkeys. The model is of interest since it shares a 93% phylogeny with humans, and has more comparable cognitive functions, age-related structural, neuronal and biochemical decline to humans.

Research has established that normalizing klotho levels in mice leads to improvements in neural plasticity and alleviation of symptoms associated with neurodegenerative diseases. The two goals of the present study were to see if enhanced serum klotho levels ensured improved cognition in rhesus monkeys and if such improvements were dose dependent.

Testing the Efficacy in Rhesus Monkeys

First, the secreted form of rhesus monkey’s klotho was synthesized. The generated ortholog bore a 96% homology with human klotho. They confirmed its efficacy at enhancing cognition in mice at 10 μg/kg after 4 hours of peripheral injection, along with a significant increase in serum klotho levels.

Among the various concentrations of klotho injected into test monkeys, the 10 μg/kg dose emerged as the lowest concentration capable of increasing serum klotho levels by five-fold. As a result of demonstrating a connection with enhanced cognition in mice and aligning with the concentration observed in human umbilical cord blood, they consequently selected this level of increase for further investigation.

The scientists evaluated trained rhesus monkeys, with an average age of 21.78 years, equivalent to 65 human years, using spatial delayed response (SDR) tasks. They assessed both working and spatial memories, utilizing normal memory load (NML, easier tasks) and high memory load (HML, harder tasks), all of which experienced age-related disruption.

Initially, researchers trained the monkeys to identify the spatial location of highly palatable food rewards among multiple wells at a consistent time each day. Subsequently, the scientists acclimatized the monkeys to injection stress by administering a control vehicle injection, followed by an injection of klotho. After four hours, the researchers conducted HML tasks with the monkeys, followed by NML tasks, and concluded with HML tasks over two weeks following treatment.

In both NML and HML testing, they observed improved cognition compared to monkeys injected with the vehicle, and this improvement was independent of sex. The result is comparable to what was observed in mice. The effect of the hormone lasted for two weeks after injection, outlasting the half-life of monkey klotho (29.5 h).

Conclusion

Augmenting klotho can enhance cognition within a therapeutic range in rhesus monkeys, and researchers may extrapolate this potential to humans. Further cognitive improvement is, however, absent for higher doses of klotho in monkeys. The main limitations of the test were that they only tested the SDR task, and used the same monkeys for subsequent testing with different doses.

The future scope of the research may be to check for cognitive impairment due to still higher doses of klotho. Since peripherally injected klotho does not cross the blood-brain barrier, its signal transduction into the brain may also be identified.

Also read: Techniques in Molecular Biology: Training-cum-Internship program

Reference:

Castner, S.A., Gupta, S., Wang, D. et al. Longevity factor klotho enhances cognition in aged nonhuman primates. Nat Aging (2023). https://doi.org/10.1038/s43587-023-00441-x

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