Fight Aging!

Klotho is one of the few genuinely longevity-associated genes, in that greater than normal expression increases life span in mice, while lower than normal expression shortens life span in mice. In humans, greater levels of circulating soluble klotho correlate with greater longevity. Klotho is thought to operate in the kidneys, in some way that is protective against the mechanisms of age-related decline, but there is a great deal of evidence for greater circulating klotho to improve cognitive function. At the same time, it seems unclear as to whether klotho is actually doing anything in the brain; it may be that the benefit is derived from preventing loss of kidney function, as kidney function is quite important to brain health. Still, this is subject to further discovery, and far from being a settled answer.

Various groups are working towards the use of the recombinant klotho protein as a therapy, or some form of gene therapy as a way to increase circulating levels in humans. This seems as likely to be initially developed as a treatment for cognitive impairment as for kidney conditions, given the evidence on the table. Certainly, that is the intent at UNITY Biotechnology, a company that licensed academic work from recent years on the effects of soluble klotho on cognitive function in mice. That same line of work now leads to today's study, in which soluble klotho is tested as a protein therapy in aged non-human primates. It appears to work as a way to improve cognitive function, but interestingly only at lower doses, suggesting that the path forward is probably going to be more complex than desired.

Longevity factor klotho enhances cognition in aged nonhuman primates

Klotho (KL) is a longevity factor that declines in aging. Elevating KL boosts cognitive functions in mice through transgenic overexpression and acute peripheral administration. KL (secreted α-klotho) circulates as a hormone following cleavage from its transmembrane form and impacts insulin and fibroblastic growth factor (FGF) signaling, Wnt and N-methyl-d-aspartate receptor (NMDAR) functions. Systemic elevation of KL in mice increases synaptic plasticity, cognition, and neural resilience to aging, Alzheimer's, and Parkinson's disease-related toxicities. Notably, systemic administration of KL does not cross the blood-brain barrier. Human relevance for KL in brain health is supported by studies showing that individuals with elevated KL, due to genetic Klotho variation or other reasons, demonstrate better cognition, attenuated neuropathological measures, or decreased dementia risk in aging and Alzheimer's disease.

We sought to test whether a low-dose, subcutaneous administration of KL could, in parallel to mice, boost cognition in aged rhesus macaques, a type of non-human primate (NHP). Like humans, rhesus macaques undergo age-induced cognitive decline with synaptic changes, without significant neuronal loss, impairing brain regions, including the hippocampus and prefrontal cortex (PFC). Targeted earlier by aging, the PFC subserves executive functions such as working memory and, in rhesus macaques, shows age-induced deficits in neuronal firing, regulated protein kinase C (PKC) activity, neurotransmitter balance and structural decline.

Our primary goal was to test whether a KL dose in rhesus macaques that increases serum levels to a range present during the human lifespan, and is comparable to therapeutically effective increases in mice, can enhance cognition. Our secondary goal was to explore higher KL doses in rhesus macaques to test whether KL-mediated benefits on cognition could be dose-dependent. Our data show that KL (10 μg/kg) enhanced cognition in aging rhesus macaques, an effect that persisted for at least 2 weeks in measures of memory. KL-mediated cognitive enhancement similarly persisted in mice for at least 2 weeks, suggesting organizational, longer-lasting and beneficial effects on the synapse and brain. In both species, the cognitive effect outlasted the putative half-life of the hormone, 7 minutes in rodents and estimated at 29.5 hours in aging rhesus macaques.

Higher doses of KL (20 and 30 μg/kg) did not enhance cognition in monkeys. Of note, the higher doses tested did not impair cognition as the 2-5% changes were not significantly increased or decreased statistically; however, it remains to be determined whether doses even higher than those tested could impair cognition. Together, these data indicate that KL-mediated cognitive enhancement extends to NHPs in a complex genetic, anatomical, and functional brain similar to humans. These data also suggest that lower, more 'physiological' levels of the hormone in the body may be required for a therapeutic window of cognitive enhancement in humans.