Cognition, a critical aspect of brain function, is significantly impacted by aging and age-related conditions like Alzheimer's disease. As the global population continues to age, finding effective pharmacological interventions for cognitive impairment becomes an imperative biomedical challenge.
Klotho, a renowned longevity factor, naturally declines with age. Previous studies have demonstrated that transgenic overexpression of Klotho or peripheral administration of the drug extends the lifespan of mice, enhances synaptic and cognitive function, and promotes neural recovery from age-related toxicity, Alzheimer's disease, and Parkinson's disease.
Moreover, people with high levels of Klotho exhibit superior cognitive performance, reduced neuropathological indicators, and a lower risk of aging and Alzheimer's disease. These findings suggest a correlation between Klotho and human brain health.
On July 3, 2023, researchers from Yale University School of Medicine and the University of California, San Francisco published a research paper in Nature Aging titled "Longevity Factor Klotho Enhances Cognition in Aged Nonhuman Primates."
The study reveals that a single injection of the longevity protein Klotho improves cognitive function in aged monkeys, presenting a potential breakthrough in translating Klotho into a therapy for restoring brain function.
While studies in mice have provided valuable insights for the development of various therapies, it is clear that mouse models are not suitable for the advancement of human cognitive therapies. Therefore, further research on animal models with more complex brain structures and functions, such as aging non-human primates (NHPs), is crucial.
In this latest study, the team investigated whether low-dose subcutaneous injections of Klotho could enhance cognitive function in aging rhesus monkeys. Compared to mice, rhesus monkeys share 93% phylogenetic similarity with humans (compared to only 70% in mice) and possess more intricate higher-order cognitive functions.
Like humans, rhesus monkeys experience age-related cognitive decline accompanied by synaptic changes, without significant neuronal loss that impairs brain regions including the hippocampus and prefrontal cortex (PFC). The PFC, responsible for executive functions such as working memory, exhibits age-induced impairments in neuronal firing, regulated protein kinase C (PKC) activity, neurotransmitter homeostasis, and structural decline in rhesus monkeys.
The primary objective of the study was to test whether a single dose of Klotho treatment could increase serum Klotho levels in rhesus monkeys to a range similar to that observed in humans throughout their lifetime. Additionally, the researchers aimed to explore whether the cognitive benefits mediated by Klotho were dose-dependent by administering higher doses of the protein to the monkeys.
Klotho exists in transmembrane protein form and circulating hormone form. This study utilized the circulating hormone form, known as alpha-klotho protein. The researchers first generated rhesus monkey Klotho protein (96% homologous to human Klotho protein) and verified its functional activity through mouse experiments. In these experiments, a dose of 10 ug/kg body weight of rhesus monkey Klotho protein enhanced synaptic remodeling and working memory in mice.
To examine the effects of Klotho on cognitive function in NHPs, the research team administered a single low dose of Klotho (10 ug/kg body weight) to 18 aged rhesus monkeys (average age 21.78 years). The results demonstrated that a single dose of Klotho improved cognitive function in aged rhesus monkeys, as evidenced by assessments of working memory and spatial memory. Notably, this improvement persisted for at least two weeks.
In contrast, higher doses of Klotho administered to aged rhesus monkeys did not yield cognitive improvement. However, mice continued to exhibit enhanced cognitive function even at higher doses of Klotho, highlighting a disparity between mice and rhesus monkeys that may be attributed to the increased complexity of brain structure and networks in rhesus monkeys.
Given that Klotho levels decline with age in humans, this study indicates that a lower dose of 10 ug/kg body weight (similar to levels at birth) of injected Klotho enhances cognitive function in older NHPs. These findings suggest that peripheral treatment or supplementation with Klotho could potentially have therapeutic effects in aging humans and contribute to the development of future interventions combating cognitive decline in the elderly.