Could α-Klotho Unlock the Key Between Depression and Dementia in the Elderly: from Animal to Human Studies

α-Klotho is known for its aging-related functions and is associated with neurodegenerative diseases, accelerated aging, premature morbidity, and mortality. Recent literature suggests that α-Klotho is also involved in the regulation of mental functions, such as cognition and psychosis. While most of studies of α-Klotho are focusing on its anti-aging functions and protective role in dementia, increasing evidence showed many shared symptoms between depression and dementia, while depression has been proposed as the preclinical stage of dementia such as Alzheimer’s disease (AD). To see whether and how α-Klotho can be a key biological link between depression and dementia, in this review, we first gathered the evidence on biological distribution and function of α-Klotho in psychiatric functions from animal studies to human clinical investigations with a focus on the regulation of cognition and mood. Then, we discussed and highlighted the potential common underlying mechanisms of α-Klotho between psychiatric diseases and cognitive impairment. Finally, we hypothesized that α-Klotho might serve as a neurobiological link between depression and dementia through the regulation of oxidative stress and inflammation.