UCSF

Aging leads to cognitive decline and increased risk for age-related neurodegenerative diseases such as Alzheimer’s disease. The increasing rate of population aging places a larger number of people at risk for such cognitive dysfunction. This highlights the need for therapeutic approaches that maintain cognitive integrity in the aging brain. Calorie restriction (CR) is one of the most effective and well-studied non-genetic, rejuvenating systemic interventions—reversing hallmarks of brain aging and improving cognitive function in aged animals. However, adherence is difficult in the elderly, necessitating methods to rescue cognition without the limitations of onerous dietary intervention. We show that circulating blood factors transfer restorative cognitive effects of CR to the aged brain. Systemic administration of blood plasma derived from aged mice undergoing late-onset, short-term CR increased adult neurogenesis, elicited hippocampal synaptic-related transcriptional changes and restored cognition in aged ad libitum fed mice. Circulating levels of kidney-derived Glutathione Peroxidase 3 (GPX3) increased in blood plasma after CR in aged mice and humans. Elevating systemic GPX3 recapitulated neurogenic-related cellular and transcriptional changes in the hippocampus and ameliorated cognitive impairments in aged mice. Mechanistically, we identified the selenocysteine-mediated hydroperoxide detoxification activity of systemic GPX3 as necessary for cognitive improvements. Together, these data identify a kidney-brain rejuvenation axis by which blood factors confer cognitive benefits of CR in old age.