Targeting iron-associated protein Ftl1 in the brain of old mice improves age-related cognitive impairment.

Laura Remesal, Juliana Sucharov-Costa, Yuting Wu, Karishma J B Pratt, Gregor Bieri, Amber Philp, Mason Phan, Turan Aghayev, Charles W White, Elizabeth G Wheatley, Bende Zou, Brandon R Desousa, Julien Couthouis, Isha H Jian, Xinmin S Xie, Yi Lu, Jason C Maynard, Alma L Burlingame, Saul A Villeda

Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA. [email protected] of Anatomy, University of California, San Francisco, San Francisco, CA, USA. [email protected]. · pubmed

Paper

Abstract

Understanding cellular and molecular drivers of age-related cognitive decline is necessary to identify targets to restore cognition at old age. Here we identify ferritin light chain 1 (FTL1), an iron-associated protein, as a pro-aging neuronal factor that impairs cognition. Using transcriptomic and mass spectrometry approaches, we detect an increase in neuronal FTL1 in the hippocampus of aged mice, the levels of which correlate with cognitive decline. Mimicking an age-related increase in neuronal FTL1 in young mice alters labile iron oxidation states and promotes synaptic and cognitive features of hippocampal aging. Targeting neuronal FTL1 in the hippocampi of aged mice improves synaptic-related molecular changes and cognitive impairments. Using neuronal nuclei RNA sequencing, we detect changes in metabolic processes, such as ATP synthesis, and boosting these metabolic functions through NADH supplementation mitigated pro-aging effects of neuronal FTL1 on cognition. Our data identify neuronal FTL1 as a key molecular mediator of cognitive rejuvenation.

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Research summary

Targeting neuronal FTL1 in the hippocampi of aged mice improves cognitive impairments associated with aging. The paper addresses a specific molecular mechanism linked to cognitive decline in aging, aiming to restore cognitive function, which aligns with the goals of longevity research.

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