Targeting iron-associated protein Ftl1 in the brain of old mice improves age-related cognitive impairment
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.
Authors
- Karishma Pratt (ORCID: https://orcid.org/0000-0002-3040-4829)
- Jason C. Maynard (ORCID: https://orcid.org/0000-0001-7838-5420)
- Bende Zou
- Charles White
- Gregor Bieri (ORCID: https://orcid.org/0000-0003-0737-231X)
- Saul Villeda (ORCID: https://orcid.org/0000-0002-2726-9582)
- Elizabeth Wheatley (ORCID: https://orcid.org/0000-0001-5459-8827)
- Julien Couthouis (ORCID: https://orcid.org/0000-0002-2378-4595)
- Laura Remesal (ORCID: https://orcid.org/0000-0003-0765-6849)
- Mimi H. Phan
- Alma L. Burlingame (ORCID: https://orcid.org/0000-0002-8403-7307)
- Brandon R. Desousa (ORCID: https://orcid.org/0000-0003-3765-3809)
- Amber R. Philp (ORCID: https://orcid.org/0000-0001-6380-6851)
- Xinmin Xie (ORCID: https://orcid.org/0000-0002-4049-6499)
- Turan Aghayev (ORCID: https://orcid.org/0000-0003-2208-9918)
- Yuting Wu (ORCID: https://orcid.org/0000-0003-3196-5916)
- Yi Lu (ORCID: https://orcid.org/0000-0003-1221-6709)
- Isha H Jian
- Juliana Sucharov-Costa
Institutions
- Gladstone Institutes (US)
- University of Illinois Urbana-Champaign (US)
- University of California, San Francisco (US)
- Institute on Aging (US)
- AfaSci (United States) (US)
- University of San Francisco (US)
- The University of Texas at Austin (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Aging
- Published
- 2025-08-19
- DOI
- https://doi.org/10.1038/s43587-025-00940-z
- Citations
- 6
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 6.99
Funders
- National Science Foundation
- Simons Foundation
- Larry L. Hillblom Foundation
- National Institute on Aging