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

  • Nat Aging. 2025 Oct;5(10):1957-1969. doi: 10.1038/s43587-025-00940-z.
Laura Remesal  1 ,  Juliana Sucharov-Costa  2  3 ,  Yuting Wu  4  5 ,  Karishma J B Pratt  2  6 ,  Gregor Bieri  2 ,  Amber Philp  2 ,  Mason Phan  2 ,  Turan Aghayev  2 ,  Charles W White 3rd  2  6 ,  Elizabeth G Wheatley  2  6 ,  Bende Zou  7 ,  Brandon R Desousa  8  9 ,  Julien Couthouis  10 ,  Isha H Jian  8  9 ,  Xinmin S Xie  7 ,  Yi Lu  4  5 ,  Jason C Maynard  11 ,  Alma L Burlingame  11 ,  Saul A Villeda  12  13  14  15  16
Affiliations
  • 1. Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA. [email protected].
  • 2. Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.
  • 3. Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
  • 4. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • 5. Department of Chemistry, The University of Texas at Austin, Austin, TX, USA.
  • 6. Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
  • 7. AfaSci Research Laboratory, Redwood City, CA, USA.
  • 8. Department of Biochemistry, University of California, San Francisco, San Francisco, CA, USA.
  • 9. Gladstone Institute of Cardiovascular Disease, Gladstone Institutes, San Francisco, CA, USA.
  • 10. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
  • 11. Mass Spectrometry Facility, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
  • 12. Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA. [email protected].
  • 13. Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA. [email protected].
  • 14. Developmental and Stem Cell Biology Graduate Program, University of California, San Francisco, San Francisco, CA, USA. [email protected].
  • 15. Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, San Francisco, CA, USA. [email protected].
  • 16. Bakar Aging Research Institute, San Francisco, CA, USA. [email protected].
PMID: 40830655 DOI: 10.1038/s43587-025-00940-z
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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