Researchers from the University of California San Francisco (UCSF) have identified a protein they say plays a central role in the aging of the brain. Their study, published in Nature Aging, showed that increased levels of the iron-binding protein ferritin light chain 1 (FTL1) drives structural and metabolic changes in the hippocampus impair memory and learning in aged mice. By reducing FTL1 in aged mouse models, the researchers restored synaptic function and cognitive performance.
“It is truly a reversal of impairments,” said senior author Saul Villeda, PhD, associate director of the UCSF Bakar Aging Research Institute. “It’s much more than merely delaying or preventing symptoms.”
The hippocampus, which regulates learning and memory, is highly vulnerable to aging. Understanding what drives this susceptibility is essential for identifying interventions that could preserve cognitive health or reverse age-related decline. Using both transcriptomic and proteomics analyses, the UCSF team sought to better understand molecular changes within this brain region that may drive brain aging.
Leveraging RNA sequencing of hippocampal neurons and mass spectrometry of synaptic proteins, the UCSF investigators compared the data from young (three-month-old) and aged (18-month-old) mice. Data from these comparisons showed that FTL1 was the only protein consistently increased with age across both datasets. “We observed a significant negative association between increased hippocampal FTL1 expression by western blot and impaired overall cognitive performance,” the researchers wrote.
FTL1, part of the ferritin complex involved in iron storage, has not been previously identified as playing a functional role in brain aging. To test how it affects the brain, the researchers increased FTL1 in the hippocampus of young adult mice using neuron-specific viral vectors. Their results showed that in instances with increased levels of the protein, neurons exhibited fewer dendritic branches, reduced synaptic density, impaired long-term potentiation (LTP), and cognitive deficits in memory tests such as the novel object recognition and Y maze tasks. “Our functional data indicate that mimicking an age-related increase in neuronal FTL1 negatively regulates synaptic plasticity and hippocampal-dependent memory,” the researchers wrote.
Conversely, targeting FTL1 for reduction in the hippocampus of aged mice produced the opposite effect. Using RNA interference, CRISPR-Cas9, and conditional knockout strategies, researchers suppressed neuronal FTL1 expression. Aged mice then showed enhanced dendritic complexity, restored levels of synaptic markers (such as NR2A, AMPA receptors, and synapsin), and improved memory performance in the same cognitive tasks. “These data suggest that targeting hippocampal FTL1 restores known age-related synaptic molecular changes and cognitive function in aged mice,” the researchers wrote.
Mechanistically, the study linked FTL1’s effects to disrupted iron metabolism and mitochondrial energy production. Neurons overexpressing FTL1 accumulated oxidized iron (Fe³⁺), which can interfere with cellular respiration. Gene expression analysis and Seahorse metabolic assays showed that increased FTL1 suppressed ATP production, while reducing FTL1 enhanced it.
To test whether impaired metabolism could be counteracted, the team treated FTL1-overexpressing neurons with NADH, a coenzyme that supports oxidative phosphorylation. NADH rescued neurite outgrowth and reversed cognitive deficits in mice. “These data indicate that the pro-aging effects of increased neuronal FTL1 on cognitive function are mediated, at least in part, through alterations in metabolic processes,” the researchers wrote.
The study also highlights potential implications beyond normal aging. FTL1 mutations cause a condition called neuroferritinopathy, a rare monogenic disorder that has cognitive symptoms. Further, elevated ferritin in cerebrospinal fluid has been associated with progression to Alzheimer’s disease. “Our data raise the exciting possibility that the beneficial effects of targeting neuronal FTL1 at old age may extend more broadly, beyond cognitive aging, to neurodegenerative disease conditions in older people,” the researchers wrote.
For their next steps, the researchers now plan to investigate how FTL1 interacts with other aging-related processes and whether pharmacologic inhibition or gene therapy targeting FTL1 could translate to human therapies. “We’re seeing more opportunities to alleviate the worst consequences of old age,” Villeda said. “It’s a hopeful time to be working on the biology of aging.”
