![[Adobe Stock]](https://sp-ao.shortpixel.ai/client/to_webp,q_glossy,ret_img,w_750,h_375/https://www.psypost.org/wp-content/uploads/2023/07/neurons-in-the-brain-750x375.jpg)
A new study published in Nature Aging provides evidence that a single protein in the brain may play a central role in age-related memory loss—and that suppressing this protein could restore cognitive function in older animals. Researchers at the University of California, San Francisco found that increasing levels of a protein called ferritin light chain 1 (Ftl-1) in neurons impairs memory and synaptic function in young mice, while reducing its levels in aged mice rejuvenates brain function.
Cognitive decline is a common feature of aging, even in the absence of disease. Past work has shown that this decline is not primarily caused by neuron death, but rather by changes in how neurons function, especially at their synapses—points of communication between cells that are essential for learning and memory.
The research team sought to identify specific molecules that contribute to this decline and could potentially be targeted to reverse it. The hippocampus, a brain region known for its role in memory, is especially vulnerable to aging. The researchers reasoned that if they could uncover the molecular drivers of age-related hippocampal dysfunction, it might open the door to therapeutic interventions for cognitive aging—and perhaps even for age-related diseases like Alzheimer’s.
“Since I was a kid, I’ve always felt passionate about the brain, and in the last few years I’ve become really excited about aging. Joining Dr. Saul Villeda’s lab at UCSF as a postdoc gave me the chance to connect my two passions—brain and aging—and work on the mechanisms responsible for brain aging,” said Laura Remesal, the lead author of the new study and the founding scientist of Babylon Biosciences.
The study began by examining changes in gene expression in neurons taken from the hippocampi of young and aged mice. Using RNA sequencing, the team identified dozens of genes that were expressed at higher or lower levels with age. When they compared these transcriptional changes with age-related shifts in protein expression, measured by mass spectrometry, one molecule stood out: Ftl-1.
Ftl-1 is a component of ferritin, a protein complex that stores iron in cells. The researchers found that Ftl-1 was elevated in the hippocampal neurons of aged mice and that its expression levels were strongly linked to poorer performance on memory tasks. This correlation suggested that Ftl-1 might be more than just a marker of aging—it could be a contributing factor.
To test this idea, the team used a virus-based method to increase Ftl-1 expression specifically in the hippocampal neurons of young mice. The consequences were significant. These mice exhibited structural changes in their neurons, including shorter dendrites and fewer synapses—features typically associated with aging. They also performed worse on memory tests, showing little interest in exploring new objects or novel maze arms, in contrast to healthy young controls.
Next, the researchers reversed course. They used several approaches—short hairpin RNA, CRISPR gene editing, and conditional knockout models—to reduce Ftl-1 levels in the hippocampi of aged mice. Remarkably, this intervention led to improved memory performance. Aged mice with reduced Ftl-1 performed better on tests of recognition and spatial memory, and their hippocampal neurons showed more youthful characteristics, including restored synaptic markers and improved signaling.
“The degree of improvement in memory and synaptic measures were striking,” Remesal told PsyPost. “It suggested that changing a single aging-related factor can produce meaningful functional gains.”
To understand how Ftl-1 affects neuron function, the team looked more closely at cellular processes. They found that Ftl-1 overexpression disrupted the balance between different oxidation states of iron within neurons, increasing the level of oxidized iron. This shift can interfere with mitochondrial function, particularly the cell’s ability to produce ATP, which is critical for energy-intensive processes like maintaining synaptic activity.
Indeed, neurons overexpressing Ftl-1 showed diminished ATP production. In contrast, knocking down Ftl-1 enhanced cellular energy output. These results pointed to a link between iron metabolism, mitochondrial health, and brain aging.
The researchers wondered if they could counteract the effects of Ftl-1 by supporting mitochondrial function directly. To test this, they gave mice a supplement called NADH, which plays a key role in ATP production during oxidative phosphorylation. In mice that had been genetically altered to overexpress Ftl-1, NADH supplementation improved both neuronal structure and memory performance. These animals, which had previously failed to show a preference for novel objects or maze arms, regained that ability after treatment.
At the molecular level, NADH appeared to rescue the neurons’ energy metabolism. RNA sequencing of neurons from treated mice revealed increased expression of genes involved in mitochondrial respiration and ATP synthesis, such as Sdhb, Atp5o, and Ndufa10.
Taken together, these findings indicate that Ftl-1 contributes to brain aging by disrupting iron homeostasis and energy metabolism, and that both removing this protein and supporting mitochondrial function can restore cognitive abilities.
“The most important takeaway is that cognitive impairment can be reversed, not just prevented or delayed,” Remesal explained. “Treating the aged brain might have more potential than we first thought.”
While the results are promising, the study was conducted entirely in mice. The extent to which these findings will translate to humans remains unknown. Ftl-1, or FTL in humans, performs a conserved role in iron storage, and mutations in the gene have been linked to a rare neurodegenerative disorder known as neuroferritinopathy. Directly targeting FTL in people would require careful evaluation of safety, as altering iron storage could have unintended consequences.
“This work was done in mice, so I’m wary of drawing hard translational lines to humans,” Remesal said. “Still, the biology is indeed shared between mouse and human and the protein plays the same core role. This gives us confidence that this protein therefore might be a therapeutic target worth pursuing.”
The authors are optimistic that their findings provide a foundation for future work. They note that iron dysregulation has already been implicated in Alzheimer’s disease and other neurodegenerative conditions. In fact, elevated ferritin levels in the cerebrospinal fluid have been shown to predict cognitive decline over time in people with mild cognitive impairment.
The study also supports a growing body of research suggesting that the aging brain remains plastic—that is, capable of recovering function. Targeting individual molecular pathways, even late in life, might not only slow cognitive decline but partially reverse it. This perspective marks a shift away from the idea that age-related memory loss is inevitable and irreversible.
The next steps for the team include investigating whether Ftl-1-targeted therapies can benefit mouse models of neurodegenerative diseases. They are also interested in examining how Ftl-1 is regulated during aging and whether its effects differ across brain regions. Ultimately, they hope to explore whether similar interventions could be developed for human use.
The study, “Targeting iron-associated protein Ftl1 in the brain of old mice improves age-related cognitive impairment,” was authored by Laura Remesal, Juliana Sucharov-Costa, Yuting Wu, Karishma J. B. Pratt, Gregor Bieri, Amber Philp, Mason Phan, Turan Aghayev, Charles W. White III, Elizabeth G. Wheatley, Bende Zou, Brandon R. Desousa, Julien Couthouis, Isha H. Jian, Xinmin S. Xie, Yi Lu, Jason C. Maynard, Alma L. Burlingame, and Saul A. Villeda.
