Ageing is notoriously unkind to the hippocampus, the region of the brain that underpins our ability to learn, store memories, and recall past experiences. Over time, this critical structure begins to weaken, leading to forgetfulness and cognitive decline, which are often associated with the ageing process. Now, researchers at UC San Francisco believe they have uncovered one of the central drivers of this process. In a study recently published in Nature Aging, the team identified a single protein that seems to accelerate the brain’s decline — and, remarkably, showed that reducing it can restore youthful function in aged mice.

The discovery emerged from a careful analysis of the genes and proteins expressed in the hippocampus across the lifespan of mice. Amidst the thousands of potential candidates, the scientists found just one that consistently differed between young and old animals: a protein known as FTL1. In older mice, levels of FTL1 were markedly higher, and this increase coincided with a noticeable reduction in the number of synaptic connections between hippocampal neurons. Behaviourally, these animals also demonstrated poorer performance in tasks designed to measure learning and memory, suggesting that the elevated FTL1 was more than a bystander — it was actively shaping how the brain functioned.

The researchers then tested this link directly by manipulating FTL1 levels. When they artificially elevated FTL1 in young mice, the consequences were swift and dramatic: the animals’ brains began to exhibit the same cellular deterioration observed in their elderly counterparts, and their behaviour shifted accordingly. In laboratory dishes, neurons engineered to overproduce FTL1 sprouted only rudimentary, single-armed neurites rather than the complex branching structures that typically allow cells to form robust networks. These findings strongly suggested that excessive FTL1 undermines the brain’s ability to build and maintain the connections that underpin memory and learning.

Perhaps the most exciting results, however, came from the opposite experiment. When FTL1 levels were reduced in the hippocampus of old mice, their brains appeared to revert to a younger state. The animals regained synaptic density, their neurons formed healthier networks, and they performed much better on memory tests. “It is truly a reversal of impairments,” said Saul Villeda, PhD, associate director of the UCSF Bakar Aging Research Institute and senior author of the study. “It’s much more than merely delaying or preventing symptoms.” Further experiments revealed another damaging effect of FTL1: in older brains, it slowed cellular metabolism. But when scientists treated the hippocampal cells with a compound that stimulates metabolism, they were able to block these harmful consequences.

For Villeda and his team, the findings point toward a new frontier in the biology of ageing. Suppose therapies can be developed to limit the effects of FTL1 in the human brain. In that case, it may one day preserve memory and learning well into old age, or even restore these abilities after decline has begun. “We’re seeing more opportunities to alleviate the worst consequences of old age,” Villeda explained. “It’s a hopeful time to be working on the biology of ageing.” While the research is still in its early stages, the notion that a single protein could be targeted to reverse age-related impairments offers a powerful sense of optimism about what the future of neuroscience might hold.

More information: Laura Remesal et al, Targeting iron-associated protein Ftl1 in the brain of old mice improves age-related cognitive impairment, Nature Aging. DOI: 10.1038/s43587-025-00940-z

Journal information: Nature Aging Provided by University of California – San Francisco