UCSF researchers demonstrate that the pro-aging effects of FTL1 can be reversed, restoring robust neural connectivity in mice.
A new study published in Nature Aging has revealed that an iron-associated protein plays a key role in driving cognitive decline during aging, and may present a promising and unexpected therapeutic target. Researchers at UC San Francisco have identified FTL1 as a pro-aging factor in the hippocampus, the brain region essential for learning and memory, and claim that its negative effects can potentially be reversed.
In studies in mice, levels of FTL1 were found to be elevated in the hippocampus of old mice, coinciding with diminished connections between brain cells and poor performance on memory tasks. When the authors artificially increased FTL1 in young mice, these animals began to exhibit the hallmarks of old age – including memory deficits and less complex neural wiring.
To probe the therapeutic potential of manipulating FTL1, the team knocked down its expression in aged mice using targeted molecular techniques. The results were striking: older mice regained robust neural connectivity and performed as well on memory tests as their youthful counterparts.
“It is truly a reversal of impairments,” said the paper’s senior author, Dr Saul Villeda in an article on the UCSF web site. “It’s much more than merely delaying or preventing symptoms.”
Molecular analyses revealed that FTL1 is tightly linked to metabolic decline and mitochondrial dysfunction in neurons. Elevated levels of FTL1 slows neuronal metabolism, but boosting metabolic pathways (for instance, with NADH supplementation) was able to partly counteract the protein’s deleterious effects.
Mechanistic studies in cell culture further underscored the impact of FTL1: neurons engineered to overproduce the protein developed drastically simplified neurites, losing the complex branching critical for healthy synaptic function. By contrast, reducing FTL1 restored dendritic complexity and synaptic plasticity.
The findings suggest that FTL1 aggregation leads to iron accumulation, oxidative stress, and subsequent interruption of key neuronal processes. Notably, these pathological changes may pave the way for the treatment of neurodegenerative diseases, such as Alzheimer’s – a possibility the researchers are eager to explore further.
“We’re seeing more opportunities to alleviate the worst consequences of old age,” said Villeda. “It’s a hopeful time to be working on the biology of aging.”
While the study’s interventions are not yet applicable to humans, the discovery of a single neuronal factor that can be manipulated to potentially reverse cognitive decline is significant. Could targeting FTL1 or its metabolic consequences one day yield therapies that go beyond simply slowing brain aging and enable true rejuvenation of cognitive function? Let’s hope so.
