The Aging Hippocampus and the Discovery of FTL1

Aging is particularly harsh on the hippocampus, the brain region critical for learning and memory. Researchers at UC San Francisco have identified a protein, FTL1, that appears central to this decline. Their findings, published in Nature Aging on August 19, 2024, suggest that targeting FTL1 could offer a new avenue for treating age-related cognitive impairment. Nature Aging is a peer-reviewed scientific journal covering all aspects of aging and age-related diseases.

The research team analyzed changes in genes and proteins within the hippocampus of mice as they aged. Among all the changes observed, only one consistently differed between young and old animals: the level of FTL1. Older mice exhibited significantly higher levels of this protein.

FTL1’s Impact on Brain Structure and Function

increased FTL1 levels in older mice correlated wiht fewer connections between brain cells (neurons) in the hippocampus and a corresponding decline in cognitive abilities. To further investigate the protein’s role, researchers artificially increased FTL1 levels in young mice.This manipulation resulted in brain changes and behavioral patterns mirroring those seen in older mice, demonstrating FTL1’s causative link to age-related cognitive decline.

Experiments conducted in vitro (in petri dishes) revealed that nerve cells engineered to overproduce FTL1 developed simpler neuronal structures. specifically,they grew single,unbranched extensions (neurites) instead of the complex,branching neurites characteristic of healthy neurons. These branching neurites are essential for forming synaptic connections and efficient dialogue between brain cells.

Reversing the Effects of FTL1

The most promising finding came when researchers reduced FTL1 levels in the hippocampus of older mice. This intervention led to a remarkable recovery: the mice regained lost neuronal connections and demonstrated improved performance on memory tests. “It is indeed 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 inquiry revealed that FTL1 slows down metabolism within hippocampal cells. However, stimulating metabolism in these cells effectively counteracted the negative effects of FTL1.

Future Directions and Potential Therapies

Dr.Villeda expressed optimism that these findings could pave the way for therapies designed to block the effects of FTL1 in the brain. “We’re seeing more opportunities to alleviate the worst consequences of old age,” he stated. “It’s a hopeful time to be working on the biology of aging.”

Study Authors and Funding

In addition to senior author Saul Villeda, PhD, the study authors include Laura Remesal, PhD, Juliana Sucharov-costa, Karishma J.B. Pratt, PhD, Gregor Bieri, PhD, Amber Philp, PhD, mason Phan, Turan Aghayev, MD, PhD, Charles W.White III, PhD, Elizabeth G.wheatley,PhD,Brandon R. Desousa, Isha H. Jian, Jason C. Maynard, PhD, and Alma L. Burlingame, PhD.

this research was supported by funding from the Simons Foundation, Bakar Family Foundation, National Science Foundation, Hillblom Foundation, Bakar Aging Research Institute, Marc and Lynne Benioff, and the National Institutes of Health (grant numbers AG081038, AG067740, AG062357, and P30 DK063720).