New research published today adds to growing evidence that the protein SIRT1 plays an important role in learning and memory in mice. While removing SIRT1 impairs cognitive function and alters neuronal structure, increasing SIRT1 beyond normal levels does not further enhance learning or memory, suggesting a complex, non-linear role for this protein in the brain.
Widely studied aging protein required for recall, but over-expression shows no benefit
Scientists from the University of Southern California and the National Institute on Aging report that mice lacking the SIRT1 gene display clear deficits in learning and memory, as well as simplified neuronal architecture. The new findings, published in the Journal of Neuroscience, mirror results released by another research team in Nature that also observed impaired cognition in SIRT1-deficient animals.
At the same time, the USC-led study found that mice engineered to over-express SIRT1 did not perform better on memory or learning tasks than normal mice. Their brains showed no obvious harmful changes from higher SIRT1 levels, but no cognitive improvement was observed either. These results raise important questions about the potential value of dietary or pharmaceutical strategies that aim to increase SIRT1 activity in healthy individuals.
“Over-expression of SIRT1 did not improve memory, implying that simply increasing the amount of the protein may not enhance cognitive performance,” said Valter Longo, molecular biologist at the USC Leonard Davis School of Gerontology and co-corresponding author of the study. “More research using different models is needed to fully understand whether boosting SIRT1 can be beneficial under any circumstances.”
Sirtuins, the family of proteins that includes SIRT1, are implicated in metabolism, cellular stress responses, and processes linked to aging. One widely discussed sirtuin-related compound is resveratrol, a molecule found in red wine that has been promoted as a sirtuin activator. While studies have shown resveratrol can produce health benefits in certain contexts—such as improving health and extending lifespan in mice on high-fat diets—it does not extend lifespan in otherwise normal mice. The physiological roles of sirtuins in humans remain under active investigation.
Previous work by Longo and others suggested that absence of SIRT1 can protect neurons against some forms of toxicity, while the present study highlights that SIRT1 deficiency also impairs cognitive function. “This may indicate a trade-off between protecting neurons from toxic insults and maintaining neural functions essential for learning and memory,” Longo noted. Such a trade-off could help explain why manipulating SIRT1 activity produces mixed effects in different experimental scenarios.
In the USC team’s experiments, mice missing SIRT1 not only struggled with memory and learning tests but also showed physical alterations in their neural networks. Neurons in these animals had less branching and reduced structural complexity—features that typically correlate with diminished synaptic plasticity and a reduced capacity to form new connections, both critical for learning.
Conversely, mice engineered to over-express SIRT1 exhibited no improved cognitive performance and did not display adverse neuronal features. The absence of both benefit and harm in the over-expression model suggests that SIRT1’s role in cognition is finely tuned and that simply increasing its abundance is insufficient to boost normal learning processes.
The research team included first authors Ying Li (USC) and Shaday Michan (Harvard Medical School and Instituto Nacional de Salud, Mexico); co-corresponding author Rafael de Cabo (National Institute on Aging); senior investigators Valter Longo and Michel Baudry (USC); and collaborators from Harvard Medical School, the University of South Florida and the University of Ottawa.
Funding for this work came from the National Institutes of Health, the Canadian Institutes of Health Research, the Ellison Medical Foundation, the intramural research program of the National Institute on Aging, and the Paul F. Glenn Foundation for Medical Research.
Contact: Carl Marziali
Source: University of Southern California
