Aging and wisdom are supposed to go together, but it turns out that a molecule that prevents one may actually play a role in the other.
Researchers have discovered a new role for the famous antiaging protein SIRT1. It not only fends off aging, but also aids in learning and memory, a new study published online July 11 in Nature shows.
Sirtuins, a family of proteins that includes SIRT1, help to regulate gene activity and have been implicated in governing metabolism and many of the biological processes that lead to aging. In the new study, Li-Huei Tsai, a neuroscientist and Howard Hughes Medical Institute investigator at MIT, finds that SIRT1 also plays a critical role in protecting learning and memory, at least in mice.
Tsai and her colleagues had an inkling that SIRT1 might play some role in the brain from earlier experiments showing that resveratrol, an activator of sirtuins, could help neurons survive a mouse version of Alzheimer’s disease. Resveratrol also improved the animals’ ability to learn and remember. Since resveratrol can act on all seven of the sirtuins found in mammals and also affects other biological processes (SN Online: 6/28/10), the researchers didn’t know what role, if any, SIRT1 played in the process.
To find out, Tsai and her colleagues put mice genetically engineered to lack SIRT1 in their brains through a series of learning and memory tests. The mice had trouble remembering the location of a submerged platform in a water maze, couldn’t tell the difference between a new object and an old one placed in their cages, and did poorly on other memory tests. “The ability for these animals to learn is clearly impaired,” Tsai says.
Probing into the brains of mice lacking SIRT1, Tsai and her colleagues found fewer connections, called synapses, between neurons. Fewer synapses could make it harder for the mice to forge long-term memories. That result gave the team a clue to some molecules that might be involved in the process. The team found that mice lacking SIRT1 also had lower levels of a protein called CREB in their brains. CREB works with other proteins to help regulate the strength of connections between neurons.
Delving deeper, the team discovered that SIRT1 modulates CREB levels through a small piece of RNA called microRNA-134 or miR-134. Normally, SIRT1 and a protein called YY1 team up to limit production of miR-134, but without SIRT1, more miR-134 is made. The microRNA then latches on to RNA instructions for making CREB and shuts down production of CREB protein.
The study reinforces the idea that SIRT1 is a master regulatory molecule, governing many aspects of metabolism and cell function, says Valter Longo of the University of Southern California in Los Angeles. Longo is conducting similar research, and his own work on the role of SIRT1 in learning and memory will appear in the July 21 Journal of Neuroscience.
He cautions against the idea that boosting SIRT1 activity could be a memory aid. Mice in the new study didn’t do better than normal on memory tests when SIRT1 levels were boosted. And the long-term consequences of having too much SIRT1 are still not known. Longo’s previous research suggested that elevated SIRT1 activity is bad for neurons (SN: 8/2/08, p. 14).
SIRT1 may well regulate other microRNAs too, says Paolo Sassone-Corsi, a molecular biologist at the University of California, Irvine. “I think she revealed just one pathway,” he says of Tsai’s new study. “Now you can see a new piece of the horizon that wasn’t there before. It’s really exciting.”.