An Enzyme that Rescues Age-Related Decline in Cognition and Neurogenesis

A new study suggests loss of the enzyme Tet2 may underlie age-related cognitive decline. Boosting Tet2 levels can restore neurogenesis to youthful levels and enhance cognitive function.

Previously, Saul Villeda’s lab have shown that infusing the blood of younger mice into aged mice (parabiosis) leads to brain rejuvenation, whilst the reverse causes premature brain aging in young mice. Following these findings, Tet2 was identified as a key molecular mediator of brain rejuvenation.

"At first I didn’t believe it," said Geraldine Gontier, an author of this study. "I did the experiment again and again to make sure that it was right. But it became clear that some circulating factor in the blood is able to change the level of Tet2 in the brain."

Tet2 catalyses the production of 5hmC, which has emerged as an important epigenetic modification that plays essential roles in development, aging and disease. As mice age, Tet2 expression and 5hmC levels in the hippocampus (a region of the brain involved in learning and memory) decline. This paralleled the decline in adult neurogenesis (formation of new neurons) by 6 months of age in mice. Conversely, knocking out Tet2 expression in the hippocampus of young adult (3-month old) mice caused a significant decrease in the number of newly ‘born’ and mature neurons. Loss of Tet2 also caused mice to perform worse on tests of short-term and long-term learning and memory.

The researchers further demonstrated that Tet2 is also involved in brain rejuvenation. Experimentally overexpressing Tet2 in the adult hippocampus was sufficient to restore neurogenesis to levels normally observed in a young hippocampus and improved the performance of mice during fear conditioning training. Intriguingly, when comparing genes that lost 5hmC during aging with genes that gained 5hmC from Tet2 overexpression, 39 overlapping genes were detected, of which 10 were found to be involved with neurogenesis.

Future efforts should investigate whether the findings of this study also apply in humans and explore the potential of interventions that target Tet2 to rescue age-related regenerative decline in the ageing brain.