Presupposed dogma indicates that the old brain is unable to combat the effects of aging due to a lack of inherent plasticity that facilitates permanent age-related functional impairments. The discovery of neural stem cells in the adult brain has incited possibilities for restoring regenerative and cognitive function in the elderly by enhancing adult neurogenesis in the aged brain. To date, we and others, have begun to challenge dogma by demonstrating that systemic manipulations, such as heterochronic parabiosis (in which the circulatory systems of young and old animals are connected), can restore adult neurogenesis and rejuvenate cognitive function in the aged brain1-3. Excitingly, the ability to reverse aging in the brain could have wide ranging implications for maintaining functional brain integrity and counteracting vulnerability to dementia-related neurodegenerative diseases, such as Alzheimer’s disease. However, molecular mechanisms mediating neurogenic rejuvenation remain elusive. We report that the epigenetic regulator ten eleven translocation methylcytosine dioxygenase 2 (Tet2) –which catalyzes the production of 5-hydroxymethylcytosine (5hmC)– rescues age-related decline in adult neurogenesis. Interestingly, we detected a decrease in Tet2 expression and 5hmC levels in the aged hippocampus associated with neurogenesis. Mimicking an aged condition in young adults by abrogating Tet2 expression within the hippocampal neurogenic niche, or in adult neural stem cells, decreased neurogenesis and impaired learning and memory. In a heterochronic parabiosis model of neurogenic rejuvenation hippocampal Tet2 expression was restored. Moreover, overexpressing Tet2 in the hippocampal neurogenic niche of mature adults increased 5hmC associated with neurogenic processes, offset the precipitous age-related decline in neurogenesis, and enhanced learning and memory4. Our data identify Tet2 as a novel epigenetic mechanism of neurogenic rejuvenation.
1Villeda SA et al, Nature, 2011
2Villeda SA et al, Nat. Med, 2014
3Smith LK et al, Nat. Med, 2015
4Gontier G et al, Cell Report 2018