Partial Reprogramming in the Brains of Aged Mice Improves Memory and Learning
Reprogramming is the process by which germline cells transform into embryonic stem cells of the early embryo, along the way resetting their epigenetic pattern from aged to youthful. This transformation is driven by the expression of the Yamanaka factors, Oct4, Sox2, Klf4, and c-Myc, or OSKM. In contrast, partial reprogramming involves exposing cells to the Yamanaka factors for long enough to provoke epigenetic rejuvenation, but not so long as to produce a change of state of somatic cells into what are known as induced pluripotent stem cells. Much of the early work on the implementation of partial reprogramming as a therapy is focused on the central nervous system. The results in mice are promising, but a long road remains in the matter of how to ensure the safety of reprogramming when used in human patients, the balancing act of avoiding the inadvertent generation of pluripotent cells while still generating enough epigenetic rejuvenation to be useful.
Age-associated neurodegenerative disorders represent significant challenges due to progressive neuronal decline and limited treatments. In aged mice, partial reprogramming, characterized by pulsed expression of reprogramming factors, has shown promise in improving function in various tissues, but its impact on the aging brain remains poorly understood. Here we investigated the impact of in vivo partial reprogramming on mature neurons in the dentate gyrus of young and aged mice.
Using two different approaches - a neuron-specific transgenic reprogrammable mouse model and neuron-specific targeted lentiviral delivery of OSKM reprogramming factors - we demonstrated that in vivo partial reprogramming of mature neurons in the dentate gyrus, a neurogenic niche in the adult mouse brain, can influence animal behavior, and ameliorate age-related decline in memory and learning. These findings underscore the potential of in vivo partial reprogramming as an important therapeutic intervention to rejuvenate the neurogenic niche and ameliorate cognitive decline associated with aging or neurodegeneration.