Novel longevity enhancing pathways regulated by mTOR

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Project Summary We have recently identified a novel link between the mTOR pathway and a specific long noncoding RNA, H19, which is critical during development and in adult stem cell populations. This work forms the basis for an ongoing R01 project. In this supplement, the central hypothesis is that mTOR inhibition by Rapa alleviates Alzheimer’s disease (AD) symptomatology by increasing the lncRNA H19. We find that levels of H19 decrease during senescence and differentiation, however Rapa increases H19 levels, prevents senescence, and maintains pluripotency. The results suggest that increasing H19 levels in response to mTOR inhibition may play a dual role, inhibiting senescence while simultaneously increasing pluripotency in adult stem cell populations. H19 is expressed at low levels in the brain and increased following some forms of damage, but little information exists regarding the function of H19 in the adult brain or in the context of AD. We have evidence that this axis is active in human astrocytes and we will explore the role of H19 in the CNS, first by evaluating the role of H19 during senescence of human astrocytes in response to stressors relevant to AD, second by evaluating the expression of H19 in mouse models of AD with and without rapamycin treatment, third by defining the specific binding partners of H19 in astrocytes and neurons.