Transcriptional Reprogramming to Reverse Aging-Associated Transcriptional Dysregulation in Neurons
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lenail-lenail-phd-csb-2025-thesis.pdf
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69.75 MB
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31151653006e168a7dfadda3b9e692f4
Author(s)
Lenail, Alexander Y.
Advisor(s)
Heiman, Myriam
Date Issued
May 2025
Publisher
Massachusetts Institute of Technology
Abstract
It is unclear what the mechanistic contribution of normal aging is to the neurodegenerative diseases that present in advanced age. This motivates an investigation into the molecular characteristics of neuronal aging, as well as the pursuit of interventions that could reverse neuronal aging or increase neuronal resilience to degenerative mechanisms. We cataloged the molecular differences between young and old neurons of the mouse brain with single-nucleus paired transcriptional and epigenetic assays, forming a multi-omic atlas of brain aging, revealing deficits in mitochondrial, proteostasis, and synaptic gene expression. To reverse these age-associated transcriptional profiles, we targeted endogenous homeostasis-maintenance genetic programs by increasing the dosage of relevant Transcription Factors (TFs). We computationally predicted a library of TFs most likely to engage the target transcriptional programs by integrating multiple lines of evidence and then produced a library of TFs that we administered in a pool to the aged mouse brain. Our single-nuclear RNA-seq readout describes the transcriptional consequences of each TF perturbation in each cell type in the aged motor cortex. Our results highlight certain under-studied TFs with promising rejuvenation potential and benchmark our algorithmic approaches to predict the effects of TF perturbations.
MIT Department
Massachusetts Institute of Technology. Computational and Systems Biology Program
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