Systemic aging and neurodegeneration are characterized by the progressive accumulation of aberrant molecules and cellular damage. Tissue homeostasis deteriorates due to stem cell exhaustion, chronic inflammation, and metabolic dysfunction, among other causes. In the following chapters, I present evidence of the beneficial roles that sirtuins (SIRT1-7), NAD+-dependent deacetylases, play in alleviating these conditions. Further understanding of the molecular mechanisms associated with these conditions would provide potential targets of therapeutic intervention for the alleviation of debilitating diseases, such as hematopoietic stem cell dysfunction and multiple sclerosis.

In Chapter Two, we uncover the importance of the mitochondrial unfolded protein response (UPRmt) in hematopoietic stem cell maintenance. The UPRmt is a cellular protective program that ensures proteostasis in the mitochondria, and it is known to be regulated by SIRT7. We devised three experimental approaches that enabled us to monitor quiescent and proliferating hematopoietic stem cells (HSCs) and provided direct evidence that the UPRmt is activated upon HSC transition from quiescence to proliferation, and more broadly, mitochondrial integrity is actively monitored at the restriction point to ensure metabolic fitness before stem cells are committed to proliferation.

In Chapter Three, I use a mouse model of progressive multiple sclerosis (MS), a chronic autoimmune disease of the central nervous system (CNS), and single-nuclei RNA seq data from MS patients to demonstrate that SIRT2 deficiency may drive an inflammatory phenotype within progressive MS lesions. More importantly, I show that NAD+ boosting may alleviate MS pathology.

These findings further emphasize the importance of understanding sirtuin biology for the control of homeostasis across multiple systems, such as the hematopoietic and central nervous systems.