Aging-induced structural and functional alterations of the neurovascular unit lead
to impairment of neurovascular coupling responses, dysregulation of cerebral blood
flow, and increased neuroinflammation, all of which contribute importantly to the
pathogenesis of age-related vascular cognitive impairment (VCI). There is increasing
evidence showing that a decrease in NAD(+) availability with age plays a critical
role in age-related neurovascular and cerebromicrovascular dysfunction. Our recent
studies demonstrate that restoring cellular NAD(+) levels in aged mice rescues neurovascular
function, increases cerebral blood flow, and improves performance on cognitive tasks.
To determine the effects of restoring cellular NAD(+) levels on neurovascular gene
expression profiles, 24-month-old C57BL/6 mice were treated with nicotinamide mononucleotide
(NMN), a key NAD(+) intermediate, for 2 weeks. Transcriptome analysis of preparations
enriched for cells of the neurovascular unit was performed by RNA-seq. Neurovascular
gene expression signatures in NMN-treated aged mice were compared with those in untreated
young and aged control mice. We identified 590 genes differentially expressed in the
aged neurovascular unit, 204 of which are restored toward youthful expression levels
by NMN treatment. The transcriptional footprint of NMN treatment indicates that increased
NAD(+) levels promote SIRT1 activation in the neurovascular unit, as demonstrated
by analysis of upstream regulators of differentially expressed genes as well as analysis
of the expression of known SIRT1-dependent genes. Pathway analysis predicts that neurovascular
protective effects of NMN are mediated by the induction of genes involved in mitochondrial
rejuvenation, anti-inflammatory, and anti-apoptotic pathways. In conclusion, the recently
demonstrated protective effects of NMN treatment on neurovascular function can be
attributed to multifaceted sirtuin-mediated anti-aging changes in the neurovascular
transcriptome. Our present findings taken together with the results of recent studies
using mitochondria-targeted interventions suggest that mitochondrial rejuvenation
is a critical mechanism to restore neurovascular health and improve cerebral blood
flow in aging.
