Study summary · research use only
NAD(+) rescues aging-induced blood-brain barrier damage via the CX43-PARP1 axis
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This study in aging mice, with confirmatory analysis in human brain samples, examined how blood-brain barrier (BBB) function declines with aging. Using single-nucleus transcriptomics, the authors found decreased connexin 43 (CX43) expression in Cdh5+ cerebral vascular cells in naturally aging mice, and confirmed this in human brain tissue. Global or Cdh5+ cell-specific CX43 deletion in mice worsened BBB dysfunction during aging, an effect linked to reduced NAD+ levels and mitochondrial dysfunction via NAD+-dependent sirtuin 3 (SIRT3), and CX43 was found to interact with and negatively regulate PARP1. Pharmacologic inhibition of PARP1 with olaparib, or supplementation with nicotinamide mononucleotide (NMN), restored NAD+ levels and reduced aging-associated BBB leakage in mice. The authors describe this as identifying the endothelial CX43-PARP1-NAD+ pathway's role in vascular aging.
Abstract
Blood-brain barrier (BBB) function deteriorates during aging, contributing to cognitive impairment and neurodegeneration. It is unclear what drives BBB leakage in aging and how it can be prevented. Using single-nucleus transcriptomics, we identified decreased connexin 43 (CX43) expression in cadherin-5+ (Cdh5+) cerebral vascular cells in naturally aging mice and confirmed it in human brain samples. Global or Cdh5+ cell-specific CX43 deletion in mice exacerbated BBB dysfunction during aging. The CX43-dependent effect was not due to its canonical gap junction function but was associated with reduced NAD+ levels and mitochondrial dysfunction through NAD+-dependent sirtuin 3 (SIRT3). CX43 interacts with and negatively regulates poly(ADP-ribose) polymerase 1 (PARP1). Pharmacologic inhibition of PARP1 by olaparib or nicotinamide mononucleotide (NMN) supplementation rescued NAD+ levels and alleviated aging-associated BBB leakage. These findings establish the endothelial CX43-PARP1-NAD+ pathway's role in vascular aging and identify a potential therapeutic strategy to combat aging-associated BBB leakage with neuroprotective implications.
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