Nicotinamide mononucleotide (NMN) supplementation promotes anti-aging miRNA expression profile in the aorta of aged mice, predicting epigenetic rejuvenation and anti-atherogenic effects

Abstract

Understanding molecular mechanisms involved in vascular aging is essential to develop novel interventional strategies for treatment and prevention of age-related vascular pathologies. Recent studies provide critical evidence that vascular aging is characterized by NAD+ depletion. Importantly, in aged mice, restoration of

Nicotinamide mononucleotide (NMN) supplementation promotes neurovascular rejuvenation in aged mice: transcriptional footprint of SIRT1 activation, mitochondrial protection, anti-inflammatory, and anti-apoptotic effects

“…Our bioinformatics analysis also revealed a role for Hif1α signaling, confirming earlier findings (Gomes et al 2013). Further, our recent study demonstrate that NMN treatment reverses age-related changes in miRNA expression in the aged mouse aorta (Kiss et al 2019b). In that regard, it is significant that dysregulation of miRNA expression has been shown to significantly contribute to agerelated phenotypic and functional changes in the cerebromicrovascular endothelial cells as well (Ungvari et al 2013).…”

“…Here, we report that NMN treatment rescues aging-induced changes in mitochondria-related gene expression in the NVU. Importantly, these NMN-induced changes in the mitochondria-related transcriptome are associated with attenuated mitochondrial oxidative stress and restoration of mitochondrial energy metabolism in aging cerebromicrovascular endothelial cells (Tarantini et al 2019a;Kiss et al 2019a). On the basis of previous findings (Gomes et al 2013), we posit that rescue of vascular mitochondrial function by restoring the expression of ETC subunits contributes to the neurovascular protective effects of NMN.…”

“…One group of the aged mice was injected daily with NMN (IP injections of 500 mg NMN/kg body weight per day) or the equivalent volume of PBS for 14 consecutive days at 6 PM and 8 AM on day 14 and were sacrificed 4 h after last injection. Similar dosages of NMN has been shown to exert potent anti-aging effects on mouse health span (Csiszar et al 2019;de Picciotto et al 2016), including rescue of neurovascular coupling responses, attenuation of vascular oxidative stress, and rescue of gene expression changes in the aorta (Tarantini et al 2019a;Kiss et al 2019b). All procedures were approved by the Institutional Animal Use and Care Committees of the University of Oklahoma Health Sciences Center.…”

“…Animals were killed and transcardially perfused with PBS as previously described (Tarantini et al 2019a;Kiss et al 2019b). The brains were quickly removed and rinsed in ice-cold PBS, and minced into ≈ 1 mm 2 pieces.…”

“…Accordingly, restoration of cellular NAD + biosynthesis extends lifespan in model organisms (Anderson et al 2002) and improves health span and extends lifespan in murine models of aging (Zhang, 2016 #10167) (Mitchell et al 2018). There is emerging evidence that vascular aging is also characterized by cellular NAD + depletion (Tarantini et al 2019a;Csiszar et al 2019;Kiss et al 2019a). Importantly, our recent studies showed (Tarantini et al 2019a) that in murine models of aging restoration of cellular NAD + levels by chronic treatment with the NAD + precursor, nicotinamide mononucleotide (NMN) (Yoshino et al 2018) confers potent anti-aging neurovascular effects, rescuing cerebromicrovascular endothelial dysfunction and neurovascular coupling responses, increasing cerebral blood flow, and improving cognitive performance.…”