NAD+ depletion drives impaired endothelial cell proliferation and age-related vascular decline
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1128028 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR29546216.fastq.gz | Fastqsanger.gz | |||
| SRR29546217.fastq.gz | Fastqsanger.gz | |||
| SRR29546218.fastq.gz | Fastqsanger.gz | |||
| SRR29546219.fastq.gz | Fastqsanger.gz | |||
| SRR29546220.fastq.gz | Fastqsanger.gz |
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Project description:NAD is a ubiquitous electron carrier essential for energy metabolism and the post-translational modification of numerous regulatory proteins. Perturbation of NAD metabolism is considered detrimental to health, with NAD depletion commonly thought to promote aging. However, to what extent normal NAD concentration can be decreased without deleterious repercussions is unclear. Here, we describe a mouse model where NAMPT-mediated NAD+ biosynthesis is disrupted in adult skeletal muscle. The resulting 85% decrease in muscle NAD+ abundance did not cause tissue degeneration or dysfunction, as reflected in its unchanged morphology, contractility, and exercise tolerance. The lack of defects was corroborated by intact mitochondrial respiratory capacity and unaffected muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings demonstrate that NAD depletion does not drive the age-related decline in skeletal muscle function.
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Project description:NAD is a ubiquitous electron carrier essential for energy metabolism and the post-translational modification of numerous regulatory proteins. Perturbation of NAD metabolism is considered detrimental to health, with NAD depletion commonly thought to promote aging. However, the extent to which cellular NAD concentration can be decreased without deleterious repercussions is unclear. We generated a mouse model where nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthesis is disrupted in adult skeletal muscle. The resulting 85% decrease in muscle NAD+ abundance was associated with preserved tissue integrity and functionality, as demonstrated by its unchanged morphology, contractility, and exercise tolerance. This lack of defects was corroborated by intact mitochondrial respiratory capacity and unaffected muscle transcriptomic and proteomic profiles. Furthermore, lifelong NAD depletion did not accelerate muscle aging or impair whole-body metabolism. Collectively, these findings indicate that NAD depletion does not contribute to age-related decline in skeletal muscle function.
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Project description:The decline of endothelial autophagy is closely related to vascular senescence and disease, although the molecular mechanisms connecting these outcomes in vascular endothelial cells (VECs) remain unclear. Here, we identify a crucial role for CD44, a multifunctional adhesion molecule, in controlling autophagy and aging in VECs. The CD44 intercellular domain (CD44ICD) negatively regulates autophagy by reducing PIK3R4 and PIK3C3 levels and disrupting STAT3-dependent PtdIns3K complexes. CD44 and its homologue clec-31 are increased in aging vascular endothelium and Caenorhabditis elegans, respectively, suggesting that an age-dependent increase in CD44 induces autophagy decline and aging phenotypes. Accordingly, CD44 knockdown ameliorates age-associated phenotypes in VECs. The endothelium-specific CD44ICD knock-in mouse is shorter-lived, with VECs exhibiting obvious premature aging characteristics associated with decreased basal autophagy. Autophagy activation suppresses the premature aging of human and mouse VECs overexpressing CD44ICD, function conserved in the CD44 homologue clec-31 in C. elegans. Our work describes a mechanism coordinated by CD44 function bridging autophagy decline and aging.
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Project description:NAD+ availability decreases with age and in certain disease conditions. Nicotinamide mononucleotide (NMN), a key NAD+ intermediate, has been shown to enhance NAD+ biosynthesis and ameliorate various pathologies in mouse disease models. In this study, we conducted a 12 month-long NMN administration to regular chow-fed wild-type C57BL/6N mice during their normal aging. Orally administered NMN was quickly utilized to synthesize NAD+ in tissues. Remarkably, NMN effectively mitigates age-associated physiological decline in mice. Without any obvious toxicity or deleterious effects, NMN suppressed age-associated body weight gain, enhanced energy metabolism, promoted physical activity, improved insulin sensitivity and plasma lipid profile, and ameliorated eye function and other pathophysiologies. Consistent with these phenotypes, NMN prevented age-associated gene expression changes in key metabolic organs and enhanced mitochondrial oxidative metabolism and mitonuclear protein imbalance in skeletal muscle. These effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective anti-aging interventions in humans.
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Project description:NAD is an obligate co-factor for the catabolism of metabolic fuels in all cell types. However, the availability of NAD in several tissues can become limited during genotoxic stress and the course of natural aging. The point at which NAD restriction imposes functional limitations on tissue physiology remains unknown. We examined this question in murine skeletal muscle by specifically depleting Nampt, an essential enzyme in the NAD salvage pathway. Knockout mice exhibited a dramatic 85% decline in intramuscular NAD content, accompanied by fiber degeneration and progressive loss of both muscle strength and treadmill endurance. Administration of the NAD precursor nicotinamide riboside rapidly ameliorated functional deficits and restored muscle mass, despite having only a modest effect on the intramuscular NAD pool. Additionally, lifelong overexpression of Nampt preserved muscle NAD levels and exercise capacity in aged mice, supporting a critical role for tissue-autonomous NAD homeostasis in maintaining muscle mass and function. Messenger RNA was isolated from quadriceps muscle of mice from three different age groups and three different genotypes. Wildtype mice were aged 4, 7, and 24 months. Mice deficient for Nampt in skeletal muscle (mNKO) were aged 7 months. Mice overexpressing Nampt in skeletal muscle were aged 4 and 24 months.
2016-07-22 | E-GEOD-74570 | biostudies-arrayexpress
Project description:Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite that is reported to decline in concentration in tissues of aged animals. Strategies to increase NAD+ availability have shown promise in treating many conditions in rodents, including age-related degeneration, which has in turn driven intense interest in the effects of supplements on human health. However, many aspects of NAD+ metabolism remain poorly understood, and human data are limited. Here, we discuss the state of the evidence for an age-related decline in NAD+, along with potential mechanistic explanations, including increased consumption or decreased synthesis of NAD+ and changes in the composition of cells or tissues with age. Key challenges for the field involve the development of better tools to resolve information on the NAD+ content of specific cells and subcellular compartments as well as determining the threshold levels at which NAD+ depletion triggers physiological consequences in different tissues. Understanding how NAD+ metabolism changes with age in humans may ultimately allow the design of more targeted strategies to maintain its availability, such as inhibition of key consumers in specific tissues or direct delivery of precursors to sites of deficiency. In the meantime, human clinical trials with oral supplements are poised to provide some of the first direct evidence as to whether increasing NAD+ availability can impact human physiology. Thus, it is an exciting time for NAD+ research, with much remaining to be learned in terms of both basic biology and potential therapeutic applications.
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