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Impairment of an endothelial NAD(+)-H2S signaling network is a reversible cause of vascular aging
Open accessAbstract
A decline in capillary density and blood flow with age is a major cause of mortality and morbidity. Understanding why this occurs is key to future gains in human health. NAD precursors reverse aspects of aging, in part, by activating sirtuin deacylases (SIRT1-SIRT7) that mediate the benefits of exercise and dietary restriction (DR). We show that SIRT1 in endothelial cells is a key mediator of pro-angiogenic signals secreted from myocytes. Treatment of mice with the NAD+ booster nicotinamide mononucleotide (NMN) improves blood flow and increases endurance in elderly mice by promoting SIRT1-dependent increases in capillary density, an effect augmented by exercise or increasing the levels of hydrogen sulfide (H 2 S), a DR mimetic and regulator of endothelial NAD+ levels. These findings have implications for improving blood flow to organs and tissues, increasing human performance, and reestablishing a virtuous cycle of mobility in the elderly.
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“NADP boosters (nicotinamide mononucleotide,158 nicotinamide riboside,159 P7C3,160 apigenin161) can be used resolve the NAD depletion issue and are able to prevent senescence in ECs158 and VSMCs.159”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [158]
In the citing paper
“NMN supplementation also increased the number of endothelial cells and improved endothelial cell function by increasing blood flow and endurance in elderly mice by a SIRT1-dependent mechanism210.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [210]
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“It was reported that premature endothelium senescence reversibly triggers vascular ageing and the age-associated decrease in exercise endurance in old mice [42].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [42]
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SIRT1 Antagonizes Oxidative Stress in Diabetic Vascular Complication
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“H2S is also able to activate SIRT1 indirectly by increasing intracellular NAD levels (97).”
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“Regular exercise improves aerobic capacity, cardiovascular health, metabolic health, and physical function [15, 16], but many of such improvements may be NAD/sirtuins-related [17, 18].”
BackgroundInfluentialEmerging Chemical Biology of Protein Persulfidation
Vignane, T., & Filipović, M. R. (2023) · Antioxidants and Redox Signaling · doi:10.1089/ars.2023.0352 · Cited by 100
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Role of endothelial NAD+deficiency in age-related vascular dysfunction
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“277 Anti-aging effects of treatment with NAD boosters 278 Cellular NAD levels can be increased by up-regulating the enzymes involved in NAD 279 biosynthesis, by inhibition of NAD consumers(76), or by treatment with NAD precursors(26), 280 including niacin, nicotinamide mononucleotide (NMN)(48, 107, 159), nicotinamide…”
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Macroautophagy and aging: The impact of cellular recycling on health and longevity
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The systemic role of SIRT1 in exercise mediated adaptation
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Sirtuin 2 deficiency aggravates ageing-induced vascular remodelling in humans and mice
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Apoptosis releases hydrogen sulfide to inhibit Th17 cell differentiation
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Antiaging effects of bioactive molecules isolated from plants and fungi
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“Another study show that NMN increases physical endurance in old mice by activating SIRT1 in endothelial cells.(277) The effects of NMN are associated with increased muscle angiogenesis.”
BackgroundUrolithin A augments angiogenic pathways in skeletal muscle by bolstering NAD+ and SIRT1
Ghosh, N., Das, A., Biswas, N., Gnyawali, S. C., Singh, K., Gorain, M., Polcyn, C., Khanna, S., Roy, S., & Sen, C. K. (2020) · Scientific Reports · doi:10.1038/s41598-020-76564-7 · Cited by 78
Self-citationNRH salvage and conversion to NAD+ requires NRH kinase activity by adenosine kinase
Yang, Y. J., Zhang, N., Zhang, G., & Sauve, A. A. (2020) · Nature Metabolism · doi:10.1038/s42255-020-0194-9 · Cited by 76
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Targeting senescent cells to attenuate cardiovascular disease progression
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“EC premature senescence due to sirtuin deacetylase 1 (Sirt1) inhibition (Ota et al., 2007; Zu et al., 2010) may reversibly lead to vascular ageing and age-related decrease in exercise endurance (Das et al., 2018).”
BackgroundEndothelial cell metabolism in cardiovascular physiology and disease
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“At the microvascular level, substantial evidence indicates that sirtuins, which are enzymes that use NAD + as a cofactor in deacetylation reactions, are important to preserving (coronary) microvascular functions, angiogenesis and capillary homeostasis 20,28,31,32,85 .”
InfluentialThe Role of Protein Persulfidation in Brain Aging and Neurodegeneration
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“The senescence of HUVEC cells (induced by oxidative stress or SIRT1 inhibition) was delayed upon H2S treatment by activating the SIRT1 protein (Das et al., 2018; Longchamp et al., 2018).”
BackgroundNAD+ Homeostasis and NAD+-Consuming Enzymes: Implications for Vascular Health
Campagna, R., & Vignini, A. (2023) · Antioxidants · doi:10.3390/antiox12020376 · Cited by 76
“Interestingly, in vivo NMN administration to mice, alone and in combination with exogenous hydrogen sulfide, was also proved to enhance skeletal muscle blood flow by decreasing the age-associated diminution in capillary density through the activation of vascular endothelial growth factor signaling in a SIRT1-dependent…”
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“Disruption of this balance by excessive ROS can deplete NAD + levels, and compromise vasculoprotective metabolites 28 .”
Exercise protects aged mice against coronary endothelial senescence via FUNDC1-dependent mitophagy
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Vascular Aging: Assessment and Intervention
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Metabolic regulation of exercise-induced angiogenesis
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Nitric Oxide and Hydrogen Sulfide Regulation of Ischemic Vascular Growth and Remodeling
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Roles of Sirtuins in Cardiovascular Diseases: Mechanisms and Therapeutics
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NAD+ in COVID-19 and viral infections
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“Several preclinical studies demonstrate that raising NAD concentrations in endothelial cells reverses vascular and endothelial dysfunction [8,31].”
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Metadata
- Authors
- Das, A., Huang, G. X., Bonkowski, M. S., Longchamp, A., Li, C., Schultz, M. B., Kim, L.-J., Osborne, B., Joshi, S., Lu, Y., Treviño-Villarreal, J. H., Kang, M.-J., Hung, T.-T., Lee, B., Williams, E. O., Igarashi, M., Mitchell, J. R., Wu, L. E., Turner, N., Arany, Z., Guarente, L., & Sinclair, D. A.
- Affiliations
- Harvard University (US)
- UNSW Sydney (AU)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Guarente, Leonard
- Sinclair, David A.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 173
- Issue
- 1
- Pages
- 74-89.e20
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5884172
- OpenAlex
- W2791288341
- Cited by
- 496
- References
- 87
- Citations by year
- 2026: 41 · 2025: 72 · 2024: 55 · 2023: 65 · 2022: 50 · 2021: 84 · 2020: 64 · 2019: 37 · 2018: 28
- FWCI
- 36.61
- Type
- journal article
- Language
- en
- Update notices
- erratum (2019-02-07)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- Funders
- Glenn Foundation for Medical Research (RO1 AG028730, RO1 DK100263)
- Sinclair Gift Fund
- Edward Schulak (APP1093643)
- NIH/NIA (RO1 AG015339)
- NIH/NHLBI (RO1 HL094499)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Keywords
- endothelial cells, NAD+, hydrogen sulfide, vascular aging, blood flow
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Aging, Animals, Humans, Hydrogen Sulfide, Mitochondria, NAD, Physical Conditioning, Animal, Signal Transduction, Mice, Knockout, Muscle, Skeletal, Neovascularization, Physiologic, RNA Interference, RNA, Small Interfering, Vascular Endothelial Growth Factor A, Endothelial Cells, Mice, Receptors, Notch, Microvessels, Sirtuin 1
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