Aging of the Nitric Oxide System: Are We as Old as Our NO?
Open accessAbstract
BACKGROUND: Impaired generation and signaling of nitric oxide (NO) contribute substantially to cardiovascular (CV) risk (CVR) associated with hypertension, hyperlipidemia, and diabetes mellitus. In our rapidly aging society, advanced age is, in itself, a consistent and independent CVR factor. Many processes involved in aging are modulated by NO. We therefore postulated that aging might be independently associated with impaired NO signaling. METHODS AND RESULTS: In a prospective cohort study of 204 subjects (mean age 63±6 at study entry), we evaluated the effects of 4 years of aging on parameters of NO generation and effect, including platelet aggregability and responsiveness to NO, and plasma concentrations of the NO synthase inhibitor, asymmetric dimethylarginine (ADMA). Clinical history, lipid profile, high-sensitivity C-reactive protein, routine biochemistry, and 25-hydroxyvitamin D levels were obtained at study entry and after 4 years of follow-up. Aging was associated with marked deterioration of responsiveness of platelets to NO (P<0.0001) and increases in plasma ADMA concentrations (P<0.0001). There was a significant correlation between changes in these parameters over time (r=0.2; P=0.013). On multivariable analyses, the independent correlates of deterioration of responsiveness of platelets to NO were female gender (β=0.17; P=0.034) and low vitamin D concentrations (β=0.16; P=0.04), whereas increases in ADMA were associated with presence of diabetes (β=0.16; P=0.03) and impaired renal function (β=0.2; P=0.004). CONCLUSIONS: Aging is associated with marked impairment of determinants of NO generation and effect, to an extent which is commensurate with adverse impact on CV outcomes. This deterioration represents a potential target for therapeutic interventions.
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Reduced eNOS activity and L-arginine availability, coupled with increased levels of ADMA, lead to impaired NO production and endothelial dysfunction.
“Reduced eNOS activity and availability of L-arginine, coupled with increased levels of endogenous inhibitors such as asymmetric dimethylarginine (ADMA), lead to impaired NO production and endothelial dysfunction [57].”
From Dietary Nitrate-Rich Vegetables as Natural Modulators of Health: Mechanisms and Benefits in Ageing Populations (2026) · cites this paper as [57]
The Discussion (Figure 6; page not supplied) says ADMA can inhibit and uncouple eNOS, reducing NO production and availability. The Results also describe rising ADMA as consistent with deteriorating endothelial function. Our copy does not establish reduced L-arginine availability as part of this pathway, and presents the ADMA mechanism as a potential pathway rather than a demonstrated cause in this cohort. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAgeing is related to decline in nitric oxide production and skeletal muscle blood flow.
“Ageing has also been related to a decline in nitric oxide (NO) production76 and skeletal muscle blood flow77.”
From Sarcopenic obesity in older adults: a clinical overview (2024) · cites this paper as [76]
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“Reduced eNOS activity and availability of L-arginine, coupled with increased levels of endogenous inhibitors such as asymmetric dimethylarginine (ADMA), lead to impaired NO production and endothelial dysfunction [57].”
- Authors
- Sverdlov, A. L., Ngo, D. T. M., Chan, W. P. A., Chirkov, Y. Y., & Horowitz, J. D.
- Affiliations
- Queen Elizabeth Hospital (AU)
- Venue
- Journal of the American Heart Association
- Published
- 2014-08-15
- Volume
- 3
- Issue
- 4
- ISSN
- 2047-9980 (ISSN-L)
- PMC
- PMC4310385
- OpenAlex
- W2162507201
- Cited by
- 97
- References
- 57
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 8 · 2023: 11 · 2022: 6 · 2021: 12 · 2020: 13 · 2019: 11 · 2018: 5 · 2017: 6 · 2016: 6 · 2015: 2 · 2014: 1
- FWCI
- 3.32
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Journal of the American Heart Association (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- aging, nitric oxide, nitric oxide signaling, platelet aggregation, asymmetric dimethylarginine, nitric oxide synthase, cardiovascular risk, vitamin D, diabetes mellitus, renal function, sex differences
- MeSH terms
- Aged, Aging, Arginine, Blood Platelets, Cardiovascular Diseases, Female, Follow-Up Studies, Humans, Male, Middle Aged, Nitric Oxide, Platelet Aggregation, Prospective Studies, Cohort Studies
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