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Cited by 102Nitric Oxide and Endothelin EffectsCardiovascular Health and Disease PreventionGenetics, Aging, and Longevity in Model Organisms

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An Overview of NO Signaling Pathways in Aging

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Pourbagher-Shahri, Ali Mohammad, Farkhondeh, Tahereh, Talebi, Marjan, Kopustinskiene, Dalia M., Samarghandian, Saeed, Bernatoniene, Jurga·2021·Molecules
DOI 10.3390/molecules26154533PMC PMC8348219
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Abstract

Nitric Oxide (NO) is a potent signaling molecule involved in the regulation of various cellular mechanisms and pathways under normal and pathological conditions. NO production, its effects, and its efficacy, are extremely sensitive to aging-related changes in the cells. Herein, we review the mechanisms of NO signaling in the cardiovascular system, central nervous system (CNS), reproduction system, as well as its effects on skin, kidneys, thyroid, muscles, and on the immune system during aging. The aging-related decline in NO levels and bioavailability is also discussed in this review. The decreased NO production by endothelial nitric oxide synthase (eNOS) was revealed in the aged cardiovascular system. In the CNS, the decline of the neuronal (n)NOS production of NO was related to the impairment of memory, sleep, and cognition. NO played an important role in the aging of oocytes and aged-induced erectile dysfunction. Aging downregulated NO signaling pathways in endothelial cells resulting in skin, kidney, thyroid, and muscle disorders. Putative therapeutic agents (natural/synthetic) affecting NO signaling mechanisms in the aging process are discussed in the present study. In summary, all of the studies reviewed demonstrate that NO plays a crucial role in the cellular aging processes.

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Crossref · 10.3390/molecules26154533

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Figures

Figure 1 NO production pathways and NO functions. There are several critical steps in the production of NO that might be O2-dependent or O2-independent. Inhibition of NOS cofactors is important in the aging process. Besides, aging is accompanied by the activation of superoxide. NO: Nitric Oxide; NOS: Nitric Oxide Synthase; NADPH: nicotinamide-adenine-dinucleotide phosphate; FAD: flavin adenine dinucleotide; BH4: (6r-)-tetrahydro-l-biopterin.
Figure 1 NO production pathways and NO functions. There are several critical steps in the production of NO that might be O2-dependent or O2-independent. Inhibition of NOS cofactors is important in the aging process. Besides, aging is accompanied by the activation of superoxide. NO: Nitric Oxide; NOS: Nitric Oxide Synthase; NADPH: nicotinamide-adenine-dinucleotide phosphate; FAD: flavin adenine dinucleotide; BH4: (6r-)-tetrahydro-l-biopterin.CC BY · PubMed Central
Figure 2 Effects of aging on NO pathways involved in the cardiovascular system. NO: Nitric Oxide; iNOS: Inducible Nitric Oxide Synthase; eNOS: Endothelial NOS; GPx-1: Glutathione peroxidase-1; ecSOD: Extracellular superoxide dismutase; SOD: superoxide dismutase.
Figure 2 Effects of aging on NO pathways involved in the cardiovascular system. NO: Nitric Oxide; iNOS: Inducible Nitric Oxide Synthase; eNOS: Endothelial NOS; GPx-1: Glutathione peroxidase-1; ecSOD: Extracellular superoxide dismutase; SOD: superoxide dismutase.CC BY · PubMed Central
Figure 3 Effects of aging on NO pathways involved in CNS functions. NO: Nitric Oxide; NOS: Nitric Oxide Synthase; Aβ: Amyloid-beta; GMP: guanosine monophosphate; cGMP: Cyclic guanosine monophosphate; Pde: phosphodiesterase; CNS: Central Nervous System; NMDA: N-methyl-d-aspartate receptor.
Figure 3 Effects of aging on NO pathways involved in CNS functions. NO: Nitric Oxide; NOS: Nitric Oxide Synthase; Aβ: Amyloid-beta; GMP: guanosine monophosphate; cGMP: Cyclic guanosine monophosphate; Pde: phosphodiesterase; CNS: Central Nervous System; NMDA: N-methyl-d-aspartate receptor.CC BY · PubMed Central
Figure 4 Effects of aging on NO production mechanisms and signaling pathways involved in the development of CNS ischemic injuries. NO: Nitric Oxide; NOS: Nitric Oxide Synthase; BH4: (6r-)-tetrahydro-l-biopterin.
Figure 4 Effects of aging on NO production mechanisms and signaling pathways involved in the development of CNS ischemic injuries. NO: Nitric Oxide; NOS: Nitric Oxide Synthase; BH4: (6r-)-tetrahydro-l-biopterin.CC BY · PubMed Central
Figure 5 Effects of aging on estrogen and NO pathways involved in vasculature functions. NO: Nitric Oxide; NOS: Nitric Oxide Synthase; COX: Cyclooxygenase; TXA2: thromboxane A2.
Figure 5 Effects of aging on estrogen and NO pathways involved in vasculature functions. NO: Nitric Oxide; NOS: Nitric Oxide Synthase; COX: Cyclooxygenase; TXA2: thromboxane A2.CC BY · PubMed Central
Figure 6 Effects of aging on the signaling pathways involved in oocytes aging including NO pathway. NO: Nitric Oxide; NOS: Nitric Oxide Synthase; cGMP: Cyclic guanosine monophosphate; cAMP: Cyclic adenosine monophosphate; MPF: M-phase-promoting factor.
Figure 6 Effects of aging on the signaling pathways involved in oocytes aging including NO pathway. NO: Nitric Oxide; NOS: Nitric Oxide Synthase; cGMP: Cyclic guanosine monophosphate; cAMP: Cyclic adenosine monophosphate; MPF: M-phase-promoting factor.CC BY · PubMed Central
Figure 7 Chemical structures of synthetic therapeutic agents affecting NO signaling. See Table 1 for explanations of (a–m).
Figure 7 Chemical structures of synthetic therapeutic agents affecting NO signaling. See Table 1 for explanations of (a–m).CC BY · PubMed Central
Figure 8 Chemical structures of natural therapeutic agents affecting NO signaling. See Table 2 for explanations of (a′–z′).
Figure 8 Chemical structures of natural therapeutic agents affecting NO signaling. See Table 2 for explanations of (a′–z′).CC BY · PubMed Central

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Research works printed but not linked: 4

  1. Uttenthal, 1998, Neuronal and inducible nitric oxide synthase and nitrotyrosine immunoreactivities in the cerebral cortex of the aging rat, Microsc. Res. Tech., 43, 75, 10.1002/(SICI)1097-0029(19981001)43:1<75::AID-JEMT11>3.0.CO;2-0 · DOI
  2. Billig, 1991, Regulation of oocyte maturation by changes in ovarian levels of cyclic nucleotides, Hum. Reprod., 6, 411
  3. Enna, S.J., and Bylund, D.B. (2007). Phosphodiesterase 5. xPharm: The Comprehensive Pharmacology Reference, Elsevier.
  4. Murphy, 2018, Oral PDE5 inhibitors for erectile dysfunction, U.S. Pharm., 43, 29

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Metadata

Authors
Pourbagher-Shahri, A. M., Farkhondeh, T., Talebi, M., Kopustinskiene, D. M., Samarghandian, S., & Bernatoniene, J.
Affiliations
  • Medical Toxicology and Drug Abuse Research Center (MTDRC), Birjand University of Medical Sciences, Birjand 9717853577, Iran
  • Birjand University of Medical Sciences (IR)
  • Shahid Beheshti University (IR)
  • Institute of Pharmaceutical Technologies, Faculty of Pharmacy, Medical Academy, Lithuanian University of Health Sciences, Sukileliu Pr. 13, LT-50161 Kaunas, Lithuania
  • Neyshabur University of Medical Sciences (IR)
Corresponding author
Samarghandian, Saeed
ORCID
Venue
Molecules
Publisher
MDPI AG
Published
2021-07-27
Volume
26
Issue
15
Pages
4533
ISSN
1420-3049 (ISSN-L)
DOI
10.3390/molecules26154533
PMC
PMC8348219
OpenAlex
W3185759716
Cited by
101
References
307
Citations by year
2026: 12 · 2025: 32 · 2024: 19 · 2023: 19 · 2022: 16 · 2021: 3
FWCI
1.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecules (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Lithuanian University of Health Sciences (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
nitric oxide signaling, aging, endothelial nitric oxide synthase, neuronal nitric oxide synthase, cardiovascular aging, central nervous system aging, reproductive aging, erectile dysfunction, skin aging, kidney aging, muscle aging, immunosenescence, memory and cognition, therapeutic agents
MeSH terms
Aging, Animals, Cardiovascular System, Central Nervous System, Female, Genitalia, Humans, Male, Nitric Oxide, Signal Transduction, Down-Regulation, Cellular Senescence, Nitric Oxide Synthase Type I, Nitric Oxide Synthase Type III

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