madman
Super Moderator
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.
1. Introduction
Nitric oxide (NO) is one of the main signaling molecules in the body that shows its principal performance in an unconventional manner. NO exerts its effects on several molecular targets and can regulate various functions such as neurotransmission, vascular tone, transcription of genes, translation of mRNA, and protein post-translational modifications [1]. NO can react with superoxide anion (O2 −), resulting in the formation of potent oxidant peroxynitrite (ONOO−), and subsequently interacting with biomolecules such as proteins, lipids, and DNA via direct oxidation reactions or indirect radical-mediated mechanisms [2–6]. ONOO− is responsible for many pathological processes in mammalian organelles including cytotoxicity induction, oxidation, protein modifications, lipids peroxidation, DNA damage, cell death, mitochondrial disruption, dysregulation of signal transduction, and apoptosis [7]. Besides, various methods are available for the synthesis of ONOO−. ONOO−, as a highly reactive molecule, can result in the generation of oxidizing and nitrating species [6]. ONOO− and its decomposition yields containing NO2, CO−, and OH can impair several reactions comprising the tyrosine nitration of proteins, the inactivation of superoxide dismutase (SOD), and tissue damage [8]. ONOO− induced nitrosative stress has the capacity to induce the appearance of breaks in single-strand DNA, which subsequently activates the poly-ADP-ribose polymerase (PARP) [9]. NO is produced in mammals by three distinct forms of NO synthase (NOS), coded by three distinct genes: neuronal ‘n’NOS (or NOS-I), inducible ‘i’NOS (or NOS-II), and endothelial ‘e’NOS (or NOS-III). All NOS proteins are homodimers [10–12]. Furthermore, in mammals, NO can also be formed, resulting in NOS-independent pathways, explicitly by consecutive reduction of nitrate (NO3 −) and nitrite (NO2 −). NO2 − has the capability to be univalently reduced to NO through the transition of metal-comprising enzymes, e.g., deoxymyoglobin/deoxyhemoglobin (deoxyHb/deoxyMb), and xanthine oxidase (XO) at the time in which the partial pressure of oxygen (pO2) levels is low. The aforementioned NOS-independent gates for NO production represent the NO3 −/NO2 −/NO pathway or O2-independent formation of NO [13]. NO signaling, NO donors, and NOS inhibitors are very important in the pathophysiology of age-related diseases and their associated putative therapeutic approaches. In this study, we review the role of NO in the aging processes of cells.
2. Mechanisms of NOS
2.1. nNOS
2.2. iNOS
2.3. eNOS
3. Aging and NO Signaling
3.1. Cardiovascular Aging and NO
3.2. CNS Aging and NO
3.3. Reproduction System Aging and NO
3.4. Skin Aging and NO
3.5. Renal Aging and NO
3.6. Thyroid Aging and NO
3.7. Erectile Dysfunction, Aging, and NO
The decrease of smooth muscle cells (SMCs) and collagen in the corpus cavernosum (CC) greatly contribute to erectile dysfunction (ED) during aging. One of the occurring phenomena during the aging process is tissue remodeling in the CC. The aforementioned tissue remodeling feasibly occurs by reason of phenotypic cellular alteration from SMCs to fibroblasts that latterly would cause an elevation in the content of collagen deposit [212]. According to anatomical localization, the corpora cavernosa are paired spongy cylinders that lay on the superior facet of the penis [213]. The accumulation of collagen is thought to be affected by ROS. The NO production by iNOS has been shown to suppress the ROS and thus decrease collagen accumulation [212]. To clearly describe the relationship between ROS formation and collagen accumulation, this process was described in Peyronie’s disease, which is accompanied by fibrosis and is characterized by an augmentation in collagen over the intracellular part. Fibrosis is related to the formation of profibrotic factors, including plasminogen activator inhibitor-1, transforming growth factor-beta (TGF-β), and ROS throughout oxidative stress. This is accompanied by the stimulation of the iNOS, which plays a crucial part as an endogenous antifibrotic pathway in the case of exposure with profibrotic manners [214]. Inside the arterial media SMC, Ferrini et al. (2004) explored the possibility of related mechanisms that exist within aging and that share specific common physiological roles with the cavernosal SMC [215]. Male, brown Norwegian rats aged (22–24 months) were treated with an iNOS action inhibitor. Inhibition of iNOS activity was induced by L-N-(iminoethyl)-lysine acetate. Resistance arteries of the penis showed an increased SMC apoptosis, increased collagen amounts, and elevated ROS and iNOS levels. Administration of an iNOS action inhibitor worsened the SMC/collagen ratio and increased ROS levels. A prevalent etiology can be explained in the hypotheses of ED and arteriosclerosis in aging males, namely that the SMC’s production of iNOS is an effort to combat this fibrosis [215].
Ferrini et al. (2001) showed that, as aging advances, iNOS and peroxynitrite increases in the penis of old rats. According to the overproduction of NO by reason of the induction of iNOS, the apoptotic cell fate and aging were increased, but in order to elucidate this probable interaction, more studies should be conducted in the future. These changes were suggested to contribute to the increased apoptosis and proteolysis and higher collagen deposition as a result of iNOS and peroxynitrite induction in the old penises [216].
Garbán et al. (1995) analyzed adult, old, and senescent rats to determine whether aging can decrease the erectile response and possible correspondence with lower levels of NOS in the penis [217]. Aging-induced erectile dysfunction was independent of penile NOS deficiency but can be worsened by decreased NOS in very old rats. Old and senescent rats showed lower maximum intracavernosal pressure (MIP) in the Cavernosal nerve electric field stimulation (EFS) compared to adult rats. Old and senescent rats showed more decline in MIP in response to NOS inhibition compared with adult rats. Moreover, when NOS was not inhibited, old and senescent rats had a lower erectile response to intracavernosal papaverine (PDE inhibitor) or nitroglycerin (NO donor) compared to adult rats [217].
Haas et al. (1998) studied the aging-associated erectile dysfunctions, including endothelial dysfunction of cavernosum, upregulation of eNOS, and aberrant intracellular calcium flux in aged rabbits. It was found that relaxation of corporal tissue was significantly mitigated during the treatment of acetylcholine (ACh), an endothelium-dependent vasodilator. No difference was observed in corporal tissue relaxation due to the treatment of animals with an NO donor sodium, nitroprusside. The calcium ionophore increased the reduced vasorelaxation in the aged rabbits’ cavernosum and had no effect on the young rabbits’ cavernosum. These findings proposed that erectile dysfunction in the aging rabbit cavernosum was probably related to endothelial dysfunction and was characterized by eNOS upregulation and aberrant intracellular calcium fluxes. It was proposed that the defect in the ACh-NO pathway during the aging process was attributed to the level of NO synthesis, not its activity [218].
3.8. Muscle Aging and NO
3.9. Sleep Problems, Aging and NO
4. Interventional Modalities in NO Pathway during Aging
4.1. Recombinant Adenovirus
4.2. NMDA Agonists and Inflammatory Stimuli
4.3. Intermittent Fasting
5. Therapeutic Agents Affecting NO Signaling Pathway in Aging
5.1. Synthetic Agents
5.1.1. PDE3 Inhibitors
5.1.2. PDE4 Inhibitors
5.1.3. PDE5 Inhibitors
5.1.4. Hydroxymethylglutaryl-Coenzyme A (HMG-CoA) Reductase Inhibitors, “Statins”
5.1.5. β-Blockers
5.1.6. 5-Hydroxytryptamine Subtype 3 (5-HT3) Receptor Antagonists
5.1.7. PPAR-γ Agonist
5.1.8. eNOS Cofactors
5.2. Natural Agents
5.2.1. Polyphenols
5.2.2. Curcuminoids
5.2.3. Chalcone Derivatives
5.2.4. Sphingolipids
5.2.5. Phytocannabinoids
5.2.6. Pyranocoumarins
5.2.7. Ginsenosides
5.2.8. Triterpenoid Saponins
5.2.9. Monoterpenes
5.2.10. Carotenoids
5.2.11. Alkaloids
5.2.12. Miscellaneous
5.2.13. Probiotics
5.2.14. Amino-Acids
6. Conclusions
NO production and hemostasis play the main role in human health and disease. Furthermore, the physiological and pathophysiological effects of this molecule are very important in the regulation of aging processes. However, the complex activity of NO is related to several factors including cell type, NO production, and bioavailability, as well as the type of enzymatic synthase and its reaction with target proteins. NO modulates various cellular processes during aging, inflammation, and age-related diseases, including cardiovascular, neurological, reproductive, skin, renal, thyroid, muscle, and sleep disorders. Several chemical and natural agents can increase NO bioavailability by enhancing both eNOS and nNOS expression, inhibiting iNOS, and increasing the protein-protein interaction of eNOS with sirtuin-1, leading to amelioration of aging-related diseases. However, due to the complex activity of NO in the pathogenic processes of diseases, several targets of NO should be considered, rather than a single target, to be able to identify the growing network of NO signaling processes in the body.
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.
1. Introduction
Nitric oxide (NO) is one of the main signaling molecules in the body that shows its principal performance in an unconventional manner. NO exerts its effects on several molecular targets and can regulate various functions such as neurotransmission, vascular tone, transcription of genes, translation of mRNA, and protein post-translational modifications [1]. NO can react with superoxide anion (O2 −), resulting in the formation of potent oxidant peroxynitrite (ONOO−), and subsequently interacting with biomolecules such as proteins, lipids, and DNA via direct oxidation reactions or indirect radical-mediated mechanisms [2–6]. ONOO− is responsible for many pathological processes in mammalian organelles including cytotoxicity induction, oxidation, protein modifications, lipids peroxidation, DNA damage, cell death, mitochondrial disruption, dysregulation of signal transduction, and apoptosis [7]. Besides, various methods are available for the synthesis of ONOO−. ONOO−, as a highly reactive molecule, can result in the generation of oxidizing and nitrating species [6]. ONOO− and its decomposition yields containing NO2, CO−, and OH can impair several reactions comprising the tyrosine nitration of proteins, the inactivation of superoxide dismutase (SOD), and tissue damage [8]. ONOO− induced nitrosative stress has the capacity to induce the appearance of breaks in single-strand DNA, which subsequently activates the poly-ADP-ribose polymerase (PARP) [9]. NO is produced in mammals by three distinct forms of NO synthase (NOS), coded by three distinct genes: neuronal ‘n’NOS (or NOS-I), inducible ‘i’NOS (or NOS-II), and endothelial ‘e’NOS (or NOS-III). All NOS proteins are homodimers [10–12]. Furthermore, in mammals, NO can also be formed, resulting in NOS-independent pathways, explicitly by consecutive reduction of nitrate (NO3 −) and nitrite (NO2 −). NO2 − has the capability to be univalently reduced to NO through the transition of metal-comprising enzymes, e.g., deoxymyoglobin/deoxyhemoglobin (deoxyHb/deoxyMb), and xanthine oxidase (XO) at the time in which the partial pressure of oxygen (pO2) levels is low. The aforementioned NOS-independent gates for NO production represent the NO3 −/NO2 −/NO pathway or O2-independent formation of NO [13]. NO signaling, NO donors, and NOS inhibitors are very important in the pathophysiology of age-related diseases and their associated putative therapeutic approaches. In this study, we review the role of NO in the aging processes of cells.
2. Mechanisms of NOS
2.1. nNOS
2.2. iNOS
2.3. eNOS
3. Aging and NO Signaling
3.1. Cardiovascular Aging and NO
3.2. CNS Aging and NO
3.3. Reproduction System Aging and NO
3.4. Skin Aging and NO
3.5. Renal Aging and NO
3.6. Thyroid Aging and NO
3.7. Erectile Dysfunction, Aging, and NO
The decrease of smooth muscle cells (SMCs) and collagen in the corpus cavernosum (CC) greatly contribute to erectile dysfunction (ED) during aging. One of the occurring phenomena during the aging process is tissue remodeling in the CC. The aforementioned tissue remodeling feasibly occurs by reason of phenotypic cellular alteration from SMCs to fibroblasts that latterly would cause an elevation in the content of collagen deposit [212]. According to anatomical localization, the corpora cavernosa are paired spongy cylinders that lay on the superior facet of the penis [213]. The accumulation of collagen is thought to be affected by ROS. The NO production by iNOS has been shown to suppress the ROS and thus decrease collagen accumulation [212]. To clearly describe the relationship between ROS formation and collagen accumulation, this process was described in Peyronie’s disease, which is accompanied by fibrosis and is characterized by an augmentation in collagen over the intracellular part. Fibrosis is related to the formation of profibrotic factors, including plasminogen activator inhibitor-1, transforming growth factor-beta (TGF-β), and ROS throughout oxidative stress. This is accompanied by the stimulation of the iNOS, which plays a crucial part as an endogenous antifibrotic pathway in the case of exposure with profibrotic manners [214]. Inside the arterial media SMC, Ferrini et al. (2004) explored the possibility of related mechanisms that exist within aging and that share specific common physiological roles with the cavernosal SMC [215]. Male, brown Norwegian rats aged (22–24 months) were treated with an iNOS action inhibitor. Inhibition of iNOS activity was induced by L-N-(iminoethyl)-lysine acetate. Resistance arteries of the penis showed an increased SMC apoptosis, increased collagen amounts, and elevated ROS and iNOS levels. Administration of an iNOS action inhibitor worsened the SMC/collagen ratio and increased ROS levels. A prevalent etiology can be explained in the hypotheses of ED and arteriosclerosis in aging males, namely that the SMC’s production of iNOS is an effort to combat this fibrosis [215].
Ferrini et al. (2001) showed that, as aging advances, iNOS and peroxynitrite increases in the penis of old rats. According to the overproduction of NO by reason of the induction of iNOS, the apoptotic cell fate and aging were increased, but in order to elucidate this probable interaction, more studies should be conducted in the future. These changes were suggested to contribute to the increased apoptosis and proteolysis and higher collagen deposition as a result of iNOS and peroxynitrite induction in the old penises [216].
Garbán et al. (1995) analyzed adult, old, and senescent rats to determine whether aging can decrease the erectile response and possible correspondence with lower levels of NOS in the penis [217]. Aging-induced erectile dysfunction was independent of penile NOS deficiency but can be worsened by decreased NOS in very old rats. Old and senescent rats showed lower maximum intracavernosal pressure (MIP) in the Cavernosal nerve electric field stimulation (EFS) compared to adult rats. Old and senescent rats showed more decline in MIP in response to NOS inhibition compared with adult rats. Moreover, when NOS was not inhibited, old and senescent rats had a lower erectile response to intracavernosal papaverine (PDE inhibitor) or nitroglycerin (NO donor) compared to adult rats [217].
Haas et al. (1998) studied the aging-associated erectile dysfunctions, including endothelial dysfunction of cavernosum, upregulation of eNOS, and aberrant intracellular calcium flux in aged rabbits. It was found that relaxation of corporal tissue was significantly mitigated during the treatment of acetylcholine (ACh), an endothelium-dependent vasodilator. No difference was observed in corporal tissue relaxation due to the treatment of animals with an NO donor sodium, nitroprusside. The calcium ionophore increased the reduced vasorelaxation in the aged rabbits’ cavernosum and had no effect on the young rabbits’ cavernosum. These findings proposed that erectile dysfunction in the aging rabbit cavernosum was probably related to endothelial dysfunction and was characterized by eNOS upregulation and aberrant intracellular calcium fluxes. It was proposed that the defect in the ACh-NO pathway during the aging process was attributed to the level of NO synthesis, not its activity [218].
3.8. Muscle Aging and NO
3.9. Sleep Problems, Aging and NO
4. Interventional Modalities in NO Pathway during Aging
4.1. Recombinant Adenovirus
4.2. NMDA Agonists and Inflammatory Stimuli
4.3. Intermittent Fasting
5. Therapeutic Agents Affecting NO Signaling Pathway in Aging
5.1. Synthetic Agents
5.1.1. PDE3 Inhibitors
5.1.2. PDE4 Inhibitors
5.1.3. PDE5 Inhibitors
5.1.4. Hydroxymethylglutaryl-Coenzyme A (HMG-CoA) Reductase Inhibitors, “Statins”
5.1.5. β-Blockers
5.1.6. 5-Hydroxytryptamine Subtype 3 (5-HT3) Receptor Antagonists
5.1.7. PPAR-γ Agonist
5.1.8. eNOS Cofactors
5.2. Natural Agents
5.2.1. Polyphenols
5.2.2. Curcuminoids
5.2.3. Chalcone Derivatives
5.2.4. Sphingolipids
5.2.5. Phytocannabinoids
5.2.6. Pyranocoumarins
5.2.7. Ginsenosides
5.2.8. Triterpenoid Saponins
5.2.9. Monoterpenes
5.2.10. Carotenoids
5.2.11. Alkaloids
5.2.12. Miscellaneous
5.2.13. Probiotics
5.2.14. Amino-Acids
6. Conclusions
NO production and hemostasis play the main role in human health and disease. Furthermore, the physiological and pathophysiological effects of this molecule are very important in the regulation of aging processes. However, the complex activity of NO is related to several factors including cell type, NO production, and bioavailability, as well as the type of enzymatic synthase and its reaction with target proteins. NO modulates various cellular processes during aging, inflammation, and age-related diseases, including cardiovascular, neurological, reproductive, skin, renal, thyroid, muscle, and sleep disorders. Several chemical and natural agents can increase NO bioavailability by enhancing both eNOS and nNOS expression, inhibiting iNOS, and increasing the protein-protein interaction of eNOS with sirtuin-1, leading to amelioration of aging-related diseases. However, due to the complex activity of NO in the pathogenic processes of diseases, several targets of NO should be considered, rather than a single target, to be able to identify the growing network of NO signaling processes in the body.
