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Hydrogen Sulfide, the Next Potent Preventive and Therapeutic Agent in Aging and Age-Associated Diseases  


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Hydrogen Sulfide, the Next Potent Preventive and Therapeutic Agent in Aging and Age-Associated Diseases

Yuan Zhang, Zhi-Han Tang, Zhong Ren, Shun-Lin Qu, Mi-Hua Liu, Lu-Shan Liu, Zhi-Sheng Jiang
 
DOI: 10.1128/MCB.01215-12
 

ABSTRACT

Hydrogen sulfide (H2S) is the third endogenous signaling gasotransmitter, following nitric oxide and carbon monoxide. It is physiologically generated by cystathionine-γ-lyase, cystathionine-β-synthase, and 3-mercaptopyruvate sulfurtransferase. H2S has been gaining increasing attention as an important endogenous signaling molecule because of its significant effects on the cardiovascular and nervous systems. Substantial evidence shows that H2S is involved in aging by inhibiting free-radical reactions, activating SIRT1, and probably interacting with the age-related gene Klotho. Moreover, H2S has been shown to have therapeutic potential in age-associated diseases. This article provides an overview of the physiological functions and effects of H2S in aging and age-associated diseases and proposes the potential health and therapeutic benefits of H2S.

INTRODUCTION

Aging has been a topic of great interest to the scientific community for a long time. This biological process is characterized by a time-dependent progressive decline of physiological functions accompanied by an increased incidence of age-associated diseases. The basic cellular and biochemical features of aging are very complex to elucidate clearly. Although various theories have been proposed to explain the process of aging, there is none that has been generally accepted by gerontologists. Denham Harman proposed that aging and age-associated diseases are basically caused by the deleterious side attacks of free radicals on cell constituents and connective tissues (1). This proposal, which implies that limiting or inhibiting the formation of free radicals could reduce the rate of aging and prevent age-associated diseases, is receiving growing acceptance as a possible explanation of the aging theory. Studies showing that nutritional antioxidants (vitamin C, vitamin E, and resveratrol) and antioxidant enzymes (superoxide dismutase [SOD], catalase [CAT], and glutathione [GSH] peroxidase) can promote better health and longevity by suppressing free-radical reactions are still limited and equivocal (2). However, antioxidants are receiving considerable attention and their use is increasingly being adopted in Western countries. Hydrogen sulfide (H2S), which was previously regarded as a poisonous gas, is generated endogenously in mammals. With its antioxidant and other physiological functions, it has the potential to provide many health benefits. Several studies have shown that H2S prevents free radical-induced impairment and is beneficial in treating age-associated diseases. A recent study reported that the plasma H2S level in humans over 50 to 80 years of age declines with age (3). However, the precise relationship between H2S and physiological changes that constitute aging is largely unknown. This review aims to provide detailed information on the various physiological effects of H2S on aging and age-associated diseases known to date.

GENERATION OF ENDOGENOUS H2S

H2S is a colorless, flammable, water-soluble gas with the characteristic smell of rotten eggs. In the past several centuries, H2S had been known only for its toxicity and environmental hazards. However, as a member of a family of gasotransmitters that includes nitric oxide and carbon monoxide, it is produced endogenously in mammals, including humans, and has important physiological roles in the human body (4, 5). Previous studies reported that H2S is physiologically generated by cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS) (6, 7). These two pyridoxal-5′-phosphate-dependent enzymes, which are expressed in the liver, kidney, brain, thoracic aorta, ileum, pancreatic islets, uterus, and placenta, among other locations, are crucial in the synthesis of H2S (813). CBS is predominantly expressed in the brain and the nervous system (6, 14, 15). However, expression of CSE proteins has been mainly observed in vascular smooth muscle cells and in the heart (16, 17). In addition, 3-mercaptopyruvate sulfurtransferase and cysteine aminotransferase localized to the endothelium of the thoracic aorta have also been reported to produce H2S from cysteine and alpha-ketoglutarate (18) (Fig. 1).

Fig 1

Generation of endogenous H2S. H2S is synthesized by two cytosolic pyridoxal-5′-phosphate-dependent enzymes responsible for the metabolism of l-cysteine, namely, cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE), as well as by the combined action of 3-mercaptopyruvate sulfurtransferase (3-MST) and cysteine aminotransferase (CAT).

 

PHYSIOLOGICAL EFFECTS OF ENDOGENOUS H2S

H2S has various physiological effects on the human body. First, H2S is a major endothelium-derived hyperpolarizing factor (EDHF) that causes hyperpolarization and vasorelaxation of vascular endothelium and smooth muscle cells by activating ATP-sensitive, intermediate-conductance and small-conductance potassium channels through cysteine S-sulfhydration (19, 20). Second, H2S can prevent cytokine- or oxidant-induced oxidative damage through its antioxidative effects (2123). Additionally, H2S can inhibit the expression of proinflammatory factors by downregulating NF-κB activation or by upregulating heme oxygenase 1 expression (2428). Moreover, H2S may help regulate various functions of the human body with its cytoprotective, antifibrotic, antiapoptotic, and angiogenic properties (2932). Taken together, these known functions of H2S imply an important role in aging and age-associated diseases (Table 1).

Table 1

Physiological effects of hydrogen sulfide on aging

 

ROLE OF H2S IN REGULATION OF AGING

H2S inhibits free-radical reactions and oxidative stress. Continuous accumulation of deleterious free-radical reactions in cells and tissues is a major contributor to aging. Hence, the aging process may be caused by free-radical reactions. Free radicals and oxidative stress are believed to be important risk factors in aging and various age-associated diseases. A judicious selection of diet and antioxidant supplements is expected to promote longevity (34, 35). Consistent with this idea, many healthy volunteers with improved body redox status benefit from sulfurous water consumption, which can reduce biomolecule oxidation and provide valid protection against oxidative damage commonly associated with aging and age-related degenerative diseases. However, endogenously produced H2S can be hydrolyzed to hydrosulfide and sulfide ions. Interestingly, it has been reported that levels of both lipid and protein oxidation products, namely, malondialdehyde (the lipid peroxidation product), advanced oxidation protein products, and carbonyls decrease significantly in plasma samples of healthy volunteers subjected to a cycle of hydroponic therapy with H2S-rich water (500 ml day−1 for 2 weeks) (36). Although the underlying mechanisms of this effect are not completely understood, it implies that H2S can protect against oxidative stress. Oxidative damage to biological macromolecules is caused by increased levels of free radicals, reactive oxygen species (ROS), and reactive nitrogen species (RNS) which can disrupt the cellular reduction-oxidation (redox) balance. The primary ROS/RNS species generated in a cell are superoxide (O2), hydrogen peroxide (H2O2), and nitric oxide (NO) (37). H2S can protect mouse brain endothelial cells (bEnd3) from methionine (Met)-induced oxidative stress and cytotoxicity. Pretreatment of bEnd3 cells with NaHS (0.05 mM) can decrease H2O2, peroxynitrite (ONOO), and O2 generation induced by Met. In the ROS scavenging pathway, SOD converts O2 to H2O2, which is subsequently reduced to H2O and O2 by CAT. However, low concentrations of H2S can synergistically increase inhibitory effects of apocynin, N-acetyl-l-cysteine (NAC), reduced GSH, CAT, SOD, and Nω-nitro-l-arginine methyl ester (L-NAME) on ROS production and redox enzyme levels induced by Met (38). ONOO, a powerful oxidant and cytotoxic species which can induce nitration of tyrosine and tyrosine residues in proteins, is formed from the rapid interaction of NO and O2 (39). H2S has also been considered a potent scavenger of ONOO. H2S at low concentrations (30 μM) can significantly inhibit tyrosine nitration mediated by ONOO to an extent similar to that seen with reduced GSH, a major antioxidant in the cellular defense against oxidative stress. Additionally, H2S can also significantly inhibit cytotoxicity mediated by ONOO in human neuroblastoma SH-SY5Y cells at physiological levels (40). In addition, Whiteman et al. have shown that H2S can similarly quench NO to form a novel nitrosothiol compound in vitro. This suggests that H2S has direct chemical interactions with NO free radicals to suppress oxidative stress (41). Moreover, Kimura et al. demonstrated that H2S can protect mouse brain neuroblastoma Neuro2a cells from oxidative stress caused by H2O2 and recover GSH levels suppressed by H2O2 in those cells (42). Furthermore, modulation of oxidative stress by calorie restriction (CR) is recommended as one mechanism to slow the aging process and decline of body functions in animals (43). Thus, H2S may also slow the aging process by inhibiting free-radical reactions and oxidative stress.

The free-radical theory was revised when mitochondria were found to be responsible for the initiation of most free-radical reactions occurring in cells. The life span is also postulated to be determined by the rate of free-radical damage to mitochondria. In fact, owing to the continuous generation of free radicals throughout the life of a cell, mitochondria, especially mitochondrial DNA, are the key targets of free-radical attack (44). Kimura and coworkers showed that H2S reduces cystine to cysteine in the extracellular space and increases intracellular concentrations of cysteine to increase the production of intracellular GSH and enhances the redistribution of GSH into mitochondria in Neuro2a cells. It enables H2S to suppress oxidative stress in the mitochondria (42). In rat models of ischemia and reperfusion (I/R) injury, it has been observed that preconditioning with H2S can prevent mitochondrial dysfunction in rat intestinal mucosa by a calcium-activated, large-conductance potassium channel-dependent mechanism (45). Under I/R conditions, production of ROS increases, which has a pivotal role in the pathogenesis of myocardial I/R injury. Inhibition of oxidative stress has been reported to underlie the cardioprotective effects of H2S under I/R conditions. Sun et al. showed that treating cardiomyocytes with 50 μM NaHS, which is close to the level found in rat plasma, decreases the levels of ROS by inhibiting mitochondrial complex IV3 and increasing SOD activities in cardiomyocytes under I/R conditions. H2S has also been found to inhibit electron transport to reduce harmful ROS generation under cardiac I/R conditions (46). Thus, protection against oxidative stress-induced mitochondrial damage may be a novel mechanism through which H2S could furnish valid protection and possibly increase life span.

H2S activates SIRT1 to resist aging. The silent information regulator 2 genes (SIR2) family, which is conserved from prokaryotes to eukaryotes (Staphylococcus aureus, fission yeast, Arabidopsis, Caenorhabditis elegans, mouse, rat, human), has functions in silencing, cell cycle progression, and chromosome stability (47). SIR2 is a determinant of life span in yeast mother cells. It can promote longevity in Saccharomyces cerevisiae by suppressing the generation and accumulation of extrachromosomal ribosomal DNA (rDNA) circles, which are considered a cause of aging in yeast (48). Similarly, it has been demonstrated that SIR2, which encodes a histone deacetylase, extends the life span of Caenorhabditis elegans through signaling pathways involving DAF-2/insulin receptor and DAF-16/FOXO (49, 50). Mammals have seven Sir2 homologues (SIRT1 to -7), of which SIRT1 is most closely related to Sir2. These proteins have a highly conserved NAD-dependent sirtuin core domain, first identified in the yeast Sir2 protein, making them good candidates for life span regulators (51). Interestingly, it has been reported that exogenous H2S has a protective effect on maintaining the circadian rhythm of clock genes in isolated hepatocytes by changing the NAD+/NADH ratio and enhancing the activity of SIRT1 protein (52). SIRT1 has thus emerged as a major life span regulator, and H2S has been hypothesized to delay aging, in part by activating SIRT1.

Calorie restriction is the only established antiaging experimental paradigm in a variety of species, including mammals, flies, nematodes, and yeast, that has been accepted by many researchers. It has been reported that CR can extend life span by increasing Sir2 activity and activating Sir2 deacetylase in yeast and Drosophila. Additionally, the expression of mammalian Sir2 (SIRT1) is induced in calorie-restricted rats and also in human cells cultured in the presence of serum from such rats. SIRT1 can deacetylate the DNA repair factor Ku70, causing it to sequester the proapoptotic factor Bax away from the mitochondria, thereby inhibiting stress-induced apoptotic cell death. A major cause of aging is perceived to arise from the cumulative effects of cell loss over time. Moreover, it has also been reported that CR can inhibit the insulin/insulin-like growth factor 1 (IGF-1) pathway to increase SIRT1 expression. Thus, CR can promote longevity by inducing SIRT1 expression and promoting long-term survival of irreplaceable cells (33). Correspondingly, when exposed to H2S, nematodes are apparently healthy and do not exhibit phenotypes consistent with metabolic inhibition. Instead, animals exposed to H2S are long-lived, and this phenotype requires Sir2 activity, which may translate environmental changes into physiological alterations to improve survival (53). CR also has potential benefits for CSE and CBS in both the aorta and liver by reducing oxidative stress and ameliorating the negative effect of age on H2S concentration. Consistent with this, Predmore et al. inferred from their study that CR may help maintain the H2S signaling system during aging (54). CR and H2S apparently have a synergistic antiaging effect by regulating SIRT1 activity. Our laboratory recently demonstrated that H2S has protective effects against human umbilical vein endothelial cell senescence, which may involve the regulation of SIRT1 activity. Similar to resveratrol, H2S is likely a CR mimetic with potential antiaging functions mediated via SIRT1 activation. It has been reported that SIRT1 could deacetylase the FOXO transcription factors in vitro and within mammalian cells to increase cellular stress resistance, which is correlated with extended organismal longevity (55). However, the hypothesis that the antiaging effects of H2S are mediated via the SIRT1/FOXO pathway needs to be validated with further investigations.

Resveratrol, a polyphenol found in red wine, is a CR mimetic with potential antiaging and antidiabetogenic properties. Resveratrol ameliorates age-related metabolic phenotypes by inhibiting cyclic AMP (cAMP) phosphodiesterases (PDE). Inhibiting PDE4 with rolipram reproduces all the metabolic benefits of resveratrol, including prevention of diet-induced obesity and promotion of mitochondrial function, physical stamina, and glucose tolerance in mice. Therefore, PDE4 inhibitors may also prevent and ameliorate the symptoms of age-related metabolic diseases (56). H2S also acts as an endogenous inhibitor of phosphodiesterase activity (57). However, whether H2S uses the same mechanism for inhibiting phosphodiesterases to prevent age-related diseases and for exerting antiaging effects via SIRT1 activation remains unknown. Figure 2 gives an overview of the pathways that underlie the antiaging effects of H2S.

Fig 2

H2S exerts its antiaging effects by directly inhibiting free radicals and oxidative stress and by upregulating SIRT1 activity. H2S can directly inhibit the free radicals ROS/RNS and increase inhibitory effects of GSH and SOD on ROS production and redox enzyme levels to increase cellular stress resistance, which is correlated with extended organismal longevity. CR and resveratrol have been reported to have antiaging properties. CR and resveratrol share similar antiaging mechanisms: they both increase SIRT1 expression to inhibit oxidative stress or to play antiapoptotic roles. Resveratrol can also ameliorate age-related metabolic phenotypes by inhibiting cAMP phosphodiesterases (PDE). Similarly, H2S has been reported to enhance the activity of SIRT1 and to inhibit PDE activity. As shown in the figure, H2S may have antiaging functions through several shared pathways related to CR and resveratrol.

 

Effect of H2S on the age-related gene Klotho. The age-related gene Klotho suppresses the expression of multiple age-associated phenotypes to extend life span. Klotho increases resistance to oxidative stress by activating the FOXO forkhead transcription factors that induce the expression of manganese SOD (58). Klotho also represses DAF-2 (insulin/IGF-like) receptors under physiological conditions, thereby inducing derepression of DAF-16 (FOXO) and subsequent overexpression of factors such as antioxidant enzymes that improve longevity and stress resistance (59).

Klotho is predominantly expressed in the kidney. Downregulation of Klotho in the kidneys aggravates the development of renal damage induced by angiotensin II via increased oxidative stress, whereas induction of Klotho expression has therapeutic effects against angiotensin II-induced end-organ damage (60). Yoon et al. confirmed that angiotensin II plays a pivotal role in regulating the expression of Klotho in cyclosporine (CsA)-induced renal injury and that angiotensin II type 1 (AT1) receptor blocker inhibits aging by decreasing CsA-induced oxidative stress (61). Interestingly, H2S has a direct inhibitory effect on angiotensin-converting enzyme (ACE) activity, which catalyzes the conversion of angiotensin I into angiotensin II (62). Moreover, H2S can decrease angiotensin II-induced mitogen-activated protein kinase (MAPK) activation, AT1 receptor binding, and the binding affinity of AT1 receptor in a dose-dependent manner (63). In addition, Lu et al. demonstrated that H2S inhibits renin activity, which participates in the renin-angiotensin system (64). Thus, H2S may enhance Klotho expression via negative regulation of angiotensin II activity. Given these findings, H2S may be a potent preventive and therapeutic agent in aging and age-associated diseases. Figure 3 summarizes the indirect effects of H2S on Klotho expression to show that H2S may be involved in regulation of aging through the Klotho pathway.

Fig 3

H2S may have an effect on the age-related gene Klotho to promote longevity. Klotho can improve longevity by inhibiting IIS signaling, inducing FOXO derepression, and decreasing angiotensin II-induced oxidative stress, among other effects. However, angiotensin II may downregulate the expression of Klotho. Interestingly, H2S exhibits direct inhibitory action on ACE activity, which catalyzes the conversion of angiotensin I to angiotensin II. Moreover, H2S can decrease the binding affinity between angiotensin II and AT1 receptor and can inhibit renin activity, which participates in the renin-angiotensin system. Hence, H2S may improve Klotho expression to promote longevity via negative regulation of angiotensin II production.

 

H2S: A NOVEL THERAPEUTIC AGENT IN AGE-ASSOCIATED DISEASES?

H2S has been generally recognized as an important signaling molecule in cardiovascular and nervous systems. Enhancement of the physiological effects of H2S has been confirmed by understanding the therapeutic implications of H2S in age-associated diseases, such as cardiovascular system diseases, central nervous system degenerative diseases, diabetes, and cancer, among others (Table 2).

Table 2

Effects of H2S or its donors on age-associated diseasesa

 

Cardiovascular system diseases.Aging is considered a principal risk factor in the progression of hypertension (81). The plasma concentration of H2S in spontaneously hypertensive rats is substantially lower than that in normotensive control animals (65). Similarly, the plasma H2S level and H2S production are greatly reduced and transcription and activity of CSE in vascular tissues are also obviously inhibited in rats with hypertension induced by NG-nitro-l-arginine methyl ester (l-NAME). However, H2S can prevent the development of hypertension induced by l-NAME. This suggests that the H2S synthase/H2S pathway participates in the pathogenesis of hypertension (82). The fundamental hemodynamic abnormality in hypertension is increased peripheral vascular resistance (83). It has been reported that H2S can relax rat aortic tissues in vitro in an ATP-sensitive K+ (KATP) channel-dependent manner and that H2S at physiologically relevant concentrations induces vasorelaxation via activation of KATP channels in isolated mesenteric artery smooth muscle cells (17, 84). KATP channels are activated by binding of its Kir subunits to phosphatidylinositol-4,5-bisphosphate (PIP2) along with a reduction in binding to the inhibitor ATP (85). H2S causes vascular endothelial and smooth muscle cell hyperpolarization and vasorelaxation by activating KATP channels through cysteine S-sulfhydration, which can enhance Kir6.1-PIP2 binding and reduce Kir6.1-ATP binding (19). Additionally, considering that human hypertensive pulmonary vascular disease represents a disease of excessive smooth muscle cell proliferation (86), H2S could also suppress the proliferation of cultured aortic vascular smooth muscle cells of rats in vitro through the MAPK pathway (87). Because H2S is a major EDHF and a primary determinant of vasorelaxation in numerous vascular beds (20), drugs that alter CSE activity or H2S-mediated channel sulfhydration may be effective therapeutic agents for treating hypertension.

Atherosclerosis, characterized by lesions in large and medium arteries, is the primary cause of coronary artery disease. Not only is this condition a chronic inflammatory disease that can lead to an acute clinical event by plaque rupture and thrombosis, but it is also an inevitable degenerative consequence of aging (88). Atherosclerosis is characterized by multiple key events, including endothelial dysfunction, infiltration of monocytes and their differentiation into macrophages, conversion of lesion-resident macrophages into foam cells, and smooth muscle cell proliferation. Fortunately, atherosclerosis can be interrupted by H2S. Increasing evidence has proven that H2S plays a significant role in all these biological processes and that disruption of H2S homeostasis may contribute to the pathogenesis of atherosclerosis (89). For instance, H2S plays an antiatherogenic role by suppressing the formation of human macrophage foam cells. H2S inhibits the formation of macrophage-derived foam cells, which is a crucial event in the development of atherosclerosis, by downregulating CD36, SR-A, and ACAT-1 expression and inhibiting oxidized low-density lipoprotein (oxLDL) binding and uptake of macrophages (66, 67). In addition to its important role in preventing atherosclerosis, H2S has also direct benefits for coronary heart disease (CHD) patients. Plasma H2S levels in patients with CHD show a significant inverse correlation with the severity of CHD and changes in the coronary artery (90). Moreover, providing H2S balneotherapy to CHD patients has been shown to result in significant prolongation of stress bicycle exercise. In the hot climate of arid zones, use of moderate H2S baths raises the tolerance of CHD patients to exercise, attenuates clinical manifestations of CHD, and consequently reduces daily nitrate need (91). Additionally, stem cell transplantation has become a promising therapeutic approach for treatment of myocardial infarction (MI). However, poor survival of the donor cells after transplantation has restricted its therapeutic efficacy. H2S has been applied to inhibit cell apoptosis and promote cell survival in such cases. It has been demonstrated that H2S preconditioning effectively promotes stem cell survival under conditions of ischemic injury and helps cardiac repair after MI (92).

Degenerative diseases of the central nervous system.Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive loss of dopaminergic neurons in the substantia nigra (SN). In a 6-hydroxydopamine (6-OHDA)-induced PD rat model, the endogenous H2S level has been found to be markedly reduced in the SN. However, H2S treatment can specifically inhibit 6-OHDA-evoked NADPH oxidase activation, oxygen consumption, and microglial activation in the SN, and accumulation of proinflammatory factors in the striatum (68). PD is one of the most common neurodegenerative diseases with various manifestations, among which cognitive deficiency, namely, dementia, has a prominent role. Dementia is usually ascribed to changes in the nucleus basalis of Meynert and the cerebral cortex (93). H2S has also been suggested to attenuate vascular dementia injury via inhibition of apoptosis by markedly improving the ratio of Bcl-2 to Bax, upregulating Bcl-2 expression, and downregulating Bax expression (69).

Alzheimer's disease (AD) is the most common form of dementia. AD initially targets memory and progressively destroys the mind (94). This disease is pathologically characterized by the accumulation of senile plaques containing activated microglia and amyloid beta peptides (Abeta) (95). As mentioned previously, endogenous H2S is predominantly produced in the brain from cysteine by CBS (5, 96). Endogenous levels of H2S of between 50 and 160 μM are detected in the brains of humans (40). In the brains of AD patients, lower levels of H2S as well as accumulation of homocysteine (Hcy), a strong risk factor for the development of Alzheimer's disease (AD), are observed (71, 72). Neurotoxicity of elevated Hcy is associated with inhibition of endogenous H2S generation and downregulation of expression and activity of CBS in PC12 cells, which is mediated by extracellular signal-regulated kinase 1 and 2 (ERK1/2) activation. It has been suggested that H2S could reduce neurotoxicity induced by Hcy and that enhancement of H2S synthesis may be a useful therapeutic strategy against Hcy-induced AD (97). Accordingly, Liu and Bian have demonstrated that H2S demonstrates protective effects against Abeta-induced cell injury by inhibiting inflammation, promoting cell growth, and preserving mitochondrial function in a p38- and Jun N-terminal protein kinase (JNK)–mitogen-activated protein kinase (MAPK)-dependent manner (70). Moreover, H2S can protect neurons from oxidative stress, which is responsible for neuronal damage and degeneration in AD. H2S protects neurons against glutamate-mediated oxidative stress by enhancing the activities of γ-GCS and cystine transport, which results in incremental changes of glutathione levels (98). These findings suggest that H2S is a promising therapeutic target for treating neurodegenerative diseases.

Diabetes.Diabetes is a chronic metabolic disease with influence on the metabolism of carbohydrates and other nutrients. The pathogenesis of diabetes is associated with decreased functional beta cell mass and increased activities of KATP channels in pancreatic beta cells (99, 100). It has been reported that in streptozotocin-induced diabetes in mice, pancreatic H2S production and CSE activity are significantly upregulated (73, 76). Similarly, it has also been found that pancreatic CSE expression and H2S production are higher in Zucker diabetic fatty (ZDF) rats than in Zucker fatty and Zucker lean rats (101). Enhanced endogenous production of H2S in diabetes can induce apoptosis of insulin-secreting beta cells by enhancing endoplasmic reticulum (ER) stress via p38 MAPK activation and also stimulate KATP channels in insulin-secreting cells (7375). These results imply that H2S at high concentrations contributes to the pathogenesis of diabetes mellitus.

Diabetes mellitus is also characterized by the resistance of peripheral tissues to insulin (102, 103). l-Cysteine which is synthesized from methionine is a main precursor of H2S. However, adipose tissue is an important organ of methionine metabolism (104) and is also an insulin-sensitive organ that mediates glucose uptake and metabolism. With age, the endogenous CSE/H2S system is upregulated in adipose tissues. Increased H2S in adipose tissues inhibit basal or insulin-stimulated glucose metabolism and regulate insulin sensitivity. This suggests that H2S may be a novel insulin resistance regulator (105). Additionally, Kaneko et al. suggested that elevation of the H2S levels as a result of l-cysteine metabolism may inhibit insulin release from isolated mouse islets and the mouse β-cell line MIN6 under diabetic conditions (11). In ZDF rats, abnormally high pancreatic production of H2S has been reported to suppress insulin release (101). These findings indicate that high concentrations of H2S in pancreas could have deleterious effects on the development of diabetes and that new therapeutic measures for diabetes may involve inhibiting endogenous H2S production from pancreas.

In contrast, Jain et al. have reported that blood H2S levels are significantly lower in type 2 diabetes patients than in age-matched healthy subjects and in streptozotocin-treated diabetic rats than in control Sprague-Dawley rats. Low blood H2S levels may contribute to the vascular inflammation observed in diabetes because supplementation with H2S can prevent inflammatory factor interleukin-8 (IL-8) and monocyte chemoattractant protein 1 (MCP-1) secretion by monocytes cultured in high-glucose medium (77). It has also been observed that H2S levels in plasma and aortic tissue are progressively reduced in nonobese diabetic (NOD) mice. This suggests that reduced endogenous H2S production is associated with diabetes-related endothelial dysfunction in NOD mice (106). Endothelial dysfunction plays a pathogenic role in the development of diabetic vascular complications. However, protective effects of H2S on the endothelial cells under high-glucose conditions have also been observed. Pretreatment with NaHS (50 μmol/liter) protects against high-glucose-induced apoptosis in endothelial cells by increasing SOD activity, decreasing ROS generation and malondialdehyde levels, and downregulating the Bax/Bcl-2 ratio (107). These findings are consistent with those of Suzuki et al. showing that in vitro hyperglycemia is associated with increased H2S degradation caused by mitochondrial ROS overproduction and that H2S replacement has cytoprotective effects on endothelial cells in hyperglycemia in vitro. H2S protects against the development of hyperglycemia-induced endothelial dysfunction by attenuating the hyperglycemia-induced enhancement of ROS formation, attenuating nuclear DNA injury, reducing the activation of the nuclear enzyme poly(ADP-ribose) polymerase, and improving cellular viability (108).

Furthermore, inhibiting ACE, a Zn-dependent enzyme, has been recommended to prevent diabetic nephropathy (109). The H2S level and CSE expression in the renal cortex of diabetic rats have been shown to be significantly decreased (110). As indicated earlier, H2S at a physiological concentration exhibits direct inhibitory action on ACE activity in human umbilical vein endothelial cells by interfering with the Zn2+ in the active center of the enzyme (62). Thus, it appears that H2S could also protect against diabetes nephropathy by functioning as an ACE inhibitor. These findings imply that H2S at normal physiological concentrations may have beneficial effects on the control of diabetes owing to its anti-inflammatory and antioxidative roles. Therefore, inhibiting pancreatic H2S biosynthesis may be a potential approach to protect β cells from death during the induction phase of diabetes, whereas supplementation with H2S could be considered a potential approach to maintain diabetic blood vessel potency (111).

Cancer.The slow-releasing H2S donor GYY4137 can kill seven different human cancer cell lines (HeLa, HCT-116, Hep G2, HL-60, MCF-7, MV4-11, and U2OS) in a concentration-dependent manner. This indicates that H2S could be a potential anticancer agent (112). Moreover, H2S-releasing nonsteroidal anti-inflammatory drugs (HS-NSAID) composed of a traditional NSAID to which an H2S-releasing moiety is covalently attached have significant anti-inflammatory properties. It has been shown that HS-NSAID can inhibit the growth of all cancer cells, such as human colon, breast, pancreatic, prostate, lung, and leukemia cancer cells, by inhibiting cell proliferation, inducing apoptosis, and causing G0/G1 cell cycle block. These data indicate that H2S may have potential antigrowth activity against various human cancer cells (113).

Sulforaphane, a sulfur-containing compound with properties against prostate cancer, can release a large amount of H2S. Pei et al. showed that H2S can decrease the viability of PC-3 cells (a human prostate cancer cell line) in a dose-dependent manner (78). Importantly, both CSE and CBS are expressed in the prostate. Thus, H2S-releasing diets or drugs may be beneficial in the treatment of prostate cancer. Similarly, H2S-releasing aspirin, a novel and safer derivative of aspirin, has shown promise as an anticancer agent against hormone-independent estrogen receptor-negative breast cancers by inhibiting cell proliferation, inducing apoptosis, and decreasing NF-κB levels (79). Moreover, NOSH-aspirin, a NO- and H2S-releasing agent, has been found to inhibit colon cancer growth by inhibiting cell proliferation, inducing apoptosis, and causing G0/G1 cell cycle block (80). Overall, these results indirectly demonstrate that H2S has strong anticancer potential that merits further evaluation.

PERSPECTIVES

The findings discussed in this review strongly argue in favor of a role for H2S in aging and age-associated diseases. However, the mechanisms of action of this role of H2S have not yet been sufficiently characterized and await elucidation by further studies. A better understanding of the roles of H2S in aging can provide insights into potential therapeutic interventions against aging and reduce age-associated diseases. More specifically, data available so far strongly suggest that H2S may become the next potent preventive and therapeutic agent for preventing and ameliorating the symptoms of aging and age-associated diseases, and this should be addressed in future studies.

ACKNOWLEDGMENTS

This work was supported by grants from the National Natural Science Foundation of China (81170277 to Z.-S.J.), by the Special Research Fund for the Doctoral Program of Higher Education of China Project (20124324110003 to Z.-S.J.), and by the Aid Program for Science and Technology Innovative Research Team in Higher Educational Institutions of Hunan Province.

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Infinite Aging Radio Show

The Greatest Health Miracle Show:

Psychedelic Therapy:

Psychedelic Drug Psilocybin Tamps Down Brain’s Ego Center plus Getting Closer to Nature, One Bite at a Time

Psychedelic Drug Psilocybin Tamps Down Brain’s Ego Center plus Getting Closer to Nature, One Bite at a Time – Dr. Frederick Barrett – Steve Brill – Violet Brill – Perhaps no region of the brain is more fittingly named than the claustrum, taken from the Latin word for -hidden or shut away-. The claustrum is an extremely thin sheet of neurons deep within the cortex, yet it reaches out to every other region of the brain. Its true purpose remains -hidden away- as well, with researchers speculating about many functions. What is known is that this region contains a large number of receptors targeted by psychedelic drugs such as LSD or psilocybin the hallucinogenic chemical found in certain mushrooms. To see what happens in the claustrum when people are on psychedelics, Johns Hopkins Medicine researchers compared the brain scans of people after they took psilocybin with their scans after taking a placebo. PLUS Steve and Violet Brill looks at a forest the same way most people think about a supermarket. Walkthrough a park or wooded area with them and they can show you a number of wild plants that might make for tasty additions to your dinner plate. They would tell you how yellow wood sorrel tastes just like lemonade or how black birch can be used as a minty flavoring for pudding. With the advent of this pandemic, foraging may be more important than ever. Some are including it in their home-schooling curriculum in hopes of arming their children with this almost-forgotten art.

    Longevity – Life Extension – Anti-Aging Board

    LONGEVITY MEDICINE:

    THE CURRENT FRONTIER IN MEDICINE IS LONGEVITY MEDICINE BECAUSE IT’S PREVENTIVE & FOR EVERYONE WHO WANTS TO PREVENT A MEDICAL ISSUE NATURALLY – EVEN USING SYNTHETIC SUBSTANCES – TO PREVENT AGING & ENCOURAGE HEALTH & WELLBEING.

    Preventative Medicine

    Allopathic Medicine

    LifeStyle Medicine

    Herbal Medicine

    Chinese Medicine

    Ayurveda

    … … … 

    DRUGS/HOME REMEDIES/ACTIVITIES

    “An ounce of prevention is worth a pound of cure.”

     

     

    lon·​gev·​i·​ty | \ län-ˈje-və-tē , lȯn- \
    Definition of longevity
    : long duration of individual life
    The members of that family are noted for their longevity.
    b: length of life

    Medicine Definition: Meds (slang)

     

     

    med·i·cine
    /ˈmedəsən/noun
    1.
    the science or practice of the diagnosis, treatment, and prevention of disease (in technical use often taken to exclude surgery).
    Similar:
    medical science
    practice of medicine
    healing
    therapeutics
    therapy
    treatment
    healing art
    2.
    a compound or preparation used for the treatment or prevention of disease, especially a drug or drugs taken by mouth.

    “give her some medicine”

    OBJECTIVES

    OPEN DISCUSSION / ANTI-AGING -RESOURCE BOARD THAT WILL NEVER DIE


    Share the joy

    Peptides – a Powerful Piece of the Longevity Puzzle

    In this episode of Living Beyond 120, Mark and Dr. Gladden begin by talking about how we need to manifest goals in our minds first in order to make them realities.

    Next, they discuss some recent health tests Dr. Gladden participated in, along with the remarkable results regarding his cardiovascular health and age. He talks about his plans for getting in the best shape of his life.

    They continue their conversation revisiting the subject of peptides, discussing specific peptides, and the amazing outcomes that Dr. Gladden is seeing in his practice. From better immune function to healing the gut, improved fat burning, and much more, they describe which peptides have had positive health effects on many different conditions. To learn more about peptides, you can visit https://tailormadecompounding.com/.

    WHY DOES COVID-19 KILL SOME PEOPLE & SPARE OTHERS WITH TED RYCE

    The novel coronavirus causing COVID-19 seems to hit some people harder than others, with some people experiencing only mild symptoms and others being hospitalized and requiring ventilation. In this episode, Ted shares the latest research on the coronavirus.

    Preventing Cardiovascular Disease – an Interview with Dr. Jeffry Life 

    In this episode, we’re featuring a special RAAD Fest discussion from last year between Dr. Gladden and Dr. Jeffry Life, a doctor who has focused his practice on healthy aging and helping patients avoiding heart attacks and strokes. He incorporates the Bale-Doneen Method (learn more in the book Beat the Heart Attack Gene) in his treatment plans, which is about aggressively looking for vascular inflammation that causes heart disease and working to stop it.

    They discuss some of the testings that can be done to identify vascular risk factors, which fall outside of the normal insurance-based model of healthcare.

    Ketogenic Diet Hacks:

    Doing The Perfect Keto Diet: Doing Perfect Keto – Chris Irvin –

    Everyone agrees that a low-carb, low-sugar Keto lifestyle reduces inflammation and resets insulin sensitivity. Yet there is still confusion about what to eat too and what not to eat. So much so there are entire books dedicated to the subject. And much of that information in those books become outdated as soon as new research provides insights into which foods and supplements work or don’t work as originally expected. And when it comes to snack foods and sweet treats the water gets even murkier. What if there was a website that was driven by current science and gave you access to everything you needed to do low-carb Keto right? Perfect Keto.

    RSS Anti Aging Hacks

    • Replicating Nature’s Energy to Charge Your Cells – Jim Girard and Jim Law with Dave Asprey : 741 September 17, 2020
      In this episode of Bulletproof Radio, BioCharger™ co-founders Jim Girard and Jim Law join me to talk about how energy affects our bodies on a cellular level and what we can do about it. There are four types of energy in nature—light, PEMFs, voltage, and frequencies and harmonics—and we need all of them. A cool invention called […]
      Dave Asprey
    • These Are Not Uncertain Times: Ways to Pivot, Lead and Thrive – Simon Sinek with Dave Asprey : 740 September 15, 2020
      In this episode of Bulletproof Radio, my guest is someone who considers himself to be an unshakable optimist. "Optimism is not the denial of the current state,” says Simon Sinek. “Optimism is the belief the future is bright and so, to be optimistic is the same as saying, Look, we're in a dark tunnel. It's hard and I […]
      Dave Asprey
    • How to Think Like a Monk – Jay Shetty with Dave Asprey : 739 September 10, 2020
      For this special episode of Bulletproof Radio, I’m going to ask you to tune in for a while longer. I think you’ll really like what you hear.My guest is Jay Shetty, a British-born former monk who never expected to meet a monk, let alone become one. “It's really humbling and ironic when you go to […]
      Dave Asprey
    • How to Think Like a Rocket Scientist – Ozan Varol with Dave Asprey : 738 September 8, 2020
      In this episode of Bulletproof Radio, my guest, is a real-life rocket scientist. Ozan Varol definitely brings the goods in this conversation. You’ll learn how to think big, flirt with uncertainty, not be afraid to fail, and launch your success.In his new book, “Think Like a Rocket Scientist: Simple Strategies You Can Use to Make Giant […]
      Dave Asprey
    • Body Out of Balance? Bring it Back to Harmony with Chinese Herbal Medicine – Chloe Weber with Dave Asprey : 737 September 3, 2020
      In this episode of Bulletproof Radio, my guest, Chloe Weber, L.Ac, MSOM, is a licensed acupuncturist and herbalist who’s also co-founder and CEO of Radical Roots Herbs. She’s on a mission to expand the reach of Chinese herbology and bring ancient healing into the modern world. You’ll learn a lot in this episode, I know I did! Chloe has taken […]
      Dave Asprey
    • Biotech Ninja Moves Are Disrupting How We Age & What We Eat – Jim Mellon with Dave Asprey : 736 September 1, 2020
      In this episode of Bulletproof Radio, my guest is Jim Mellon, a British entrepreneur, investor, author and global philanthropist.We talk about the financial investments that are leading to real-time breakthroughs in human longevity, as well as developments in cellular agriculture that can feed a planet—without harming any animals.Where I think Jim is pulling a bit of a […]
      Dave Asprey
    • Mini-Episode: Cool Facts Friday #2 August 28, 2020
      Cool Facts are back, baby!Thanks to everyone who let us know they wanted to keep getting quick hits of new human and world science! We’ve taken the Cool Facts out of the Bulletproof Radio podcast episodes and curated them into a short burst just for you. This fun compilation will publish one Friday a month.Here’s […]
      Dave Asprey
    • The Carnivore Conversation with a Surprisingly Sweet Twist: Paul Saladino, M.D., with Dave Asprey : 735 August 27, 2020
      In this episode of Bulletproof Radio, Paul Saladino, M.D., returns to the show to talk about his current findings about eating all carnivore. He’s author of the book, “THE CARNIVORE CODE: Unlocking the Secrets to Optimal Health by Returning to Our Ancestral Diet.” He recently published an updated version to include all the latest science he discovered.We […]
      Dave Asprey
    • From Food Divorce to Emotional Overhaul: Randy Jackson’s Health Journey : 734 August 25, 2020
      In this episode of Bulletproof Radio, my guest Randy Jackson is a successful tv producer and author, spent 12 years as a judge on the music competition series “American Idol” and now is a wellness entrepreneur. “I had to completely change my lifestyle, all of my habits, and really dedicate and commit to myself that I want […]
      Dave Asprey
    • The Common Mold: Your Guide to Toxicity, Symptoms and Treatments – Dr. Neil Nathan with Dave Asprey : 733 August 20, 2020
      In this episode of Bulletproof Radio, my guest is one of the leading experts treating people who have medical problems related to mold exposure.Over the past 25 years, Neil Nathan, M.D., has become a researcher, complex medical problem-solver and healer—especially of mold toxicity. He treats patients who become too toxic and sensitive, and don’t tolerate usual […]
      Dave Asprey
    • Mold’s Toxic Effects on Hormones, Brains and Kids – Dr. Margaret Christensen with Dave Asprey : 732 August 18, 2020
      In this episode of Bulletproof Radio, my guest shares her compelling story of attempting to solve the riddle of her own and her family’s complex health challenges. She, her husband and her children were all tired, cranky and sick with various illnesses and she didn’t know why. Dr. Margaret Christensen also didn’t know it at […]
      Dave Asprey
    • Bonus Redux: Sleep is the Boss of You – Matthew Walker, Ph.D., with Dave Asprey : 616 August 17, 2020
      Join the Dave Asprey Sleep Challenge starting Aug. 17 at https://daveasprey.com/sleepchallenge/In this episode of Bulletproof Radio, my guest is Matthew Walker, Ph.D., author of the international best-selling book, “Why We Sleep: Unlocking the Power of Sleep and Dreams."“We’re in the midst of a “catastrophic sleep-loss epidemic,” he says. With candor like that about a subject […]
      Dave Asprey