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Hydrogen sulfide (H2S) is the third endogenous signaling gasotransmitter, following nitric oxide and carbon monoxide. H2S is physiologically generated by three enzymes, cystathionine-γ-lyase(CSE), cystathionine-β-synthase(CBS) and 3-mercaptopyruvate sulfurtransferase (3MST). It is increasingly being regarded as an important endogenous signaling molecule as a result of exerting significant effects in the cardiovascular and nervous systems. Besides, evidence is accumulating to demonstrate that hydrogen sulfide could involve in the aging process, such as inhibiting free radical reactions, activating SIRT1 and probably interacting the age-related klotho gene and that hydrogen sulfide have therapeutic implications in age-associated diseases. This article overviews the physiological significances of H2S, summarizes the effects of H2S in aging process and in age-associated diseases and proposes the potential health-care and therapeutic exploitation of H2S.
Hydrogen sulfide H2S aging age-associated diseases
Aging is always a hot topic that has excited curiosity and challenged imaginations since the origins of human consciousness. Aging is a biological process characterized by time-dependent, progressive, physiological declines accompanied by the increased incidence of age-associated diseases. The basic cellular and biochemical features of the aging process are too complex to elucidate clearly. So far, there are many theories to be proposed to explain the aging process, but none has yet been generally accepted by gerontologists. Nevertheless, the initial proposal by Denham Harman that aging and age-associated diseases are basically ascribed to the deleterious side attacks of free radicals on cell constituents and on the connective tissues, is receiving growing acceptance as a possible explanation of the aging theory. The proposal implies that interventions aimed at limiting or inhibiting the free radical reaction should be able to reduce the aging rate and the development of age-associated diseases. Although the supporting evidences that antioxidants, such as nutritional factors(Vitamin C, Vitamin E, resveratrol) and antioxidant enzymes(superoxide dismutase(SOD), catalase, and glutathione (GSH) peroxidase), could promote healthy longevity by suppressing the free radical reaction are still limited and equivocal, antioxidants are receiving mounting attention and are increasingly adopted in Western countries. Hydrogen sulfide which is previously regarded as a poisonous gas and is also generated endogenously, however, is good for health with its anti-oxidation and other various physiological functions. It has been reported that hydrogen sulfide prevents from impairment of free radical and is beneficial in treating age-associated diseases. A recent study indicates that plasma H2S level in humans over 50-80 years of age may decline with age, but the relationship between hydrogen sulfide and aging is unknown. In this review, we intend to provide detailed information about the various physiological effects exhibited by hydrogen sulfide and to describe the possible implications of hydrogen sulfide in the aging process and age-associated diseases.
Generation of endogenous hydrogen sulfide
Hydrogen sulfide (H2S) is a colorless, flammable, water-soluble gas with the characteristic smell of rotten eggs. In the past several centuries, hydrogen sulfide had only been known for its toxicity and environmental hazard, however, it is also produced in mammals including humans and has important physiological effects on our body, belonging to the family of gasotransmitters along with nitric oxide and carbon monoxide. According to previous studies, it has been known that hydrogen sulfide (H2S) is physiologically generated by cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS) . Cystathionine-β-synthase (CBS) and cystathionine-γ-lyase(CSE), which are expressed in the liver, kidney, brain, thoracic aorta, ileum, pancreatic islets, uterus, the placenta and so on, are two key pyridoxal-5'-phosphate-dependent enzymes involved in the synthesis of hydrogen sulfide. CBS is predominantly expressed in most areas of the brain, however, expression of CSE proteins has been mainly observed in vascular endothelial cells. Moreover, it is reported recently that 3-mercaptopyruvate sulfurtransferase (3MST) and cysteine aminotransferase (CAT) are localized to vascular endothelium in the thoracic aorta and produce hydrogen sulfide from cysteine and alpha-ketoglutarate (Fig. 1).
Fig.1. Generation of endogenous hydrogen sulfide.
H2S is synthesized by two cytosolic pyridoxal-5'-phosphate-dependent enzymes responsible for metabolism of l-cysteine: 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).
Role of endogenous hydrogen sulfide
It has been known that hydrogen sulfide has emitted various physiological effects on our body. Firstly, H2S has been widely acknowledged to be a major endothelium-derived hyperpolarizing factor (EDHF) that causes vascular endothelial and smooth muscle cell hyperpolarization and vasorelaxation by activating the ATP-sensitive, intermediate conductance and small conductance potassium channels through cysteine S-sulfhydration. Secondly, H2S can protect from oxidative damage induced by cytokines or oxidants as a result of anti-oxidative stress . Additionally, H2S can also inhibit the expression of pro-inflammatory factors via the mechanisms of down-regulating nuclear factor-kappaB activation or up-regulating heme oxygenase-1 expression . Moreover, H2S may help regulate the functions of the body owing to its physiological roles of cytoprotection, anti-fibrosis, anti-apoptosis, angiogenesis . By understanding the roles of hydrogen sulfide and aging, it can be concluded that hydrogen sulfide is involved and interacted in the aging process, as well as in age-associated diseases (Table 1).
Interaction between hydrogen sulfide and aging (Fig. 2)
Hydrogen sulfide inhibits free radical reaction and oxidative stress
It has been indicated that the accumulating deleterious free radical reactions going on continuously throughout the cells and tissues constitutes the aging process or is a major contributor to it, in other words, the aging process may be owing to free radical reactions. Free radicals and oxidative stress have been believed to be important risk factors in the biology of aging and of many age-associated diseases. It is reasonable to expect that a judicious selection of diets and antioxidant supplements will increase the healthy and active life span . Fortunately, inducing SOD expression and reducing ROS levels, hydrogen sulfide as an antioxidant plays a regulatory role in aortic endoplasmic reticulum stress (ERS) and reduces atherosclerotic lesions . And in mouse brain endothelial cells, it has been demonstrated that H2S protects the cells from oxidative stress induced by hyperhomocysteinemia(HHcy), which causes cerebrovascular dysfunction by inducing oxidative stress. Additionally, it has been shown that many healthy volunteers of the improved body redox status benefits from sulfurous water consumption, which can reduce bio-molecule oxidation and furnish valid protection against oxidative damage commonly associated with aging and age-related degenerative diseases. Correspondingly, modulation of oxidative stress by calorie restriction is recommended as one mechanism to slow the aging process and the decline of body functions in animals. Given all that, it implies that hydrogen sulfide may inhibit free radical reaction and oxidative stress to increase human health.
The free radical theory was revised when mitochondria were identified as responsible for the initiation of most of the free radical reactions occurring in the cells. It was also postulated that the life span is determined by the rate of free radical damage to the mitochondria. In fact, mitochondria, in which there is a continuous generation of free radicals throughout cell life, and especially mitochondrial DNA, are key targets of the free radical attack. Similarly, Kimura et al. have show that hydrogen sulfide increases glutathione production and suppresses oxidative stress in mitochondria. It has also been shown that preconditioning with H2S could prevent post-ischemic mitochondrial dysfunction by a calcium-activated, large conductance potassium channel-dependent mechanism . Additionally, it has been confirmed that peroxisome proliferator-activated receptor-gamma (PPAR γ) has a novel role in protecting against age-induced oxidative stress and endothelial dysfunction. Hydrogen sulfide happened to been shown to up-regulate peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha, a key gluconeogenic regulator that enhances the gene expression of fructose-1,6-bisphosphatase, to regulate glucose metabolism and methylglyoxal generation. However, the direct evidence, whether hydrogen sulfide can also protect against age-induced oxidative stress via PPAR γ or not, is to be investigated further.
Hydrogen sulfide activates SIRT1 to resist aging
The silent information regulator 2 (SIR2) gene family which are conserved from bacteria to humans functions in silencing, cell cycle progression and chromosome stability . In Caenorhabditis elegans, it has been surveyed that increased dosage of a Sir2 gene could extend lifespan . Mammals have seven Sir2 homologs (sirtuins, SIRT1-7). These proteins have a highly conserved NAD-dependent sirtuin core domain, first identified in yeast Sir2 protein, making them good candidates as lifespan regulators. The Sir2 homolog SIRT1 is the most studied of the seven human sirtuin family members. It has emerged as a major lifespan regulator. Hydrogen sulfide, however, has been shown to change NAD+/NADH content ratio in hepatocytes and enhances the activity of SIRT1 protein directly or indirectly . It is hypothesized that hydrogen sulfide could activate SIRT1 to resist aging.
In the fly, Sir2 mediates longevity through a pathway related to calorie restriction. Caloric restriction (CR), which has been accepted by many researchers as the only established anti-aging experimental paradigm, delays aging by activating the Sir2 deacetylase in yeast. It has been shown that expression of mammalian Sir2 (SIRT1) is induced in CR rats as well as in human cells that are treated with serum from these animals. Insulin and insulin-like growth factor 1(IGF-1) signaling (IIS), which regulates animal aging, attenuates this response . SIRT1 deacetylates the DNA repair factor Ku70, causing it to sequester the pro-apoptotic factor Bax away from mitochondria, thereby inhibiting stress-induced apoptotic cell death. A major cause of aging is thought to arise from the cumulative effects of cell loss over time. Thus, CR could extend life-span by inducing SIRT1 expression and promoting the long-term survival of irreplaceable cells . 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 these phenotypes require Sir2 activity which may translate environmental change into physiological alterations to improve survival. It is also appeared that CR benefits CSE and CBS protein in both aorta and liver, potentially by reducing oxidative stress and ameliorating the negative effect of age on H2S concentration. Therefore, Predmore et al. think that CR may help maintain the H2S signaling system during aging . It seems that CR and H2S have a synergistic effect on anti-aging by regulating SIRT1 activity. Recently, our laboratory has demonstrated that H2S protects against HUVECs senescence and its mechanism may involve regulation of SIRT1 activity. Maybe, hydrogen sulfide is a calorie restriction mimetic with potential anti-aging just as resveratrol by activating SIRT1, but this propose needs to be clarified with further investigations.
Resveratrol, a polyphenol in red wine, has been reported as a calorie restriction mimetic with potential anti-aging and anti-diabetogenic properties. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Inhibiting PDE4 with rolipram reproduces all of the metabolic benefits of resveratrol, including prevention of diet-induced obesity and an increase in mitochondrial function, physical stamina, and glucose tolerance in mice. Therefore, it is considered that administration of PDE4 inhibitors may also protect against and ameliorate the symptoms of metabolic diseases associated with aging . It so happens that H2S acts as an endogenous inhibitor of phosphodiesterase activity . Yet, the evidence that H2S shares the same mechanism of inhibiting phosphodiesterase to interact aging, similar to anti-aging with activity of SIRT1, has not been testified.
Hydrogen sulfide may influence an aging-related gene: Klotho
The klotho gene, an aging-related gene, suppresses the expression of multiple aging-associated phenotypes to extend life span. Activating the FOXO forkhead transcription factors which induces expression of manganese superoxide dismutase, Klotho protein increases resistance to oxidative stress which potentially contributes to the anti-aging properties of klotho. It has also been reported that klotho represses the DAF-2 (Insulin/IGF-like) receptors under physiological conditions, inducing DAF-16(FOXO) de-repression and subsequent overexpression of longevity factors such as antioxidant enzymes, to improve longevity and stress resistance .
The klotho gene has been indicated to be predominantly expressed in the kidney. It is suggested that downregulation of the renal klotho gene may have an aggravative role in the development of renal damage induced by angiotensin II with increased oxidative stress, and that induction of the klotho gene may have therapeutic possibilities in treating angiotensin II-induced end organ damage. And Yoon et al. also confirm that angiotensin II may play a pivotal role in regulating Klotho expression in cyclosporine(CsA)-induced renal injury and that an angiotensin II type 1 (AT1) receptor blocker may inhibit the aging process by decreasing oxidative stress caused by CsA. Interestingly, H2S exhibits direct inhibitory action on angiotensin converting enzyme (ACE) activity, which catalyzes the conversion of angiotensin I to angiotensin II. Moreover, it has been demonstrated that H2S could dose-dependently decrease angiotensinII-induced MAPK activation, AT1 receptor binding and the binding affinity of the AT1 receptor . In addition, Lu et al. demonstrate that H2S may inhibit renin activity, which participates in the body's renin-angiotensin system(RAS) . Overall, if hydrogen sulfide may improve Klotho expression by having a negative impact on angiotensin II, the prospects that hydrogen sulfide would be next health-care and therapeutic substrate in the aging process and age-associated diseases could be rosier.
Fig.2. Interaction between hydrogen sulfide and aging.
CR, resveratrol, klotho have been considered to have anti-aging property. CR, resveratrol share the similar anti-aging mechanisms via increasing SIRT1 expression, inhibiting oxidative stress or anti-apoptosis. Klotho can improve longevity by inhibiting IIS signaling, inducing FOXO de-repression, decreasing angiotensinâ…¡-induced oxidative stress and so on. H2S has already been reported that it can also suppress oxidative stress in mitochondria, change NAD+/NADH content ratio, enhance the activity of SIRT1 activity and inhibit PDE or ACE activity and so forth. From this figure, it is concluded that H2S may have anti-aging function through several shared pathways related to CR, resveratrol, klotho.
Therapeutic implications of hydrogen sulfide in age-associated diseases
Hydrogen sulfide has been generally recognized as an important signaling molecule in the cardiovascular and nervous systems. The enhancement of H2S physiological effects 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, Cancer and so on.
Cardiovascular system diseases
Aging has been regarded as a principal risk factor in the progression of hypertension. In spontaneously hypertensive rats , plasma concentration of H2S has a substantial lower level compared with normotensive control animals. It is reliable that hydrogen sulfide participates in hypertension and prevents the development of hypertension . Although Ishii et al. have shown that deletion of CSE does not significantly alter blood pressure in mice, it is important to point out that in this study blood pressure was measured by using the tail-cuff method which is not only less precise but also leads to highly variable measurements hindering proper analysis of the data. Beyond all question, H2S elicits endothelium-independent vasorelaxation involving several different ion channels and seems to converge at the vascular smooth muscle cell voltage-gated Ca2+ channel in mouse aorta . Further, the finding that H2S is a major EDHF acting by means of sulfhydrating potassium channels, as well as its novel mechanism of action may have important therapeutic implications. It means that drugs altering CSE activity or H2S-mediated channel sulfhydration may be beneficial in treating hypertension .
Atherosclerosis, a lesion in the large and medium arteries, is the primary cause of coronary artery disease. It is now clear that atherosclerosis is not simply a chronic inflammatory condition that can be converted into an acute clinical event by plaque rupture and thrombosis, but rather an inevitable degenerative consequence of aging . Atherosclerosis is characterized by multiple key events including endothelial dysfunction, monocytes infiltration and their differentiation into macrophages, conversion of lesion-resident macrophages into foam cells, and smooth muscle cell proliferation. Fortunately, atherosclerosis could be interrupted by hydrogen sulfide. Increasing evidences have indicated that H2S plays a potentially significant role in all of these biological processes and that malfunction of H2S homeostasis may contribute to the pathogenesis of atherosclerosis. For instance, H2S plays an antiatherogenic role by suppressing human macrophage foam cell formation. Down-regulating CD36, SR-A and ACAT-1 expressions and inhibiting oxLDL binding and uptake of macrophages, H2S inhibits formation of macrophage-derived foam cells which is a crucial event in the development of atherosclerosis . Consistent with the roles of hydrogen sulfide in atherosclerosis, there is a direct evidence that hydrogen sulfide can be beneficial to coronary heart disease (CHD) patients. In patients with CHD, plasma H2S levels show a significant inverse correlation with the severity of CHD and changes of the coronary artery. Moreover, the hydrogen sulfide balneotherapy with CHD patients results in a significant prolongation of stress bicycle exercise (SBE). And it is recognized that in a hot climate of the arid zone, use of moderate H2S baths raises tolerance of CHD patients to exercise, attenuates clinical manifestations of CHD and, consequently, reduces daily need in nitrates. Additionally, for the treatment of myocardial infarction (MI), stem cell transplantation has become a promising therapeutic approach. But the poor survival of the donor cells after transplantation has restricted its therapeutic efficacy. However, H2S has been applied to inhibit cell apoptosis and promote cell survival. It has been demonstrated that H2S preconditioning effectively promotes stem cells survival under ischemic injury and helps cardiac repair after MI .
Central Nervous System Degenerative Diseases
Parkinson's disease (PD) is a neurodegenerative disease characterized by a progressive loss of dopaminergic neurons in the substantia nigra (SN). In a 6-hydroxydopamine (6-OHDA)-induced PD rat model, the endogenous H2S level is markedly reduced in the SN. However, treatment of H2S could specifically inhibit 6-OHDA evoked NADPH oxidase activation, oxygen consumption microglial activation in the SN, and accumulation of pro-inflammatory factors in the striatum . Parkinson's disease is one of the most common neurodegenerative diseases with various manifestations, among which the cognitive deficit, dementia, has a prominent role. Dementia is usually ascribed to changes in the nucleus basalis of Meynert and the cerebral cortex. H2S has also been suggested to attenuate vascular dementia injury via inhibiting apoptosis by markedly improving the ratio of Bcl-2 over Bax , increasing Bcl-2 expression and decreasing Bax expression.
Alzheimer's disease, AD, is also the most common form of dementia. AD initially targets memory and progressively destroys the mind. Alzheimer's disease (AD) is pathologically characterized by the accumulation of senile plaques, containing activated microglia and amyloid-beta peptides (Abeta). In the brains of Alzheimer's disease (AD) patients compared with the brains of the age matched normal individual, it has been discovered that the levels of H2S are severely decreased. As previously mentioned, hydrogen sulfide is endogenously produced in the brain from cysteine by cystathionine-beta-synthase (CBS). Additionally, S-adenosyl-l-methionine (SAM), a CBS activator, is much reduced in AD brain. These observations suggest that CBS activity is reduced in AD brains and the decrease in H2S may be involved in some aspects of the cognitive decline in AD. Accordingly, Liu's study shows that H2S has been demonstrated to protect cell against Abeta-induced cell injury by inhibition of inflammation, promotion of cell growth and preservation of mitochondrial function in a p38- and JNK-MAPK dependent manner. Anyhow, it indicates that hydrogen sulfide has a promising therapeutic implication in neurodegenerative diseases.
The pathogenesis of diabetes is associated with reduced beta-cell mass and increased activities of ATP-sensitive K+ channels in pancreatic beta cells. However, H2S can induce apoptosis of insulin-secreting beta cells by enhancing ER stress via p38 MAPK activation and also stimulate KATP channels in insulin-secreting cells. It indicates that H2S play a pathogenic role in diabetes . Diabetes mellitus is also characterized by resistance of peripheral tissues to insulin . Similarly, H2S generated by adipose tissues might inhibit basal or insulin-stimulated glucose metabolism in adipose tissues, regulate insulin sensitivity and contribute to the pathogenesis of diabetes mellitus. With age, the endogenous CSE/ H2S system was up-regulated in adipose tissues. H2S, therefore, may be a novel insulin resistance regulator. In diabetic rats, H2S formation was increased in pancreas and liver because CSE and CBS mRNAs were increased. Insulin treatment restored the changes in H2S metabolism. It also implies that H2S may play a part in the aetiology or development of diabetes in this animal model. By contrast, blood H2S levels are significantly lower in fasting blood obtained from type 2 diabetes patients compared with age-matched healthy subjects, and in streptozotocin-treated diabetic rats compared with control Sprague-Dawley rats. It is speculated that lower blood H2S levels may contribute to the vascular inflammation in diabetes because supplying with H2S can prevents inflammatory factor IL-8 and MCP-1 secretion . To sum up above points, it seems as if hydrogen sulfide has a negative effect on diabetes. Nevertheless, it has also been indicated that the protective effects of H2S on endothelial cells in the condition of high glucose. There are contradictory versions of what role hydrogen sulfide has in diabetes. It shows that inhibiting pancreatic H2S biosynthesis can be regard as a potential approach to protect β-cells from death during the induction phase of diabetes, whereas supplementation with H2S would be considered as a potential approach to maintain diabetic blood vessel potency, and possibly to protect against diabetic nephropathy and cardiomyopathy of diabetic complications .
The slow-releasing hydrogen sulfide (H2S) donor, GYY4137, can cause concentration-dependent killing of seven different human cancer cell lines (HeLa, HCT-116, Hep G2, HL-60, MCF-7, MV4-11 and U2OS). Therefore, it implies that hydrogen sulfide should be a potential anti-cancer agent . Moreover, hydrogen sulfide-releasing non-steroidal anti-inflammatory drugs (HS-NSAID), which consist of a traditional NSAID to which an H2S -releasing moiety is covalently attached, are capable of significant anti-inflammatory properties. HS-NSAID could inhibit the growth of all cancer cell such as human colon, breast, pancreatic, prostate, lung, and leukemia cancer cell by inhibiting cell proliferation, inducing apoptosis, and causing G0/G1 cell cycle block. It indicates again that hydrogen sulfide may have potential anti-growth activity against various human cancer cells.
It has also been found that Sulforaphane(SFN), a sulfur-containing compound that exhibits anticancer properties in treating prostate cancer, can release a large amount of H2S. Pei's study shows that H2S can decrease the viability of PC-3 cells (a human prostate cancer cell line) in a dose-dependent manner. More importantly, it has been known that both cystathionine-gamma-lyase (CSE) and cystathionine-beta-synthase(CBS) are expressed in prostate. In the future, H2S-releasing diet or drug might be beneficial in the treatment of prostate cancer . Similarly, hydrogen sulfide-releasing aspirin (HS-ASA) a novel and safer derivative of aspirin, has shown promise as an anti-cancer agent against hormone-independent estrogen receptor negative (ER-) breast cancers associated with inhibition of cell proliferation, induction of apoptosis and decrease in NF-kappa B levels. . Moreover, it has been recently reported that NOSH-aspirin, which is an NO- and H2S-releasing agent, can inhibit colon cancer growth with the role of inhibiting cell proliferation, inducing apoptosis, and causing G0/G1 cell cycle block. Taken together, these results indirectly demonstrate that hydrogen sulfide has strong anti-cancer potential and merits further evaluation.
All the above-mentioned views imply that hydrogen sulfide participates in the development of aging and age-associated diseases, even though the mechanisms of action of hydrogen sulfide in the aging process and age-associated diseases have not yet been characterized in sufficient detail. More studies about hydrogen sulfide, therefore, need to be pursued and performed further. A better understanding of the roles of hydrogen sulfide involved in aging can provide insights into potential interventions that may affect the aging process and reduce age-associated diseases, thereby promoting healthy longevity. In the foreseeable future, it is not impossible that hydrogen sulfide may become next health-care and therapeutic substrate in the aging process and age-associated diseases.