The wonder of gasotransmitters:
H₂S and the origin of life

Gasotransmitters are small gaseous molecules that are released by cells and easily diffuse within the cell, to other cells and in circulation to modulate almost every biological function. In spite of their massive effects, due to their vanishing nature, these gases excaped our observation for long time. In 1998, a nobel price was assigned to the discovery of nitric oxide (NO) signalling and the new era started. After NO and carbon monoxide (CO), hydrogen silfide (H₂S) was the third discovered and most exciting gasotransmitter.

The pivotal role of H₂S was discovered in hydrothermal vents, volcaninc springs at the bottom of the oceans guesting a rich echo system at a place where life should not be possible. The sulphur gasses were feeding ancient bacteria using H₂S as their source of energy. Years later, paleobiologist are loocking at H₂S as the origin of life on the planet, astrobiologists are loocking for underwater life across the universe and physiologists are loocking at gaseous signals to understand the secrets of life.

As soon as H₂S is released, thousands of proteins (enzymes) suddenly modify their activity to adapt their function to the metabolic needs. The effects of these changes vary according to the place of release and to the amount and may impact the main physiologic functions including:

• Inflammation and immunity
• Redox balance
• Coagulation and platelets
• Endothelial function and blood pressure
• Iron turn-over
• Glucose metabolism and insulin signalling
• Resistence to hypoxia and reperfusion
• Bioenergetics: At the end of the journey, any excess or storage of H₂S can be used in mitochondria to provide ATP without generating Reactive Oxygen Species (ROS)

Feeding H₂S release and signalling:
The role of vitamin B6

Hydrogen sulfide (H₂S) is a small reducing molecule generated from the -SH (sulfide) group of the aminoacid cysteine. The release occurs both under the action of several enzymes, which is strictly regulated in response to metabolic signals, or in circulation from a spontaneous reaction between B6, cysteine and iron, which is in direct connection with the diet.

The amount of H₂S released depends on the availability of the concerned enzymes, of their main substrate, cysteine, and of vitamin B6 in its active form pyridoxal 5-phosphate (P5P). Both the enzymatic production and the spontaneous generation are strictly P5P dependent, i.e. the higher the concentration of P5P, the higher the release of H₂S.

Vitamin B6 behavior is unique among vitamins: It gets “consumed” by the inflammatory processes that it is intended to mitigate so that it can be in shortage just where and when it is more needed. Indeed, the only B6 active form, P5P, can be inactivated by oxidation or by de-phosphorylation, both induced by inflammation. Thus, the supra-physiologic amounts of P5P of Redostim may compensate such losses keeping P5P level high enough to work, possibly also in subjects more exposed to shortages due to their diet and/or gentics and/or diseases.

H₂S release is also favoured by increased availability of cysteines, provided in Redostim in their soluble and circulating form of L-cystine (formed by 2 cysteines). Within cells, L-cystine releases free cysteine on-demand and any excess is disposed as taurine. Redostim also contains taurine so to give a negative feedback to cysteine elimination and to further increase the availability of free cysteines for H₂S release.

In summary, Redostim mimics a diet very enriched of vitamin B6 and cysteines and this results in an improved background ability to release H₂S by the spontaneous intravascular processes. Moreover, when and if signals for an enzymatic release should be in place, also this H₂S response would be improved.

H₂S in the life journey:
Reproduction and aging

H₂S might be defined as the master regulator of life, from reproduction to the aging process.

Both the testes and the ovaries are a main site of H₂S release. In spermatogenesis it has a pivotal role in keeping the redox balance and in avoiding oxidative damages to sperm DNA. In ovarian follicles H₂S is increasingly released to favour follicle maturation and rupture and thereafter by the corpus luteum, both sending messages to the neighboring endometrium to initiate the changes necessary for embryo implantation. H₂S release is thereafter provided by the placenta, under hCG and progesterone push, with progressively increasing release up to delivery, which is triggered by a sharp fall of H₂S.

The role of H₂S in pregnancy is pivotal:

• Activates innate immunity to induce tolerance to the sperm (allogenic) and to the embryo (semi-allogenic, entirely allogenic if from oocyte donation)
• Inhibits uterine contractions to avoid the explusion of the implanting embryo, thereafter to keep the uterus at rest until the end of pregnancy
• Activates the neovascularization of the endometrium to ensure full blood support to the embryo and then to the foetus.
• Induces vasodilation in the uterine artery to increase the flux of blood

The release of H₂S also changes during life. Very low at birth (following the sharp fall during labour), it progressively increases during development. Women in fertile age enjoy peaks of H₂S in connection with the follicular cycle, a possible reason for their improved protection from CVD until menopause. In adulthood, the ability to release H₂S, and all the H₂S-sustained functions, progressively decline with aging so that such decrease can be considered a marker of the aging process.

Caloric restriction is a well validated antiaging intervention in animal studies. Interesting, most of the antiaging effects of caloric restriction are mediated by the onset of a stronger H₂S signalling.

Boosting the H₂S system:
Who, when, how

A shortage of H₂S signalling is well described in a variety of human diseases.

In reproduction, a decrease of H₂S is well documented in preeclampsia and likely to be in place in cases of repeated implantation failure and of follicular arrest. In males, a bulk of data point to hampered H₂S signals in varicocele.

A reduced H₂S release is well documented in chronic inflammatory diseases including CVD, diabetes, hypertension, neurodegeneration. A defective activation of innate immunity due to lack of H₂S is reported in many autoimmune diseases.

The reasons for the failure of H₂S release are likely in the individual genetics and its interaction with dietary and environmental factors as well as with intercurring diseases and, obvously, the aging process. Among these, the easiest factor to modify is the diet. Cysteines are the least abundant amino acid in dietary proteins, however vegetable proteins are a better source. Vitamin B6 is widely available in both animal and vegetal food. However, foods mostly contain non activated forms of B6 and those with a weak genetics for B6 activation may remain in relative shortage of P5P, even more if an inflammatory process is in place (consumption of B6). Subjects carrying defective genetic variants of the H₂S-releasing enzymes may enjoy full compensation by adding larger amounts of B6 (better P5P) to their diet.

Checking chronic inflammation:
hsCRP

Chronic inflammation is a silent and continuous inflammatory process that contributes to all the above mentioned diseases and that plays a key role in the aging process. The best validated test to monitor chronic inflammation is the C-reactive protein (CRP). It moves very fast between normal and very high values in case of acute inflammation. To investigate the changes of CRP in chronic inflammation we need to look at smaller changes, sometimes within the normal limit, by means of a high sensitivity CRP testing (hs(CRP).

The hsCRP test is offered by every clinical lab and is of common use, mainly to monitor the activity of CVD. However, everybody can check the own hsCRP to monitor the effect of dietary changes. Any decrease of thehsCRP value will mark a lower inflammation grade and, likely, a slower aging.