NOTE: End date changed to 12/31/2032 per C. Ribeiro/JSC. The period of performance was updated after the "Select for Flight" was completed (Ed., 8/18/23)

In ground analog studies, end-tidal CO2, a reflection of arterial CO2, response to acute head-down tilt (HDT) bed rest and CO2 exposure was related to G and C alleles of MTRR A66G and SHMT1 C1420T and B-vitamin status. Supportive of this, these same alleles were related to the presence of optic disc edema in different bed rest subjects. Subjects were exposed to strict 6°-HDT bed rest and 0.5% CO2 for 30 days and 5 out of 11 subjects developed optic disc edema. The number of G and C alleles were found to be associated with the change in total retina thickness (?TRT), a quantitative measure of optic disc edema. Based on our data, differences in genetics and altered one-carbon biochemistry before flight support that one-carbon metabolism may be involved.

We hypothesize that genetics and B-vitamin status are indispensable elements of this phenomenon, along with other potential factors. Dietary B-vitamin insufficiencies and variants in genes involved in the one-carbon metabolic pathway can contribute to lower B-vitamin status and pathway inefficiency, which can affect numerous outcomes, including nitric oxide (NO) production and endothelial function.

To that end, we propose a nutraceutical containing bioactive B-vitamins as a countermeasure to optimize function of the one-carbon pathway and prevent or mitigate optic disc edema during spaceflight.

This proposal aims to test the hypotheses that one-carbon pathway genetics can predispose an individual to SANS pathologies during flight, and that this effect may be prevented or mitigated through supplementation of vitamins that can affect one-carbon pathway function.

The hypothesis will be tested in the following specific aims:

1. Determine whether provision of a daily nutraceutical containing 5-methyltetrahydrofolate (5-MTHF), pyridoxine, methylcobalamin (vitamin B12), and riboflavin prevents or mitigates SANS pathology (significant ?TRT) compared to astronauts who did not take the supplement in previously flown astronauts with available TRT data.

2. Determine one-carbon pathway SNP profiles in all participating astronauts being supplemented, and assess whether individuals with 3-4 risk alleles for MTRR A66G and SHMT1 C1420T polymorphisms have greater mitigation of ?TRT during and after spaceflight.

3. Determine whether subjects with 3-4 risk alleles exhibit differences in biomarkers of endothelial function, compared to subjects with 0-2 risk alleles.

We propose to provide the nutraceutical countermeasure to all participating crewmembers before and during flight, and we will assess whether the supplement provides greater mitigation of changes in TRT in individuals with 3-4 risk alleles. We will include assessments of ocular health, along with determinants of vascular endothelial function, advanced glycation end products, and nutritional status and one carbon biochemistry. These additional measures will be critical for the further definition of the causes of SANS, and in understanding the effect of the countermeasure. Finally, the supplemented subjects in this study will be compared against TRT data from previously flown astronauts known to have not taken supplements during their missions.

Sixteen subjects will be recruited for the study. All 16 will take the proposed B-vitamin supplement. Several individuals have signed up for the study to date. Active recruiting for additional subjects is ongoing.

Previously flown crewmembers who did not take B-vitamin supplements are also being recruited to serve as retrospective control subjects.

NOTE: End date changed to 12/31/2032 per C. Ribeiro/JSC. The period of performance was updated after the "Select for Flight" was completed (Ed., 8/18/23)

In ground analog studies, end-tidal CO2, a reflection of arterial CO2, response to acute head-down tilt (HDT) bed rest and CO2 exposure was related to G and C alleles of MTRR A66G and SHMT1 C1420T and B-vitamin status. Supportive of this, these same alleles were related to the presence of optic disc edema in different bed rest subjects. Subjects were exposed to strict 6°-HDT bed rest and 0.5% CO2 for 30 days and 5 out of 11 subjects developed optic disc edema. The number of G and C alleles were found to be associated with the change in total retina thickness (?TRT), a quantitative measure of optic disc edema. Based on our data, differences in genetics and altered one-carbon biochemistry before flight support that one-carbon metabolism may be involved.

We hypothesize that genetics and B-vitamin status are indispensable elements of this phenomenon, along with other potential factors. Dietary B-vitamin insufficiencies and variants in genes involved in the one-carbon metabolic pathway can contribute to lower B-vitamin status and pathway inefficiency, which can affect numerous outcomes, including nitric oxide (NO) production and endothelial function.

To that end, we propose a nutraceutical containing bioactive B-vitamins as a countermeasure to optimize function of the one-carbon pathway and prevent or mitigate optic disc edema during spaceflight.

This proposal aims to test the hypotheses that one-carbon pathway genetics can predispose an individual to SANS pathologies during flight, and that this effect may be prevented or mitigated through supplementation of vitamins that can affect one-carbon pathway function.

The hypothesis will be tested in the following specific aims:

1. Determine whether provision of a daily nutraceutical containing 5-methyltetrahydrofolate (5-MTHF), pyridoxine, methylcobalamin (vitamin B12), and riboflavin prevents or mitigates SANS pathology (significant ?TRT) compared to astronauts who did not take the supplement in previously flown astronauts with available TRT data.

2. Determine one-carbon pathway SNP profiles in all participating astronauts being supplemented, and assess whether individuals with 3-4 risk alleles for MTRR A66G and SHMT1 C1420T polymorphisms have greater mitigation of ?TRT during and after spaceflight.

3. Determine whether subjects with 3-4 risk alleles exhibit differences in biomarkers of endothelial function, compared to subjects with 0-2 risk alleles.

We propose to provide the nutraceutical countermeasure to all participating crewmembers before and during flight, and we will assess whether the supplement provides greater mitigation of changes in TRT in individuals with 3-4 risk alleles. We will include assessments of ocular health, along with determinants of vascular endothelial function, advanced glycation end products, and nutritional status and one carbon biochemistry. These additional measures will be critical for the further definition of the causes of SANS, and in understanding the effect of the countermeasure. Finally, the supplemented subjects in this study will be compared against TRT data from previously flown astronauts known to have not taken supplements during their missions.

The first crew were briefed in an informed consent briefing and we are waiting to hear if any of those crew have signed up for the study.

In ground analog studies, end-tidal CO2, a reflection of arterial CO2, response to acute head-down tilt (HDT) bed rest and CO2 exposure was related to G and C alleles of MTRR A66G and SHMT1 C1420T and B-vitamin status. Supportive of this, these same alleles were related to the presence of optic disc edema in different bed rest subjects. Subjects were exposed to strict 6°-HDT bed rest and 0.5% CO2 for 30 days and 5 out of 11 subjects developed optic disc edema. The number of G and C alleles were found to be associated with the change in total retina thickness (ΔTRT), a quantitative measure of optic disc edema. Based on our data, differences in genetics and altered one-carbon biochemistry before flight support that one-carbon metabolism may be involved.

We hypothesize that genetics and B-vitamin status are indispensable elements of this phenomenon, along with other potential factors. Dietary B-vitamin insufficiencies and variants in genes involved in the one-carbon metabolic pathway can contribute to lower B-vitamin status and pathway inefficiency, which can affect numerous outcomes, including nitric oxide (NO) production and endothelial function.

To that end, we propose a nutraceutical containing bioactive B-vitamins as a countermeasure to optimize function of the one-carbon pathway and prevent or mitigate optic disc edema during spaceflight.

This proposal aims to test the hypotheses that one-carbon pathway genetics can predispose an individual to SANS pathologies during flight, and that this effect may be prevented or mitigated through supplementation of vitamins that can affect one-carbon pathway function.

The hypothesis will be tested in the following specific aims:

1. Determine whether provision of a daily nutraceutical containing 5-methyltetrahydrofolate (5-MTHF), pyridoxine, methylcobalamin (vitamin B12), and riboflavin prevents or mitigates SANS pathology (significant ΔTRT) compared to astronauts who did not take the supplement in previously flown astronauts with available TRT data.

2. Determine one-carbon pathway SNP profiles in all participating astronauts being supplemented, and assess whether individuals with 3-4 risk alleles for MTRR A66G and SHMT1 C1420T polymorphisms have greater mitigation of ΔTRT during and after spaceflight.

3. Determine whether subjects with 3-4 risk alleles exhibit differences in biomarkers of endothelial function, compared to subjects with 0-2 risk alleles.

We propose to provide the nutraceutical countermeasure to all participating crewmembers before and during flight, and we will assess whether the supplement provides greater mitigation of changes in TRT in individuals with 3-4 risk alleles. We will include assessments of ocular health, along with determinants of vascular endothelial function, advanced glycation end products, and nutritional status and one carbon biochemistry. These additional measures will be critical for the further definition of the causes of SANS, and in understanding the effect of the countermeasure. Finally, the supplemented subjects in this study will be compared against TRT data from previously flown astronauts known to have not taken supplements during their missions.