Life on Earth is insulated from the harmful effects of galactic cosmic rays and solar particle events through particle deflection by the Earth’s magnetosphere and shielding by Earth’s atmosphere. With the exception of the Apollo lunar missions, manned spaceflight has taken place exclusively in LEO where atmospheric protection from space radiation is essentially absent, but protection by the Earth’s geomagnetic field is present. Under these conditions, it has been broadly assumed that missions in LEO or short excursions to the Moon would not increase the long-term risk for CVD among astronauts16,18. Using non-flight astronauts as a comparison group, the data show that this group had a mortality rate of approximately 9% due to CVD (Fig. 1). The mortality rate for CVD among all US flight astronauts, including both LEO and Apollo lunar astronauts, was not different than that in the non-flight astronauts. However, when considered as a separate group, the Apollo lunar astronauts, the only group of humans to have traveled outside of the Earth’s protective magnetosphere, demonstrate a higher mortality rate due to CVD compared to both the cohort of astronauts that did not travel into space, as well as astronauts who remained in LEO (Fig. 1). These data suggest that human travel into deep space may be more hazardous to cardiovascular health than previously estimated.

Astronaut mortality has been reported in four previous studies. In the first by Peterson et al.22, it was reported that of the 20 deceased US astronauts from 1959–1991 the causes of death were due to circulatory disease (10%), cancer (5%), accidents (80%) and other causes (5%). Using the US population as the reference group, it was found that mortality due to CVD was significantly lower in astronauts and accidental deaths were significantly higher22. A subsequent study by Hamm et al.23 focused solely on cancer-specific mortality among astronauts through 1995 and included an additional reference group of Johnson Space Center employees. This comparison group was part of a Longitudinal Study of Astronaut Health initiative by the National Aeronautics and Space Administration (NASA) to better assess the occupational health risks of astronauts, since the health characteristics of astronauts and the overall environment in which they train at Johnson Space Center were deemed to be different from that of the general US population24. Results from this study indicated that there was not a significant difference in cancer mortality between astronauts and Johnson Space Center employees or Texas residents living in the area surrounding Johnson Space Center23. In a follow-up study by Hamm et al.25, cause-specific mortality rates beyond just cancer were examined. The only significant difference found was a higher number of accidental deaths among astronauts (69%) relative to Johnson Space Center employees (14%). Finally, in the most recent study published by Reynolds and Day26, the cause-specific mortality rates from 1980–2009 were reported in astronauts and residents of Harris County, Texas, where Johnson Space Center is located. The results indicated a lower risk of death due to CVD and cancer in astronauts versus Harris County residents and a higher risk of death due to accidents26. Collectively, these studies indicate that the risk of death due to chronic diseases appears to be lower in astronauts, particularly those involving CVD22,26.

The current analysis of mortality rates among astronauts differs from these previous studies in several important ways. The first is the reference population used to gauge the significance of cause-specific mortality rates among astronauts. The biomedical characteristics of astronauts are very different from individuals in the general population. According to the Review of NASA’s Longitudinal Study of Astronaut Health by the Institute of Medicine24, astronauts have substantially higher incomes, levels of education, general fitness and lifelong access to medical care, all of which are factors known to contribute to high levels of health and well-being. With such large baseline differences between astronauts and comparison groups, it is difficult to ascertain what specific impact spaceflight might have on astronaut health. For this reason, the Institute of Medicine recommended in 2004 that astronauts who have never flown in space be used as a reference population24; the present study is the first to incorporate non-flight astronauts as a comparison group. Consequently, current results demonstrate that previous conclusions suggesting the risk of death due to CVD is lower among flight astronauts22,26 are no longer tenable.

The second unique feature of the present study is that it is the first to examine the long-term mortality risks of spaceflight in LEO and deep space. Exposure to charged particles comprising the galactic cosmic rays in deep space has the potential to elicit a number of complications in biological tissue. Recent work in rodents and cell culture has highlighted the potentially harmful effects of such exposures on the cardiovascular system20,27,28,29,30, which may translate to astronauts engaged in deep space expeditions.

While traveling from LEO to the Moon and back, the Apollo lunar astronauts traversed regions of geomagnetically trapped electrons and protons known as the Van Allen belts and, depending on the duration of their mission and the specific activities in which they were engaged (e.g., lunar surface and intravehicular Command and Lunar Module activities), were continuously subjected to varying levels of high-energy cosmic rays31. Fortunately, there were no major solar particle events during any of the Apollo missions. The lunar astronauts also experienced a visual phenomenon of light flashes (~17/hour) when the spacecraft was dark and tests indicated that the flashes were the result of HZE cosmic rays traversing the retina31,32.

Interactions of the galactic cosmic rays with the spacecraft hull will have a large impact on the radiation exposure of astronauts. Charged particles traversing the hull or “shielding” of the ship will incur nuclear interactions that depend on the composition and thickness of the hull material. These interactions will result in fragmentation products and particles of reduced energy but higher LET that contribute to the radiation dose within the spacecraft. The average radiation dose for the seven deceased Apollo crew was 0.59 ± 0.15 cGy (range 0.18–1.14 cGy)31. If we assume representative shielding scenarios (10 g/cm2) for the Apollo Command Module and radiation quality factors drawn from the most recent International Commission on Radiological Protection33, then the average radiation dose from the galactic cosmic rays to the Apollo astronauts would be approximately 0.295 cGy, or roughly half the total dose during their lunar excursions9. Using similar assumptions, astronauts in LEO would receive 50–100 mSv over a 6–12 month stay, of which the galactic cosmic rays would account for approximately two-thirds of this total dose9. Thus, given their mean mission duration of 15.6 days, the deceased LEO astronauts would receive approximately 0.29 cGy, a galactic cosmic ray dose very similar to the Apollo lunar astronauts.

Despite virtually identical estimates for galactic cosmic ray exposure, the mortality rate of LEO astronauts for CVD is significantly lower than in Apollo lunar astronauts. Furthermore, LEO astronauts do not exhibit significant differences in mortality compared to non-flight astronauts. Several factors may account for this apparent paradox. First, lunar and LEO galactic cosmic ray dose estimates were made using certain assumptions that are constantly being revised. For instance, if actual shielding levels for the Apollo missions were less than 10 g/cm2, calculated lunar galactic cosmic ray doses may be underestimates. Second, activities on the lunar surface and inside the lightly shielded Lunar Module may also include dose contributions from scattered albedo neutrons, which are relatively insignificant inside a spacecraft. And finally, lunar and deep space exposures will include dose contributions from less energetic and lighter particles. For astronauts in LEO, the relative contribution of particles with energies below the geomagnetic cutoff is lower since they will be deflected by the Earth’s magnetosphere. While it remains uncertain whether differences in absorbed dose profiles can account for the elevated lunar CVD mortality rates reported here, it is equally difficult to disregard this possibility. As a result, these findings highlight the potential adverse impact of charged particles and their unique microdosimetric properties on post-mitotic cellular structures responsible for maintaining longer-term cardiovascular health.

The possibility of long-term degenerative effects of deep space travel on cardiovascular function has not been well described or substantiated. Only in the last decade, when multiple spacefaring nations and corporate entities have announced plans to embark on manned exploratory missions to Mars and prolonged habitation on the Moon, has biomedical research been directed towards identifying possible CVD risks associated with the deep space radiation environment. Consequently, there is limited information available on the effects of charged particle HZE radiation on the cardiovascular system.

Results from the present study address the question of possible long-lasting interactive effects of simulated weightlessness and space radiation on vascular function. To experimentally address this question, vascular responses of resistance arteries were determined 6–7 months after the cessation of a 14-day hindlimb unloading treatment, a 1 Gy 56Fe irradiation treatment, or a treatment consisting of a combination of the two. Given that the average life-span of male C57BL/6 mice is 878 ± 10 days34, the 6–7 month period represents approximately 23% of animals’ life or roughly the equivalent of 18–20 years in humans. The data show that hindlimb unloading alone had no persistent effect to significantly diminish endothelium-dependent vasodilation, while HZE irradiation alone and in combination with unloading impaired endothelium-dependent vasodilation (Fig. 2) through the NO signaling mechanism (Fig. 3). This decrement in NO signaling appears to be mediated primarily through greater NO scavenging by reactive oxygen species, as evidenced by higher vascular protein content (Fig. 5A,B)20,27 and activity27 of XO in peripheral and coronary arteries. These data indicate that the long-lasting effects of simulated weightlessness and space radiation on vascular endothelial function are the result of the radiation exposure and are not due to an interaction with weightlessness. As dysfunction of the vascular endothelium is central to the pathogenesis of vascular disease35,36, such adverse arterial effects could lead to the development of occlusive arterial diseases, including myocardial infarction and stroke.

Although results from the present study provide new evidence that even short-term spaceflight beyond the Earth’s protective magnetosphere may have adverse effects on CVD mortality, there are limitations to consider. First, the sample size for cause-specific deaths among lunar astronauts is small. Therefore, caution must be used in drawing definitive conclusions regarding specific health risks. Second, although deep space radiation seems a likely cause underlying the higher proportional mortality rate due to CVD in Apollo astronauts, it remains unknown what specific factor(s) in the space environment is responsible. And third, although the HZE irradiation used in the animal studies was selected to mimic that which deep space travelers might encounter, the absorbed dose (1 Gy) and the dose rate (single exposure, 10cGy/min) would be higher and faster than that experienced by the Apollo lunar astronauts31. It would be more representative of the space environment to have the radiation exposure occur at a lower dose rate and over an extended time period. Unfortunately, that type of exposure paradigm using 56Fe ions is not currently feasible at Brookhaven National Laboratory. Despite these limitations, results from these animal studies demonstrate that space relevant irradiation induces long-lasting vascular dysfunction of the type known to presage the development of atherosclerotic cardiovascular disease35,36.

In summary, results from the present study reveal that Apollo lunar astronauts have a significantly higher mortality rate due to CVD than either the cohort of astronauts who never flew an orbital space mission or astronauts who never flew beyond LEO (Fig. 1). Moreover, the CVD mortality for lunar flight astronauts was higher than that in the age-matched US population, although this difference was not statistically significant. These findings suggest that in spite of the “healthy worker” effect, short-duration deep space travel by this highly educated, trained and physically fit group results in a significantly elevated risk of death from CVD. The major environmental factor that would appear to underlie this phenomenon is deep space radiation. Estimates indicate that the dose of galactic cosmic ray irradiation to which LEO and lunar astronauts were exposed were not greatly different. However, qualitative differences in the absorbed dose profiles resulting from the effect of the Earth’s magnetosphere to deflect less energetic and lighter galactic cosmic ray particles away from Earth may account for the lower CVD mortality rate among LEO astronauts. Animal studies also indicate that while simulated weightlessness and space-relevant irradiation interact to induce early impairment of endothelium-dependent vasodilation20, the only sustained vascular endothelial cell dysfunction is that mediated by exposure to HZE particles and not by simulated weightlessness (Fig. 2). If such results translate to the human condition, then long-term dysfunction of the vascular endothelium induced by charged HZE particles could be a major contributor to the development of atherosclerotic cardiovascular disease in astronauts.