From June 5438+065438+ 10, 2020, Cell Report published five research articles on the physiological changes of astronauts after space operations. As we all know, telomere is very important for aging and maintaining the integrity of genes. One of the articles made a detailed assessment of telomere length changes and DNA damage related to long-term space flight.
Due to the problem of terminal replication, the telomere length is eroded and shortened with cell division, and when it reaches a very short length, the cell cycle will be permanently stagnant. During the space flight, the researchers observed from the samples obtained from the crew that their telomere length became significantly longer; However, after space flight, the telomere length of astronauts was significantly shortened. The longitudinal analysis shows that shortly after astronauts return to Earth, the telomere length becomes shorter sharply, and the average telomere length after space flight is shorter than that before flight, which is the general trend of astronaut telomere change.
Note: The individual telomere length distribution of three groups of astronauts at the earliest and latest space flight time points is determined by hierarchical clustering of average telomere length.
Radiation exposure in long-term space flight will induce mitochondria to continuously produce reactive oxygen species. Because telomere region is particularly vulnerable to oxidative damage and difficult to repair, it will accumulate and eventually lead to DNA damage. This study proves that exposure to chronic oxidative stress will instantly activate alternative telomere extension pathways, that is, in this environment, astronauts' telomere length will increase significantly. This partly explains why telomeres become significantly longer during astronauts' flight.
In a word, this study proves that telomeres will respond adaptively to chronic oxidative damage in extreme environment, thus instantly activating telomere elongation pathway in normal somatic cells. Although the mechanism is still uncertain, this viewpoint put forward by the author of this paper is helpful for scientists to further study telomere theory and provide more possibilities for anti-aging
The following is an excerpt from the original content:
Telomere length dynamics and DNA damage response were evaluated before, during and after the relatively large astronaut queue (n = 1 1) on the International Space Station (ISS). Although they are generally healthy individuals, compared with the age-and gender-matched ground control group, astronauts usually have significantly shorter telomeres and lower telomerase activity before and after space flight. Although telomeres have become longer in space flight regardless of the duration of the mission, the telomere length has been shortened rapidly after returning to earth, and the overall telomeres of astronauts after space flight are shorter than before; Individual differences are certain. During the space flight, all crew members experienced oxidative stress, which was positively correlated with telomere length dynamics. The frequency of chromosome inversion observed during and after space flight increased significantly; Changes in the cell population were also detected. We propose the adaptive response of telomere to chronic oxidative damage in extreme environment, so as to instantly activate telomerase-independent telomere substitution extension (ALT) pathway in normal somatic cells.
The human chromosome ends are covered by telomeres, which are a series of arrays of G-rich repetitive sequences composed of a large number of related protein, which can protect the chromosome ends from degradation and loss. Telomeres maintain the stability of the genome by preventing the natural ends of chromosomes from being recognized as broken DNA (double strand breaks ([DSB]) and triggering inappropriate DNA damage response (DDR). Due to the problem of terminal replication, telomere length is eroded with cell division (about 50- 100 bp/ cell division), which leads to telomere shortening until it reaches a very short length. At this point, the permanent cell cycle arrest called replication senescence is the input. Telomerase is a special reverse transcriptase, which counteracts telomere wear by adding telomere repeats at the ends of newly replicated chromosomes from scratch. . However, telomerase activity is sufficient only in highly proliferating stem cells, germ cells and cancer cells. Its level is not enough to maintain the telomere length of normal somatic cells.
As we all know, telomere length is a genetic feature, which will weaken with normal aging, oxidative stress and inflammation. People are increasingly aware that telomere length is also influenced by various other factors, including gender and lifestyle factors (for example, diet, smoking and obesity, physical activity, psychological stress and chronic stress and disease). The maintenance of telomere length represents the core integration component of the cumulative effect of genetic, environmental and lifestyle factors; That is to say, the speed of telomere shortening provides an information biomarker of overall health and indicates the speed and/or degree of human aging. In addition, the change of telomere length may be related to age-related diseases, including dementia, cardiovascular disease (CVD) and cancer. Recent quantitative estimates show that, in fact, both short telomere length and long telomere length are related to increased disease risk-to roughly the same extent-supporting the concept of cancer-aging/disease trade-off.
For all NASA astronauts (n = 1 1) and healthy ground control subjects (n = 1 1) matched in age and sex, we investigated with our twins, and collected whole blood at various time points before, during and after space flight (a mission of one year or less). DNA was isolated from isolated peripheral blood mononuclear cells (PBMC), and the average telomere length was evaluated by quantitative polymerase chain reaction (qPCR). The metaphase chromosomes (stimulated T cells) were analyzed cell by cell by telomere fluorescence in situ hybridization (Telo-FISH), and the telomere length of thousands of individuals was measured according to the relative fluorescence intensity. Generally speaking, the trends of the two tests are similar, and a large number of subjects and time points are helpful to determine the importance of the research results. Telomere length was similarly evaluated in the ground control group, and remained relatively stable during the study, just like twin astronauts on earth. Therefore, all values of all control subjects were combined and averaged to establish a standardized baseline. The average telomere length of astronauts at baseline is significantly shorter or tends to be significantly shorter than that of the ground control group. Interestingly, regardless of mission duration, measurement methods (including sequencing), cell type or sample type (including urine), significantly longer telomeres (n = 3) were observed at all time points during space flight and all crew members who could obtain flight samples. Even so, on the whole, astronauts' telomeres have been or tend to be significantly shortened after space flight. Individual differences are certain.
The longitudinal analysis reveals the dynamic changes of telomere length in the astronaut queue, and the cluster analysis of individual telomere response determines the crew (qPCR, Telo-FISH) who show similar telomere response before and after space flight. Generally speaking, shortly after returning to Earth (65438+ 0-7 days after returning; R+7) observed a sharp decrease in telomere length, and the general trend was that the average telomere length after space flight was shorter than before. The average telomere length of all astronauts at all time points before and after flight was stratified clustering, and no clustering group could be identified. The remarkable characteristics of each group include: the average telomere length showed a downward trend after space flight (R+270), and it dropped sharply soon after returning to Earth (Group 2) or remained unchanged (Group 3), and it was used for 1 occupant (Group 1), and increased in two R+7 and R+270 (Figure 650 of average telomere length after space flight)
Although telomerase activity is the most obvious candidate for telomere de novo extension in space flight, it can not be obtained directly from the samples collected by the International Space Station. Similar to our experience and results in NASA's twin research, the telomerase activity of all blood samples collected during the flight was "lost in space", which may be due to inevitable heat and/or the time related to the return of environmental samples from the International Space Station to Earth. Generally speaking, for this group of astronauts (n = 1 1), the level of telomerase activity before space flight was significantly lower than that of the healthy ground control group matched by age and sex, and the level of astronauts before and after space flight was similar. There are great individual differences in the level of telomerase activity among different time points (Figure 4B). There is no hierarchical clustering of telomerase activity at each time point, and there are no clearly defined reaction groups (Figure 4)C and 4D at the earliest pre-flight (L-270), immediately after flight (R+7) and finally after flight (R+270). However, a notable exception is the first time point (R+7) after returning to Earth, which indicates that the change of telomerase activity is significantly compressed. This observation may reflect the * * * enjoyment mechanism of adjustment/disorder during space flight, or it may be a reaction to the sudden lack of space-specific factors (such as microgravity, space radiation, environmental conditions) and/or related severe stress (such as physical, psychological and immune).
Here, we prove that cluster analysis can identify astronauts who have similar reactions to space flight at independent telomere and cytogenetic endpoints. We further assume that these basic endpoints can be analyzed more comprehensively to determine space-specific features; Specifically, telomere length (qPCR, Telo-FISH) and DNA damage reaction (inversion, translocation, centromere, terminal SCE and satellite binding). Therefore, we use Unified Manifold Approximation and Projection (UMAP) to reduce the dimension, which provides a powerful and intuitive visualization method, in which the distance between points can be explained word by word according to the similarity. In order to determine whether the data can distinguish different stages of space flight (before, during and after space flight), the astronaut ID and time point information are deleted from the data, UMAP is implemented, and tags are reapplied for drawing purposes. It is worth noting that the data in flight are obviously separated. Although the data points before and after the flight have abnormal values, most of them tend to be separated, which supports the spatial correlation characteristics.
In history, only 563 people participated in space flight, most of them were men aged 35-55, and the mission time was less than 20 days. Therefore, with the increasing number and diversity of space travelers and tourists, it is very important to better understand how long-term space flight affects human health, so as to maintain the performance of astronauts and improve their aging trajectory in future exploration missions.
Here, similar to our NASA twin research survey, we evaluated the telomere length dynamics and DDR of a group of unrelated astronauts (n = 1 1) before, during and after their missions on the International Space Station for one year or less. Generally speaking, astronauts' telomeres at baseline are significantly shorter than those of healthy ground control subjects with age and gender matching (n = 1 1), which may reflect the pressure experienced by astronauts in the process of intensive training, selection and preparation for space flight. The telomerase activity of astronauts was also significantly lower than that of the control group, and the level was similar before and after space flight.
The most surprising thing is that during the space flight, all crew members (n = 3) and all flight samples analyzed observed significantly longer telomeres, regardless of mission duration or measurement methods. Interestingly, another unique aging study conducted on the International Space Station reported that the telomeres of worms (Caenorhabditis elegans) flying 1 1 day were slightly elongated. The relatively large astronaut cohort reported here is helpful to further verify the importance of telomere length and the increase of telomere and chromosome aberration frequency observed in space flight, and provides additional support for our previous mechanism connection with long-term exposure to space radiation environment. . Interestingly, after returning to earth, the telomere length of all crew members has been shortened rapidly and significantly. Generally speaking, astronauts have much more short telomeres after flying in space than before, although individual differences have also been found.
Although the decision mechanism involved in these alien processes is still elusive, we propose the instantaneous activation of telomerase-independent ALT/ALT-like phenotype to cope with the chronic oxidative damage of telomeres, as well as the dynamic changes of cell groups caused by aging/apoptosis (the key is telomere shortening), the radiation sensitivity of lymphocytes and the redistribution of leukocyte subsets, which is helpful for telomere lengthening observed in space flight. During space flight, astronauts will experience a variety of physiological system disorders, and they will experience persistent low-level inflammation and oxidative stress, which is consistent with any combination of chronic space radiation exposure and/or space flight-specific stressors, including microgravity and endurance/aerobic exercise. Consistent with the increase in the number of white blood cells during space flight, this is very common for the crew of the International Space Station. After the astronauts returned to Earth, the white blood cell count rose sharply (R+0) immediately, and then dropped rapidly (R+3) on the third day after the flight. This is usually due to the pressure-related edge removal of neutrophils, while the absolute counts of lymphocytes and monocytes are usually unaffected. Interestingly, telomere length follows a somewhat similar timeline, and the increase of plasma concentrations of inflammatory cytokines and chemokines is highly correlated with telomere length dynamics. Chronic and low-level inflammatory reactions induced during long-term space flight, as well as the potential to continuously recruit and release more white blood cells into the circulation, may inappropriately lead to more naive stem cell-like/progenitor cell subsets with inherently long telomeres. Although it usually does not exist in the peripheral circulation of healthy individuals, physiological obstacles related to space flight may promote this process. The change of leukocyte distribution during space flight may be caused by various pressure factors, including legal immune response to pathogens; Such as external bacteria and viruses, and/or latent herpes virus reactivation, which can not be alleviated by pre-flight isolation. At present, the effects of immune system disorder and telomere length fluctuation related to space flight on health are not clear. Here, it is also observed that the radiation dose dependence of white blood cell count decreases after space flight, which provides additional support for appropriate personalized countermeasures during the upcoming deep space exploration mission.
The relatively large astronaut group reported here helps to determine the importance of the research results, and cluster analysis determines the crew group that shows similar telomere or DNA damage response to space flight. In addition, when considering the combination of telomere and DNA damage response, the specific characteristics of space flight are obvious (the aggregation of reactions before, during and after flight); However, there is no astronaut group with similar reaction. On the contrary, each astronaut demonstrated his personal comprehensive response to space flight through these key biological channels. These results show that individual differences in individual responses to stressors and exposures related to space flight dominate the overall trend, and they emphasize the necessity of individualized monitoring and drug treatment for astronauts.
In a word, our findings related to telomere length dynamics and DDR in long-term space flight are of great significance to the health and performance of astronauts involved in exploration missions, as well as long-term aging and disease risk results. More and more evidence supports the new view that telomere length-regardless of its length-is not only a biomarker, but also a determinant of cardiovascular disease and cancer. Chromosome aberration has a long history and is notorious for its association with genomic instability and most cancers. Therefore, as more and more men and women return to the moon and beyond in the next few years, determining individual differences, including gender differences, to cope with long-term related extreme environments, experiences and long-term exposure to space travel is the key next step to ensure the health of future astronauts during and after such missions.
Many restrictions related to long-term space flight inevitably affect the design and implementation of experiments. Apart from the relatively small and similar astronaut population and the challenges related to collecting and returning flight samples, the influencing factors such as microgravity, space radiation exposure, psychological stress, nutrition and exercise cannot be isolated and tested, so it is difficult, if not impossible, to determine the potential mechanism of the dynamic and dramatic changes in telomere length observed in space flight. In addition, these studies involve celebrities, who must remain healthy and confidential and live in extreme environments that cannot be completely replicated on earth.