Space travel is experiencing rapid growth
In recent years, the space industry has been making a leap from exploratory trials to commercial operations. According to Morgan Stanley’s 2023 forecast, the global space economy is expected to reach a market size of USD 1 trillion by 2040 (Figure 1), with commercial space travel and space tourism becoming key drivers of growth [1]. For example, SpaceX’s Falcon 9 rocket has achieved reusability, reducing the cost of a single launch from nearly USD 500 million in the past to about USD 62 million, significantly lowering the threshold for space access. Blue Origin and Virgin Galactic have also conducted suborbital flight tests with New Shepard and VSS Unity, respectively, and by 2024, more than 30 civilian passengers have completed edge-of-space journeys.
Figure 1. Market size of space travel [2]
In terms of market demand, according to the Space Tourism Market Forecast 2022–2032 report, by 2030 the number of global space tourism participants will exceed 60,000, and the market value is expected to surpass USD 8 billion. These customers are currently concentrated among high-net-worth individuals, but with technological maturity and decreasing costs, the market may expand to the upper-middle class in the future. Regarding pricing, the ticket for a single suborbital flight still exceeds USD 200,000, yet SpaceX and its Starship program aim to reduce orbital launch costs to several tens of dollars per kilogram, which in the long run could bring the price of space travel down to below USD 50,000 [3].
Health challenges are also a key breakthrough point for the industry. Under microgravity conditions, muscle atrophy and bone density loss are well-documented physiological issues. NASA data indicate that astronauts lose an average of 1%–1.5% of bone density per month, comparable to age-related osteoporosis. Psychological problems also deserve attention, particularly during long-duration missions in confined environments. In the future, safeguarding astronaut health will become an essential requirement, involving innovative solutions such as nutritional interventions, psychological support, probiotic supplementation, and microgravity-adapted muscle training systems.
Figure 2. Commercial space hotel “Pioneer Station” [4]
Policy and infrastructure development are advancing in parallel. In 2022, the U.S. Federal Aviation Administration (FAA) approved several private companies to conduct commercial suborbital crewed missions. Meanwhile, China has incorporated the development of commercial spaceflight into its 14th Five-Year Plan and announced plans to open the Tiangong Space Station for tourism applications after 2027. Globally, more than 30 startups are dedicated to developing space hotels, orbital transportation, and life support systems. For example, Orbital Assembly plans to complete construction of the world’s first commercial space hotel, Pioneer Station, by 2027 (Figure 2) [4].
Health Hazards of the Space Environment
Figure 3. Schematic illustrating the effect of microgravity on the differentiation of stem cells into various cell lineages[8]
In the microgravity environment of space, astronauts face multiple physiological challenges. Without Earth’s gravitational force, the body’s antigravity muscle groups (such as those in the legs and back) no longer bear continuous loads, leading to rapid disuse muscle atrophy. This condition is similar to that observed in bedridden patients on Earth, resulting in muscle volume reduction and strength loss. Moreover, microgravity reduces peripheral neural signal transmission, which decreases the synthesis of neurotrophic factors in muscle spindles, thereby damaging the ultrastructure of muscle cells—including mitochondria and myofibrils—and further impairing muscle function [5]. In vitro studies simulating microgravity have also shown reduced myogenesis: when murine myoblasts were cultured in three-dimensional hydrogels, the resulting myotubes were shorter, thinner, and exhibited diminished fusion capacity [6].
At the same time, the microgravity environment disrupts calcium homeostasis in muscle cells, impairing the function of key calcium pumps such as the sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA), and thereby promoting muscle protein degradation (Figure 3). Astronauts also experience endocrine dysregulation in space, including decreased growth hormone levels and relatively elevated glucocorticoids, both of which further accelerate muscle loss [7]. For long-duration space missions, developing effective strategies to counteract the negative impact of microgravity on muscle regeneration has become an urgent priority.
Harms of Sarcopenia
Skeletal muscle is one of the most abundant tissues in the human body, accounting for approximately 40% of body weight. Beyond its critical roles in locomotion and posture maintenance, it is also essential for energy metabolism, protein storage, and glucose homeostasis [8]. Moreover, skeletal muscle serves as the body’s largest reservoir of amino acids, supplying energy and biosynthetic precursors to the immune system and other tissues during stress, infection, and aging [9]. Thus, skeletal muscle is not only central to the musculoskeletal system but also a vital organ for maintaining overall health and metabolic stability.
First, sarcopenia leads to declines in muscle strength and balance, thereby increasing the risk of falls and fractures. It is frequently accompanied by osteoporosis, which greatly elevates the likelihood of severe fractures such as hip fractures [10]. Second, sarcopenia reduces mobility and self-care capacity, making everyday activities such as walking, standing, and lifting difficult. This loss of independence and autonomy may also trigger psychological problems such as depression and anxiety [11]. In addition, sarcopenia interacts with chronic diseases such as chronic obstructive pulmonary disease, diabetes, heart failure, and cancer, exacerbating their progression and significantly worsening clinical outcomes [12]. Finally, as the body’s largest protein reservoir and a major organ for glucose metabolism, the loss of skeletal muscle leads to malnutrition and weakened immunity, increasing susceptibility to influenza, pneumonia, and malignancies [13].
For astronauts returning to Earth, sarcopenia induced by spaceflight poses additional challenges. On the one hand, they often require prolonged rehabilitation to regain basic motor functions; without it, they face heightened risks of falls, fractures, and related injuries. On the other hand, muscle loss reduces daily activity capacity and endurance reserves, increasing the incidence of fatigue, balance disorders, and metabolic dysfunctions, all of which seriously compromise quality of life and long-term health after returning to Earth.
Exercise Approaches in Space
Figure 4. Exercise countermeasures against muscle loss in space [14]
To mitigate muscle loss in the space environment, two main intervention strategies are currently employed (Table 1). The first is physical countermeasures, centered on resistance training (e.g., using the Advanced Resistive Exercise Device, ARED), aerobic exercise (e.g., space treadmills and cycle ergometers), and electrical muscle stimulation (EMS). These aim to maintain antigravity muscle function and slow down muscle and bone loss (Figure 4). However, this approach faces significant challenges: astronauts are typically required to train for at least two hours per day, yet adherence rates are below 40%, and effectiveness is limited. One study reported that even with two hours of high-intensity training daily, exercise only delays muscle atrophy—each hour of training offsets a maximum of about three days of muscle loss [15,16]. Furthermore, the equipment is often bulky, energy-intensive, and complex to maintain, making it extremely costly for space missions. Launching such hardware can cost approximately USD 22,000 per kilogram, leading to the problem humorously described as “USD 1 million per kilogram” of resource consumption [17].
The second strategy is nutritional countermeasures, which involve supplementation with leucine-rich proteins, vitamin D, and calcium to sustain muscle synthesis and bone health while exerting anti-inflammatory and anti-catabolic effects [18]. Finally, pharmacological interventions—though still in the research or clinical trial phase—such as SARMs (selective androgen receptor modulators), anti-catabolic agents, and supplementation with growth hormone/IGF-1, have shown potential to improve muscle mass and function [19], offering prospects for more efficient health protection in future long-duration missions.
In summary, while current intervention strategies have demonstrated certain effectiveness, they still face major limitations in terms of implementation efficiency, cost control, and individual compliance.
Table 1. Current approaches to mitigating muscle atrophy in space
| Intervention category |
Specific measure |
Time-related limitations |
Cost-related limitations |
Other limitations |
| Physical interventions |
Aerobic exercise |
Requires ≥2 h training per day |
High maintenance costs for ground-based equipment |
Adherence <40% |
| Cycle ergometer (space bike) |
Intensive training schedule |
Launch cost ≈ USD 22,000/kg |
Insufficient mechanical loading under microgravity |
| Electrical muscle stimulation (EMS) |
Must be combined with training time |
Medical-grade device cost > USD 8,000 |
Risk of current diffusion in microgravity (20% incidence of diaphragmatic spasm) |
| Nutritional interventions |
Protein supplementation |
Requires frequent intake |
High cost of high-purity protein powders |
Excessive intake increases liver and kidney burden |
| Vitamin C supplementation |
Requires scheduled administration |
Cumulative long-term cost |
High doses may cause diarrhea |
HMB as a Supplement to Mitigate Sarcopenia
The International Society of Sports Nutrition (ISSN) has reported that β-hydroxy-β-methylbutyrate (HMB) can alleviate exercise-induced skeletal muscle damage and promote recovery in both trained and untrained individuals. When combined with an appropriate exercise regimen, a daily intake of 38 mg/kg body weight of HMB enhances skeletal muscle hypertrophy, strength, and power, and is suitable for both populations [20].
The therapeutic effect of HMB on sarcopenia is mainly based on two mechanisms:
First, HMB inhibits the ubiquitin–proteasome system (UPS), thereby reducing muscle protein degradation and lowering the risk of muscle loss [21]. The UPS pathway is responsible for degrading more than 80% of cellular proteins, helping the body regulate vital processes, complete metabolic renewal, and maintain overall health. However, in the space environment, the absence of mechanical loading leads to reduced myoglobin synthesis [22]. Meanwhile, when the UPS pathway remains unchecked, protein synthesis falls below degradation, ultimately causing muscle atrophy. Thus, inhibiting the UPS pathway with HMB can fundamentally alleviate sarcopenia.
Second, HMB activates the mTOR and AKT signaling pathways to promote protein synthesis [23]. mTOR plays a central role in growth and metabolism by not only facilitating amino acid uptake but also suppressing the autophagy pathway. This enhances muscle protein synthesis, reduces muscle cell autophagy, and helps maintain or increase muscle mass (Figure 5).
In addition to these mechanisms, HMB also contributes directly to increases in muscle mass [24]. Consequently, HMB is widely applied in clinical nutrition and sports supplementation, benefiting athletes, elderly populations, as well as patients with chronic diseases or critical illness [25], demonstrating its broad acceptance and utilization.
Figure 5. Mechanism of HMB in promoting skeletal muscle generation [26]
HMB Production Methods
Currently, HMB is mainly produced through traditional chemical synthesis, which relies on toxic and non-renewable chemical raw materials such as diacetone alcohol and oxidants. This process not only suffers from low efficiency but also generates toxic by-products, posing threats to both the environment and human health. Industrial production of HMB (β-hydroxy-β-methylbutyrate) primarily follows a chemical synthesis route: diacetone alcohol (DAA) reacts with an oxidant (e.g., hydrogen peroxide) to form intermediates, which are subsequently esterified to produce ethyl HMB (HMB-E). Finally, hydrolysis yields free HMB (Figure 6).
However, this synthetic pathway involves multiple toxic or hazardous reagents. For instance, diacetone alcohol is moderately toxic, and inhalation of its vapors or skin contact may cause headaches, dizziness, and skin irritation [27]. More importantly, commonly used oxidants such as hydrogen peroxide (H₂O₂) exhibit strong oxidative and corrosive properties at high concentrations, which can cause eye and skin burns, while inhalation of concentrated vapor may lead to respiratory tract inflammation [28]. In addition, harmful organic peroxides may be generated as by-products of the reaction. These compounds are explosive and potentially mutagenic, classed as hazardous chemicals [29]. Together, these factors not only raise concerns about environmental pollution but also pose significant challenges to the safety of the production process.
Figure 6. Chemical synthesis method of HMB [30]
Figure 7. Project design and engineering success
In this project, we propose to introduce a de novo biosynthetic pathway for HMB (3-hydroxy-3-methylbutyrate) into the probiotic Escherichia coli Nissle 1917 (EcN), aiming to achieve continuous intervention against sarcopenia, particularly for the prevention and mitigation of muscle atrophy under space microgravity conditions. HMB, a metabolite of leucine, has well-documented functions in inhibiting protein degradation and promoting muscle protein synthesis, and it has been widely applied in clinical nutrition and sports supplementation. Drawing on recent research advances, our design employs a synthetic biology route starting from acetyl-CoA, enabling de novo HMB biosynthesis through multi-enzyme cascade reactions in engineered EcN.
Meanwhile, considering that long-term space missions are frequently accompanied by emotional fluctuations and sleep disturbances, our project further incorporates a serotonin (5-hydroxytryptamine, 5-HT) biosynthetic module. Serotonin, derived from tryptophan metabolism, is a key neurotransmitter that regulates mood, sleep, and cognitive functions. Studies have shown that the gut microbiota can influence serotonin production and release, thereby modulating the gut–brain axis [31]. Hence, engineering EcN to co-produce both HMB and serotonin may simultaneously enhance muscle health and alleviate mood and sleep issues common in space missions, providing astronauts with more comprehensive physiological and psychological support [32,33].
Finally, we designed a safety module that allows the engineered strain to be efficiently eliminated from the host when necessary (Figure 7).
Chassis Selection
We selected Escherichia coli Nissle 1917 (EcN) as the probiotic chassis for our project, primarily due to its proven safety, stability, and broad application basis. First, EcN is a well-validated human probiotic strain with over a century of clinical use, demonstrating reliable intestinal colonization capacity and immunomodulatory effects [34]. One of the most critical advantages is its lack of typical endotoxins found in common E. coli strains. Specifically, conventional E. coli lipopolysaccharides (LPS) contain the highly immunostimulatory lipid A moiety, which can trigger host inflammatory responses or even toxic effects [35]. In contrast, EcN is characterized by high biosafety. Second, compared with standard E. coli strains, EcN is particularly suitable as a live biotherapeutic delivery platform, exhibiting strong resistance to gastric acid and bile salts, thereby ensuring longer survival and persistence in the intestinal environment [36]. Finally, EcN benefits from a relatively mature set of genetic engineering tools in the field of synthetic biology, enabling efficient genome modifications and heterologous expression of target products [37].Taken together, E. coli Nissle 1917 represents an ideal chassis organism for constructing engineered probiotics.
HMB De Novo Biosynthesis
Figure 8. De Novo Synthesis Method of HMB
The de novo synthesis pathway of HMB (3-hydroxy-3-methylbutyric acid) mainly consists of five key enzymes: AtoB (acetoacetyl-CoA synthetase), MvaS (HMG-CoA synthase), AibAB (3-methylvaleryl-CoA decarboxylase), LiuC (hydratase), and YciA (thiohydratase). This pathway uses three molecules of acetyl-CoA as substrates and ultimately produces one molecule of HMB, exhibiting high theoretical carbon conversion efficiency and independence from ATP or NADH [38]. Among these enzymes, AtoB catalyzes the conversion of two molecules of acetyl-CoA into acetoacetyl-CoA. MvaS then catalyzes the condensation of acetyl-CoA and acetoacetyl-CoA to generate HMG-CoA, which is a key node in the HMB synthesis pathway [39]. Subsequently, AibAB is responsible for catalyzing the decarboxylation of HMG-CoA to produce 3-MG-CoA, providing substrates for subsequent reactions; LiuC further converts 3-MG-CoA into HMB-CoA, the precursor of HMB; HMB-CoA can spontaneously undergo coenzyme removal to form HMB (Figure 8).
Meanwhile, through communication with teachers and literature research, our team found that thioesterase can effectively increase HMB yield. The core reason why thioesterase promotes HMB production is that it can efficiently hydrolyze HMB-CoA to release free HMB, alleviate metabolic flux bottlenecks, reduce feedback inhibition, and at the same time improve the accumulation and secretion of HMB, thereby increasing the total yield. Therefore, we heterologously expressed thioesterase in Plasmid II to test HMB yield. Additionally, YciA was ultimately introduced to hydrolyze HMB-CoA into free HMB, completing the entire synthesis process [40].
In this study, we used genetic engineering techniques to introduce the genes of the above five key enzymes into E. coli Nissle 1917, constructing engineered probiotics that can continuously express and secrete HMB in the human intestinal tract. This strategy not only significantly reduces the production cost and environmental pollution risk associated with chemical synthesis of HMB [38], but also provides a sustainable and safe solution for preventing astronauts' muscle atrophy in the scenario of long-term space travel in the future.
Serotonin Biosynthesis System
Although our constructed HMB biosynthesis system primarily focuses on alleviating muscle loss through a de novo synthetic pathway, the health challenges faced by the human body in the space environment go far beyond muscle atrophy [41]. In addition to metabolic regulation, the balance of the neurotransmitter system is equally critical. Therefore, in this project, we not only focus on the impact of microgravity on the muscular system but also pay particular attention to the disturbances in the nervous system and emotional state caused by long-term aviation and space travel.
Figure 9. Serotonin Biosynthesis and Its Functions
Serotonin (also known as 5-hydroxytryptamine or 5-HT) is an important monoamine neurotransmitter that plays a vital role in human signal transduction. It is widely recognized as a key regulator of mood, sleep, appetite, cognition, and gastrointestinal functions [42,43]. Its biosynthesis mainly depends on tryptophan (TRP) and proceeds through two sequential enzymatic steps: first, tryptophan hydroxylase (TPH) hydroxylates TRP into the intermediate 5-hydroxytryptophan (5-HTP); subsequently, tryptophan decarboxylase (TDC) decarboxylates 5-HTP to produce the active neurotransmitter 5-HT [44] (Figure 9).
Safety System
To ensure biosafety, we designed an arabinose-inducible suicide system that allows the engineered bacteria in the gut to be eliminated when necessary by administering arabinose, thereby stopping serotonin secretion.
In the absence of arabinose, the arabinose regulator protein AraC binds to the pBAD promoter and represses gene transcription. When L-arabinose is present, the arabinose operon is activated, leading to rapid induction of the pBAD promoter, which can reach maximum expression within minutes [45]. This system triggers the lysis of engineered probiotics through arabinose administration, effectively inducing the secretion of MazF and causing bacterial apoptosis. MazF is the toxin protein of the Escherichia coli mazEF toxin–antitoxin system. It specifically cleaves bacterial mRNA at ACA sequences, blocking protein synthesis and leading to rapid bacterial death [46] (Figure 10).
Figure 10. Schematic Diagram of the Arabinose Operon [47]
Regarding the concern of whether engineered bacteria might release genes into the environment, we investigated this issue in our human practices (HP). Through communication with relevant personnel, we learned that waste collection in space is carried out with strict procedures, and upon returning to Earth, the waste is incinerated, thus requiring no additional treatment (Figure 11).
Figure 11. Collection and Treatment of Waste in Space
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