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NASA NTRS2022

Brain Aging Hallmarks: A Primer for Future Studies on Space Radiation Effects

As humankind endeavors to travel farther away from Earth, many questions remain to be solved to ensure proper preparation for deep space. Multiple spaceflight stressors can elicit adverse health outcomes including exposure to space radiation. Space radiation exposure has been identified by the National Aeronautics and Space Administration (NASA) as an important contributor to cancer, degenerative tissue diseases including cataracts, cardiovascular disease, immune system dysfunction and possible central nervous system decrements. The complexity of the human central nervous system makes it difficult to adequately recapitulate in experimental model systems, which hinders quantitative description of associated decrements. The brain aging hallmarks, as introduced by Mattson and Arumugam in 2018, are measurable cellular and molecular hallmarks that generally contribute to the aging process, describe an aging phenotype, and are part of the etiology of age-related neurodegenerative diseases. These hallmarks include mitochondrial dysfunction, accumulation of oxidatively damaged molecules (oxidative stress), impaired lysosome and proteasome function, dysregulation of neuronal calcium homeostasis, compromised adaptive cellular stress response, aberrant neuronal network activity, impaired deoxyribonucleic acid (DNA) repair, inflammation, impaired neurogenesis and dysregulated energy metabolism. Cellular senescence and telomere attrition may also be considered, though more evidence is needed to regard them as brain-specific hallmarks of aging. Radiation exposure has previously been correlated with aging etiology; therefore, investigating the effects of radiation exposure within the context of the hallmarks of brain aging may provide insights into potential health risks facing NASA astronauts, and may provide a means to identify disease processes that may be important targets for disease prevention or intervention. This work describes the hallmarks of brain aging and serves as a primer for future investigation into how the hallmarks of brain aging may compare and contrast with outcomes associated with exposure to the space radiation environment. Further, it will be useful in future identification of hallmarks that may be appropriate to target for radiation countermeasures specific to the central nervous system.

Vivian Lu↗
NASA NTRS2002

The action of a dietary retinoid on gene expression and cancer induction in electron-irradiated rat skin

Current models of radiation carcinogenesis generally assume that the DNA is damaged in a variety of ways by the radiation and that subsequent cell divisions contribute to the conversion of the damage to heritable mutations. Cancer may seem complex and intractable, but its complexity provides multiple opportunities for preventive interventions. Mitotic inhibitors are among the strongest cancer preventive agents, not only slowing the growth rate of preneoplasias but also increasing the fidelity of DNA repair processes. Ionizing radiation, including electrons, is a strong inducer of cancer in rat skin, and dietary retinoids have shown potent cancer preventive activity in the same system. A non-toxic dietary dose of retinyl acetate altered gene expression levels 24 hours after electron irradiation of rat skin. Of the 8740 genes on an Affymetrix rat expression array, the radiation significantly (5 fold or higher) altered 188, while the retinoid altered 231, including 16 radiation-altered genes that were reversely altered. While radiation strongly affected the expression of stress response, immune/inflammation and nucleic acid metabolism genes, the retinoid most strongly affected proliferation-related genes, including some significant reversals, such as, keratin 14, retinol binding protein, and calcium binding proteins. These results point to reversal of proliferation-relevant genes as a likely basis for the anti-radiogenic effects of dietary retinyl acetate.

Non-NASA Center↗
NASA NTRS1987

Fragility and composition of growing rat bone after one week in spaceflight

To gain some insight into the early effects of spaceflight on skeletal metabolism, we quantified the major chemical constituents and a noncollagenous protein, osteocalcin, in the third-lumbar vertebrae and humeri from 8-wk-old rats that were part of the 7-day NASA Spacelab 3 flight experiments. The ratio of calcium to hydroxyproline in the humeral diaphysis increased from 8.5 in preflight to 9.8 in ground simulation control and only to 8.9 in flight bones. There was no demonstrable change in the fraction of nonmineralized collagen. Osteocalcin content was reduced in the humerus and vertebra. Reduced accumulation of mineral and osteocalcin with no associated decrease in collagen in flight animals suggests that both mineralization and collagen metabolism are impaired in growing animals during spaceflight within a few days after launch. Strength tests of the humeri of flight rats showed substantial deficits that appeared to be related, not only to the reduced bone mass, but also to the composition and quality of new bone formed.

STS-51B Shuttle Project↗
NASA NTRS1980

A model for hypokinesia: Effects on muscle atrophy in the rat

Hypokinesia in the hindlimbs of rats was induced by suspension; a newly developed harness system was used. The animal was able to use its forelimbs to maneuver, within a 140 deg arc, to obtain food and water and to permit limited grooming of the forequarters. The hindlimbs were nonload bearing for 7 days; following a 7-day period of hypodynamia, selected animals were placed in metabolic cages for 7 days to study recovery from hypokinesia. During the 7-day period of hypokinesia there was evidence of muscle atrophy. Gastrocnemius weight decreased, renal papillary urea content increased, and daily urinary losses of NH3 and 3-methylhistidine increased. During the 7-day recovery period muscle mass and excretion rate of urea, NH3 and 3-methylhistidine returned to control levels. Calcium balance was positive throughout the 7-day period of hypokinesia. Hypertrophy of the adrenals suggested the occurrence of some level of stress despite the apparent behavioral adjustment to the suspension harness. It was concluded that significant muscle atrophy and parallel changes in nitrogen metabolism occur in suspended rats and these changes are readily reversible.

Musacchia, X. J.↗
NASA NTRS1977

Metabolic energy requirements during manned orbital Skylab missions

The metabolic balance of nine Skylab astronauts was studied during the course of 28-, 59-, and 84-day flights. Control periods of at least three weeks preceding each flight and at least 18 days following each flight were included in the metabolic studies. Results of the investigation indicated that all members lost mass in flight without experiencing an increase in body density. Analysis of bone density, blood and urinary nitrogen levels, and overall calcium and nitrogen balances suggested that lean body mass declined through loss of protein. It thus appeared that despite adequate energy intake, the crew members did not reach equilibrium with the weightless environment within the time periods studied.

Rambaut, P. C.↗
NASA NTRS2020

A Systems Analysis Approach to Understanding the Physiological Adaptation to Spaceflight

This book is a summary of interdisciplinary research (physiology, space medicine, engineering, computer science, mathematics) that spans two decades (1972-1992). The research was an attempt to use systems analysis, mathematical modeling, computer simulations, and database systems to integrate the biomedical spaceflight data that was being collected during this period. The goal of the effort was to achieve a better understanding of the human physiological response to short-term and long-term space travel. The activity was primarily devoted to analyzing the biomedical results of Skylab (1973-74), a series of three space missions which is still ranked as the most comprehensive of all long-term biomedical space studies to date. This work was begun as a coordinated effort between the National Aeronautics and Space Administration (Johnson Space Center) and the General Electric Company’s Space Division (Houston, TX). It was the intent that this multidisciplined, integrative approach could reveal aspects of the then-new science of microgravity adaptation that were not obvious by adhering to the traditional methodology of examining each organ system in isolation. Some joint work with the Russians, including the Apollo-Soyez test project and a joint bedrest study was also supported during this period. In the 1980’s the systems analysis group’s effort was redirected to support the science management of human and animal experiments on the Space Shuttle. A few examples from this era are also included in the book. Parts of this work have been published elsewhere, presented at technical meetings, and documented in reports with limited distribution. These publications will be referenced throughout the text and the interested reader is advised to use these as resource material where additional details are desired. The intent of this book is not to reproduce these documents but rather to present a coherent view of the integrative analysis under one cover. This volume contains the first detailed publication (other than in internal reports) of an extensive metabolic balance analysis of Skylab data, the development and validation of the “Whole-Body Algorithm,” and simulation studies of diverse hypogravic environments. An analysis of cardiovascular deconditioning and a description of the calcium regulatory model are also new. A long period has passed between the completion of the main body of work represented in this book and its publication in this form. It was inevitable that new research efforts would lead to developments related to the spaceflight problems addressed and thereby make some of our biomedical conclusions obsolete. Although in some cases reference to more recent work have been included, for the most part this book should be considered an historical summary demonstrating the approach and utility of systems analysis and computer modeling in the NASA Life Sciences program at the time the studies were conducted.

Leonard, Joel I.↗
NASA NTRS2011

Using the Abitibi Greenstone Belt to Understand Martian Hydrothermal Systems and the Potential for Biosignature Preservation in High Temperature Aqueous Environments

Metabolic bone diseases like osteoporosis result from the disruption of normal bone mineral balance (BMB) resulting in bone loss. During spaceflight astronauts lose substantial bone. Bed rest provides an analog to simulate some of the effects of spaceflight; including bone and calcium loss and provides the opportunity to evaluate new methods to monitor BMB in healthy individuals undergoing environmentally induced-bone loss. Previous research showed that natural variations in the Ca isotope ratio occur because bone formation depletes soft tissue of light Ca isotopes while bone resorption releases that isotopically light Ca back into soft tissue (Skulan et al, 2007). Using a bed rest model, we demonstrate that the Ca isotope ratio of urine shifts in a direction consistent with bone loss after just 7 days of bed rest, long before detectable changes in bone mineral density (BMD) occur. The Ca isotope variations tracks changes observed in urinary N-teleopeptide, a bone resorption biomarker. Bone specific alkaline phosphatase, a bone formation biomarker, is unchanged. The established relationship between Ca isotopes and BMB can be used to quantitatively translate the changes in the Ca isotope ratio to changes in BMD using a simple mathematical model. This model predicts that subjects lost 0.25 +/- 0.07% (+/- SD) of their bone mass from day 7 to day 30 of bed rest. Given the rapid signal observed using Ca isotope measurements and the potential to quantitatively assess bone loss; this technique is well suited to study the short-term dynamics of bone metabolism.

Hurowitz, J.↗
NASA NTRS1975

Mineral and nitrogen balance study - Results of metabolic observations on Skylab II 28-day orbital mission

The prediction that various stresses of flight, particularly weightlessness, would bring about significant derangements in the metabolism of the musculoskeletal system has been based on various balance-study observations of long-term immobilized or inactive bed rest. The three astronauts of Skylab II consumed a planned dietary intake of major metabolic elements in mixed foods and beverages and provided virtually complete collections of excreta for 31 days preflight, 28 days inflight, and 17 days postflight. Analyses showed that, in varying degree among the crewmen, urinary calcium increased gradually during flight in a pattern similar to that observed in bed-rest studies. Fecal calcium excretion did not change significantly, but calcium balance, owing to the urinary calcium rise, became either negative or less positive than in preflight measurement. Increased excretion and negative nitrogen and phosphorus balances inflight indicated appreciable loss of muscle tissue in all three crewmen. Significant losses also occurred inflight in potassium, sodium, and magnesium. Based on the similarity in pattern and degree between these observations of calcium, phosphorus, and nitrogen loss, musculoskeletal integrity would not be threatened in space flights of up to at least 3 months. However, if similar changes occur in the planed Skylab flights for considerably more than 28 days, concern for capable musculoskeletal function should be serious for flights of very many months' duration.

Whedon, G. D.↗
NASA NTRS1985

Polyamines as Possible Modulators of Gravity-induced Calcium Transport in Plants

Data from various laboratories indicate a probable relationship between calcium movement and some aspects of graviperception and tropistic bending responses. The movement of calcium in response to gravistimulation appears to be rapid, polar and opposite in direction to polar auxin transport. What might be the cause of such rapid Ca(2+) movement? Data from studies on polyamine (PA) metabolism may furnish a clue. A transient increase in the activity of ornithine decarboxylase (ODC) and titers of various PAs occurs within 60 seconds after hormonal stimulation of animal cells, followed by Ca(2+) transport out of the cells. Through the use of specific inhibitors, it was shown that the enhanced PA synthesis from ODC was essential not only for Ca(2+) transport, but also for Ca(2+) transport-dependent endocytosis and the movement of hexoses and amino acids across the plasmalemma. In plants, rapid changes in arginine decarboxylase (ADC) activity occur in response to various plant stresses. Physical stresses associated with gravisensor displacement and reorientation of a plant in the gravitational field could similarly activate ADC and that resultant increases in PA levels might initiate transient perturbations in Ca(2+) homeostasis.

Galston, A. W.↗
NASA NTRS1976

Bone Formation Rate in Experimental Disuse Osteoporosis in Monkeys

Specific mechanisms underlying weightless and hypodynamic bone loss are obscure. A principal relationship which must be affected is the balance between bone formation and bone resorption rates. In order to better define the influence of those parameters on bone loss, and also to develop measurements in other species as a useful adjunct to human research, studies were undertaken with experimental monkeys. Tests were conducted with a total of 6 adult male monkeys, weighing 10-13 kg, and approximately 10-12 yrs. of age to evaluate specifically bone formation rate during the development of disuse osteoporosis and osteopenia. Three animals were restrained in a semi-recumbent position for six months; three animals served as normal caged controls. Food intake (Purina) was held relatively constant at 200g/day for each animal. Using a Norland Bone Mineral Analyzer, bone mineral losses of 3.5 to 6% were seen in the mid-shaft of the tibia and in the distal radius. Bone loss was confirmed radiographically, with observation of thinning of the proximal tibial cortex and trabeculae in the calcaneus. Bone formation rate was determined using standard Ca-47 kinetics under metabolic balance conditions. After six months of restraint, accretion was 7.2-13.2 mg Ca/kg/day, compared to 3.2-4.1 mg Ca/kg/day in caged controls and 3-8 mg Ca/kg/day in normal adult humans. Fecal and urine calcium was 25-40% higher in restrained animals than in controls. Dietary calcium absorption decreases during restraint, and calcium turnover increases, implying a rise in bone resorption rate concommitant with the observed rise in bone accretion rate. Further studies dealing specifically with bone resorption are underway to define this more fully.

Cann, Christopher↗
NASA NTRS1976

Mineral and nitrogen balance study observations - The second manned Skylab mission

A metabolic study of important body elements, particularly those of the musculoskeletal system, was carried out on the astronauts of the Skylab 3 mission during the preflight, inflight, and postflight phases. An elevation in the level of urinary calcium similar to that observed in the 28-d Skylab flight continued throughout the flight. Significant nitrogen and phosphorus losses, apparently associated with muscle tissue loss, occurred in spite of inflight exercise programs. On the basis of these results it is predicted that capable musculoskeletal function is likely to occur in flights longer than about 9 months in duration.

Whedon, G. D.↗
NASA NTRS1993

The potential role of salt abuse on the risk for kidney stone formation

The kidney stone-forming risk of a high sodium diet was evaluated by assessing the effect of such a diet on the crystallization of stone-forming salts in urine. Fourteen normal subjects participated in 2 phases of study of 10 days duration each, comprising a low sodium phase (basal metabolic diet containing 50 mmol. sodium per day) and a high sodium phase (basal diet plus 250 mmol. sodium chloride per day). The high sodium intake significantly increased urinary sodium (34 +/- 12 to 267 +/- 56 mmol. per day), calcium (2.73 +/- 1.03 to 3.93 +/- 1.51 mmol. per day) and pH (5.79 +/- 0.44 to 6.15 +/- 0.25), and significantly decreased urinary citrate (3.14 +/- 1.19 to 2.52 +/- 0.83 mmol. per day). Arterialized venous blood bicarbonate and total serum carbon dioxide concentrations decreased significantly during the high sodium diet, whereas serum chloride concentration increased. However, no change in arterialized venous pH was detected. Thus, a high sodium intake not only increased calcium excretion, but also increased urinary pH and decreased citrate excretion. The latter effects are probably due to sodium-induced bicarbonaturia and a significant decrease in serum bicarbonate concentration, respectively. Commensurate with these changes, the urinary saturation of calcium phosphate (brushite) and monosodium urate increased, and the inhibitor activity against calcium oxalate crystallization (formation product) decreased. The net effect of a high sodium diet was an increased propensity for the crystallization of calcium salts in urine.

Non-NASA Center↗
NASA NTRS2011

Nutrition Research: Basis for Station Requirements

Prior to the Shuttle program, all understanding of nutritional needs in space came from Skylab metabolic research. Because Shuttle flights were short, most less than 14 days, research focused on major nutritional issues: energy (calories), protein and amino acids, water and electrotypes, with some more general physiology studies that related to iron and calcium. Using stable isotope tracer studies and diet intake records, we found that astronauts typically did not consume adequate calories to meet energy expenditure. To monitor energy and nutrient intake status and provide feedback to the flight surgeon and the astronauts, the International Space Station (ISS) program implemented a weekly food frequency questionnaire and routine body mass measurements. Other Shuttle investigations found that protein turnover was higher during flight, suggesting there was increased protein degradation and probably concurrent increase in protein synthesis, and this occurred even in cases of adequate protein and caloric intake. These results may partially explain some of the loss of leg muscle mass. Fluid and electrolyte flight studies demonstrated that water intake, like energy intake, was lower than required. However, sodium intakes were elevated during flight and likely related to other concerns such as calcium turnover and other health-related issues. NASA is making efforts to have tasty foods with much lower salt levels to reduce sodium intake and to promote fluid intake on orbit. Red blood cell studies conducted on the Shuttle found decreased erythrogenesis and increased serum ferritin levels. Given that the diet is high in iron there may be iron storage health concerns, especially related to the role of iron in oxidative damage, complicated by the stress and radiation. The Shuttle nutrition research lead to new monitoring and research on ISS. These data will be valuable for future NASA and commercial crewed missions.

Lane, Helen W.↗
NASA NTRS1991

Spacelab life sciences 1 - Reprints of background life sciences publications

Results from investigations conducted in preparation for the first Spacelab life-sciences mission are summarized in selected previously published papers. Topics discussed are the role of calcium in osteoporosis, orthostaic hypotension, cardiovascular adjustments to gravitational stress, cell biology, exposure to stressful environments, heart-lung interactions in aerospace medicine, effects of weightlessness on human fluid and electrolyte physiology, macular bioaccelerometers on earth and in space, and metabolism of nonessential N-15-labeled amino acids and the measurement of human whole-body protein synthesis rates.

White, Ronald↗
NASA NTRS2004

Calcium balance in mature male rats with unloaded hindlimbs

BACKGROUND: Calcium balances, regulated by the calcium endocrine system, are negative during spaceflight but have not been reported in flight simulation models using fully mature small animals. METHODS: We conducted two calcium (Ca) balance studies in 6-mo-old male rats exposed to a model that unloads the hindlimbs (HU) for 4 wk. Control (C) and HU rats were fed diets with 0.5% Ca in the first and 0.1% Ca in the second study. Housing in metabolic cages enabled daily food and water intake measurements as well as collections of urine and fecal specimens. At necropsy, blood was obtained for measures of Ca-regulating hormones. RESULTS: Both C and HU rats adjusted to housing and diets with decreases in body weight and negative Ca balances during the first week of each experiment. Thereafter, averages of Ca balances were more negative in the unloaded rats than controls: -8.1 vs. -1.6 mg x d(-1) in rats fed 0.5% (p < 0.05). This difference was not due to urinary Ca excretion since it was lower in HU than C rats (1.27 +/- 0.51 mg x d(-1) vs. 2.35 +/- 0.82 mg x d(-1), p < 0.05). Fecal Ca in HU rats exceeded dietary Ca by 4-7%, Restricting dietary Ca to 0.1% was followed by an increase in serum 1,25-dihydroxyvitamin D (1,25-D) and greater intestinal Ca absorption than in rats fed 0.5% Ca. Ca balances in rats fed 0.1% Ca were also more negative in HU than C rats (-2.4 vs. -0.03 mg x d(-1), p < 0.05). Parathyroid hormone (PTH) was suppressed and 1,25-D increased in HU rats fed 0.5% Ca. C rats fed 0.1% Ca had increased PTH and 1,25-D was the same as in the HU group. CONCLUSION: After adaptation, Ca balances were more negative in mature male rats with unloaded hindlimbs than controls, an effect from increased secretion and loss of endogenous fecal Ca associated with increased 1,25-D in Ca-replete and Ca-restricted rats.

Hindlimb Suspension/physiology↗
NASA NTRS2001

Long-term measurement of bone strain in vivo: the rat tibia

Despite the importance of strain in regulating bone metabolism, knowledge of strains induced in bone in vivo during normal activities is limited to short-term studies. Biodegeneration of the bond between gauge and bone is the principle cause of this limitation. To overcome the problem of bond degeneration, a unique calcium phosphate ceramic (CPC) coating has been developed that permits long-term attachment of microminiature strain gauges to bone. Using this technique, we report the first long-term measurements of bone strain in the rat tibia. Gauges, mounted on the tibia, achieved peak or near peak bonding at 7 weeks. Measurements were made between 7-10 weeks. Using ambulation on a treadmill, the pattern and magnitude of strain measured in the tibia remained relatively constant between 7-10 weeks post implantation. That strain levels were similar at 7 and 10 weeks suggests that gauge bonding is stable. These data demonstrate that CPC-coated strain gauges can be used to accurately measure bone strain for extended periods, and provide an in vivo assessment of tibial strain levels during normal ambulation in the rat. Copyright 2001 John Wiley & Sons, Inc.

Non-programmatic↗
NASA NTRS1966

Progress in Development of Methods in Bone Densitometry

The effects of weightlessness and decreased activity on the astronaut's musculoskeletal system during prolonged space flight, missions are of concern to NASA. This problem was anticipated from the knowledge that human subjects lose significant quantities of calcium from the skeleton during periods of bedrest, immobilization, and water immersion. An accurate method of measurement of the changes in mineral content of the skeleton is required not only in the space program but also in the biological, medical, and dental fields for mineral metabolism studies and for studying various pathological conditions of the skeleton and teeth. This method is a difficult one requiring the coordinated efforts of physiologists, biophysicists, radiologists, and clinicians. The densitometry methods reported in this conference which have been used or are being developed include X-ray, beta excited X-rays, radioisotopes, sonic vibration, and neutron activation analysis Studies in the Gemini, Biosatellite, and Apollo flights use the X-ray bone densitometry method which requires making X-rays before and after the flights. An in-flight method of bone densitometry would be valuable, and use of radioisotope sources has been suggested. Many advances in bone densitometry have been made in the last five years, and the urgency of the requirement makes this working conference timely and valuable. In such a rapidly developing field with investigators working independently in a variety of scientific disciplines, a working conference is of great value in exchanging information and ideas, critically evaluating approaches and methods, and pointing out new research pathways.

DENSITOMETER↗
NASA NTRS1996

Calcium Balance in Mature Rats Exposed to a Space Flight Model

Depressed intestinal calcium absorption (Ca abs.) and lower circulating 1,25-dihydroxyvitamin D (1,25-D) are associated with less positive calcium balance in young 200 g rats exposed to skeletal unloading by hind-limb suspension than controls (C) . To determine the effect of the space flight model on calcium balance in mature rats, we exposed 6 mo. old males weighing 492 +/- 12g to the model for 4 weeks (S) and compared Ca in the diet, urine, feces and 1,25-D in S and C. Rats were fed diets containing sufficient Ca to satisfy metabolic needs, but not to cause deficiency (0.1%). At the end of 4 weeks, there was a 5 percent weight loss in S, but not in C; and no differences in dietary, urine (UCa) or fecal Ca (FCa) in S and C. Net Ca abs. (0.1 vs 2.7 %), 1,25-D (50 +/- 16 vs 47 +/- 14 pg/ml) and Ca balances (-1.8 +/- 4 vs -1.0 +/- 2.9 mg/d) were similar in C and S. UCa loss was added to the model by inducing calciuria with 8% salt diets (HiNa). A 4-fold increase in UCa in C and S was transiently higher in S than C after 1 week. After 4 weeks, loss in BW was greater in S than C, Ca abs was higher in C than S (32 +/- 10 vs 3.5 +/- 16%, p less than .05), 1,25-D greater in S than C (98 +/- 15 vs 79 +/- 14 pg/ml p less than .05) and Ca balance less in S than C (-5.2 +/- 4 vs -1.7 +/- 2 mg/d, p less than .05). Ca balance in the mature rat is unaffected by the space flight model unless calciuria intervenes and reveals the failure of the intestine to enhance Ca abs. and compensate for UCa loss.

Navidi, Meena↗