SpaceTech and Space Medicine as a Modern Precedent for Safe and Effective Human Experimentation and Therapeutic Validation in the Longevity Industry
By Dmitry Kaminskiy, Founder and General Partner of Deep Knowledge Group
In ‘Longevity Industry 1.0: Defining the Biggest and Most Complex Industry in Human History’, we distilled the complex assembly of deep market intelligence and industry knowledge that Deep Knowledge Group and its Longevity-focused subsidiaries (including Longevity.Capital and Aging Analytics Agency) have developed over the past 5 years into a full-scope documentation of the global Longevity Industry, showing the public exactly how the international consortium of commercial and non-profit entities managed to define the overwhelmingly complex and multidimensional Longevity Industry for the first time, and how they created a tangible framework for its systematization and forecasting.
Whereas Longevity Industry 1.0 charted the inception and rise of the industry up to 2020, and provided the methodology and framework for defining and analyzing the industry, its sequel, ‘Longevity Industry 2.0: DeepTech Engineering the Accelerated Trajectory of Human Longevity - The Blueprint and Pathway from Longevity Industry 1.0 to 2.0’, outlines Deep Knowledge Group’s recent work towards formulating the pathway to Longevity Industry 2.0, and presents the framework for safeguarding the sector’s current upward trajectory and ensuring its optimized, sustainable growth towards its next stage, and the realization of its practical benefits for humanity by the year 2030.
In the previous articles in this series, I described and defined what Deep Knowledge Group believes to be the the largest and most fundamental source of risk threatening the continued and future stability of the Longevity Industry (the assumption that positive results in model organisms will translate to humans successfully), and outlined an integrated set of modern technological and scientific approaches and the framework for a proposed solution to this problem which can allow for safe and effective human-centered validation of Longevity therapies and technologies at the pre-clinical trial phase, and which can be used by investors to de-risk their decision making in this sector; by Longevity companies to more reliably validate the safety and efficacy of their therapeutic pipelines; and by Longevity startups preparing to launch IPOs to prevent dramatic declines in their market capitalization following failures of their model organism results to translate to humans.
In this article, we turn to a specific modern precedent of safe and effective human experimentation and validation within the realm of SpaceTech and Space Medicine, exploring the lessons that can be learned and applied by the Longevity Industry, to facilitate a paradigm shift away from almost complete reliance on the results of model organism studies for due diligence, company valuation and investment decision making, and towards a more realistic, relevant and modern human-centered approach. We will also address some interesting scientific and technological convergences between aging and the negative effects of spaceflight, and the ways in which the specific therapeutic approaches used to protect and preserve the health of astronauts intersect with Practical Healthy Human Longevity.
Human-Centered Validation in Space Medicine and its Convergences with Longevity Science and Clinical Translation
On the topic of Longevity Industry bottlenecks and the challenges for tangible and relevant Longevity investment decision-making posed by the sector’s focus on results in model organisms (predominantly mice) as opposed to humans, there are several lessons to be learned from the arena of SpaceTech, and the approaches used in validating methods of preserving and protecting the health of astronauts during spaceflight.
In early 2019, I participated as a co-author on a scientific paper that explored convergences between SpaceTech, Space Medicine and Longevity in a concrete form in the scientific journal Oncotarget, titled ‘Vive la radiorésistance!: converging research in radiobiology and biogerontology to enhance human radioresistance for deep space exploration and colonization’.
The paper included over 30 articles, including some from the Biogerontology Research Foundation (the UK’s oldest Longevity-focused charity, for which I serve as Managing Trustee), as well as others written by scientists from NASA Ames Research Center, Environmental and Radiation Health Sciences Directorate at Health Canada, Oxford University, Canadian Nuclear Laboratories, Belgian Nuclear Research Centre, Insilico Medicine, the Biogerontology Research Center, Boston University, Johns Hopkins University, University of Lethbridge, Ghent University, the Center for Healthy Aging and others.
As I stated in the press release associated with that paper: "In linking ageing and radioresistance and tying together research into enhancing the radioresistance of astronauts with the extension of healthy Longevity, we hope to have shown how aerospace research could be used to leapfrog the massive funding deficit surrounding the clinical translation of healthspan-extending interventions, in order to brave the storm of the oncoming Silver Tsunami and prevent the looming economic crisis posed by demographic aging".
The scope of the paper was also summarized by Afshin Beheshti, another co-author of the paper, and a Bioinformatician at NASA Ames Research Center: "Our recent manuscript provides a comprehensive review of radioresistance for space radiation. Currently there is minimal research being done for radioresistance against HZE irradiation. The importance of these types of studies will be to reduce the associated health risks for long-term space exploration and allow for the development of potential countermeasures against space radiation. In addition, the synergy between understanding aging with radioresistance will allow for further benefits for humans in long-term space missions and allow for reduced health risk. This review sets the stage for the potential research the scientific community can do to allow for safe long term space exploration.”
The roadmap outlines future research directions towards the goal of enhancing human radioresistance, including upregulation of endogenous repair and radioprotective mechanisms, possible leeways into gene therapy in order to enhance radioresistance via the translation of exogenous and engineered DNA repair and radioprotective mechanisms, the substitution of organic molecules with fortified isoforms, the coordination of regenerative and ablative technologies, and methods of slowing metabolic activity while preserving cognitive function.
The paper concludes by presenting the known associations between radioresistance and Longevity and articulating the position that enhancing human radioresistance is likely to extend the healthspan of human spacefarers as well.
While this paper was published in early 2018, the role that SpaceTech can play in developing a more robust and relevant framework for validating the results of Longevity companies, to serve as the major tool for tangible investment decision-making in this sector, has been on the radar of Deep Knowledge Group for the past several years.
SpaceTech is known for its emphasis on human validation, and necessarily so, given the need to equip astronauts with the most advanced methods of health preservation and protection. As such, we can expect more robust frameworks for safe, human-centered validation of Longevity therapies and technologies to learn from both the testing and validation approaches used and developed within the scope of SpaceTech, as well as its general mindset that the only valid proof of safety and efficacy can be found in humans and not in mice.
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Scientific, Technological and Medical Convergences Between Space Medicine and Longevity Medicine
Interestingly, the convergences between the nature of SpaceTech health optimization and Longevity research are quite numerous, and each warrants a brief exploration in its own right.
One of the most far-sighted Longevity studies is related to NASA astronaut studies. It’s devoted to a multidimensional analysis of a year-long human spaceflight. But it could also be described as a study of accelerated aging.
The NASA Twins Study represents an integrated, multiomics, molecular, physiological and cognitive portrait of an astronaut and reveals the biomedical responses of the human body during a year-long spaceflight as a model of accelerated aging as well.
With a rolling fund of around $10–$20 million, SP8CEVC expects to make around 20 to 24 investments at $200–$400K in Seed, Series A and select Series B companies, split between Space and Longevity. On the space side, the focus will be mostly on infrastructure and more than 20 sub-verticals, while Longevity investments will be focused on companies addressing the nine Hallmarks of Aging, biomarkers, and diagnostics.
Given NASA’s results, it is expected that astronauts conducting exploration-class missions could experience risks (related to hallmarks of aging) from mitochondrial dysfunction, immunological stress, vascular changes and fluid shifts, and cognitive performance decline, as well as alterations in telomere length, gene regulation, and genome integrity.
Given the limitations of studying a single spaceflight subject, studies of additional astronauts on long-duration missions are needed to confirm these findings and resolve outstanding questions.
Long-duration missions that will take humans to Mars and beyond are planned by public and private entities for the 2020s and 2030s; therefore, comprehensive studies are under way to assess the impact of long-duration spaceflight on the human body, brain, and overall physiology.
The space environment is made harsh and challenging by multiple factors, including confinement, isolation, and exposure to environmental stressors such as microgravity, radiation, and noise. The selection of a pair of monozygotic (identical) twin astronauts for NASA’s first 1-year mission allowed for a study comparing the impact of the spaceflight environment on one twin to the simultaneous impact of the Earth environment on the other.
The known impacts of the spaceflight environment on human health and performance, physiology, and cellular and molecular processes are numerous and include bone density loss, effects on cognitive performance, microbial shifts, and alterations in gene regulation.
The identical twin subjects were assessed according to 10 generalized biomedical modalities before (preflight), during (inflight), and after the flight (postflight) for a total of 25 months (circles indicate time points at which data were collected). (Right) Data were integrated to guide biomedical metrics across various “-omics” for future missions (concentric circles indicate, from inner to outer, cytokines, proteome, transcriptome, and methylome).
Physiological, telomeric, transcriptomic, epigenetic, proteomic, metabolomic, immune, microbiomic, cardiovascular, vision-related, and cognitive data were collected over 25 months. Some biological functions were not significantly affected by spaceflight, including the immune response (T cell receptor repertoire) to the first test of a vaccination in flight. However, significant changes in multiple data types were observed in association with the spaceflight period; the majority of these eventually returned to a preflight state within the time period of the study.
These included changes in telomere length; gene regulation measured in both epigenetic and transcriptional data; gut microbiome composition; body weight; carotid artery dimensions; subfoveal choroidal thickness and peripapillary total retinal thickness; and serum metabolites. In addition, some factors were significantly affected by the stress of returning to Earth, including inflammation cytokines and immune response gene networks, as well as cognitive performance. For a few measures, persistent changes were observed even after 6 months on Earth, including some genes’ expression levels, increased DNA damage from chromosomal inversions, increased numbers of short telomeres, and attenuated cognitive function.
Telomere length shortens with cell division and thus with age, as well as with a variety of lifestyle factors, such as stress and environmental exposures, including air pollution and radiation. Most notable was a significant increase in telomere length during flight for TW (14.5%), as compared with his preflight and postflight measures. TW’s increased telomere length was observed in sorted CD4, CD8, and LD cells, but not in CD19 cells (Fig. B). Notably, telomere length shortened rapidly upon TW’s return to Earth, within ~48 hours stabilized to near preflight averages within months.
Spaceflight effects were more evident in isolated cells than whole organs, suggesting that tissue complexity plays an essential role in response to space-related stress. The liver undergoes more differential gene and protein expression changes than other organs, consistent with the role the liver plays as a dynamic and critical hub in sensing changes in blood composition and maintaining homeostasis. Spaceflight impacts mitochondrial function at the genetic, protein, and metabolite levels of cellular, tissue, and organismal biology.
Additionally, spaceflight causes a universal change in gene expression related to energy generation. Observed changes include altered mitochondria-associated metabolites and modified nuclear DNA (nDNA) and mtDNA OXPHOS gene expression; reduced antioxidant defenses and increased urinary markers of oxidative stress; and altered integrated stress response (ISR) gene expression. These and other related observations suggest that mitochondrial dysfunction may alter metabolic flux through mitochondrial pathways, perturb mitochondrial gene expression, and activate the ISR. Spaceflight suppresses nDNA-coded mitochondrial OXPHOS gene expression predominantly in oxidative tissues, and the induction of the mtDNA genes partially compensates for the diminished mitochondrial oxidative metabolism.
Thus, it should be clear that future success in long-duration space exploration requires a comprehensive understanding of the impact of spaceflight on human biology, and such knowledge could be used to design efficient countermeasures that would benefit astronauts and the health and lifespan of people on Earth. The domain of Longevity science, and its translation from theory into practice in the Global Longevity Industry, has a lot to learn from SpaceTech and Space Medicine, not only in its approach to and emphasis on human-centered research and validation, but also in many of its specific approaches to protecting astronauts from the physiologically detrimental effects of spaceflight, which share many fundamental consistencies with the nature of biological aging in humans.
About the Next Article
In this article, we provided an overview of perhaps the strongest and most relevant modern precedent for safe and effective human experimentation and validation within the realm of SpaceTech and Space Medicine, exploring the lessons that can be learned and applied by the Longevity Industry to facilitate a paradigm shift away from an almost complete reliance on the results of model organism studies for due diligence, company valuation and investment decision making, and towards a more realistic, relevant and modern human-centered approach. Against this background, we also gave a brief overview of several interesting scientific and technological convergences between aging and the negative effects of spaceflight, as well as the ways in which the specific therapeutic approaches used to protect and preserve the health of astronauts intersect with Practical Healthy Human Longevity.
The next article in this series will turn its attention to the ways in which the financial industry in particular can take on board some of these topics, relating both to Biomarkers of Human Longevity and to modern, sophisticated approaches and solutions to safe Human experimentation and validation of Longevity therapies. It will also look at the ways in which these two worlds (the science and technology of Practical Human Longevity, and the Global Financial Industry) intersect. The article will then chart the scope of the investment and financial approaches, entities and infrastructures that are required to truly transform these practices from tools used by a small minority of Longevity investors (like Deep Knowledge Group, Deep Knowledge Ventures and Longevity.Capital) into industry standard practices to the mutual benefit of investors, companies, the general public and the entire industry itself.