What can we do to most improve human health? How can we help people live longer, healthier lives? Several things come to mind: eradicating infectious disease, eliminating poverty and homelessness, protecting the environment. There are many efforts in these areas, and more are urgently needed. But what is not widely understood is that the process of aging is by far, indeed by a huge margin, the predominant cause of ill health, disease, and debilitation—the biggest cause of poor quality of life. 

Take COVID-19. While many know that the elderly are more susceptible, the magnitude of this higher risk is rarely appreciated. Susceptibility is in fact drastically different. At the population level, nothing is a bigger risk factor for hospitalization and death than older age. Indeed, this applies to most infectious diseases—the older you are, the more likely you are to catch and die from an infection. What is even worse, the vaccinated elderly are still at a higher risk than unvaccinated young adults. That’s not to say we shouldn’t try to target infectious diseases directly—we certainly should—but aging universally increases your risk of death from communicable and noncommunicable diseases alike.

Consider this: even in the absence of infectious disease, what maladies are you most likely to suffer and die from? Heart disease, cancer, dementia, diabetes—these will all kill you, or worse, cause years of suffering before death. And this doesn’t even account for decades-long afflictions we are all likely to suffer from: arthritis, osteoporosis, sarcopenia, hearing and vision loss, incontinence. Throughout the entire history of modern medicine these afflictions have been studied and treated individually. But now, the decades-old understanding that they all share common underlying mechanisms is finally undergoing widespread appreciation outside of the aging research community. And the idea that they can be treated or prevented simultaneously by targeting these common mechanisms is rapidly gaining strength. In other words, it makes much more sense to prevent multiple diseases simultaneously by addressing the root causes than it does to treat diseases individually. Not to mention that current practice is to start treatment only after things get so bad that the disease is obvious.

Unfortunately, the situation is only getting worse. Our population is aging. More and more of us are deteriorated, unable to enjoy time with family and friends like we once could. We all become a burden, eventually.

Understanding aging

So how can we prevent this? How can we use this knowledge—that aging is the root cause of so much suffering and death—to improve health worldwide? To reduce or eliminate the years of ill health and morbidity? We spoke with experts, dozens of them, and asked these questions: What are the biggest bottlenecks to advancing our knowledge of aging and rejuvenation? What can we do to most accelerate progress? What are those projects and experiments that wouldn’t otherwise get done? Ultimately, how can we have the biggest impact?

A clear picture quickly emerged. In mice, we have tools and treatments that target the biology of aging and improve health (termed aging interventions), but we lack a deep and fundamental understanding of how they work. We don’t know to what extent they work throughout the body. What molecular processes do they work through? Which cells do they improve? Which organs? How does that lead to functional improvement of the body as a whole? What is the magnitude and duration of these effects? How robust is the improvement in a diverse population of individuals? And if different interventions affect different facets of aging, can we combine them synergistically? Can we monitor the health of an individual non-invasively, with blood measures, imaging, and functional tests, and use that information to decide when and which kind of intervention to apply? Can we use that information to determine the success of an intervention without waiting to see if lifespan is extended? And what types of tests get us the most useful information? 

Answering these questions in humans is imperative, but it is not feasible to study molecular-level processes in our vital organs. On the other hand, commonly used models like worms, yeast, or flies can be easier to study, but they are also very different from us: For example, they all lack a closed circulatory system and an adaptive immune system. Mice strike a compromise between being closer to human aging while enabling deep phenotyping of the aging process.

The Rejuvenome Project

So, we designed the Rejuvenome, a project built and run with continuous feedback from the community, where all design considerations, data, and results will be made freely available. The Rejuvenome will characterize aging interventions in mice, both established and nascent, for which there is evidence of improved health in aged individuals (i.e. rejuvenation). Experiments will be conducted in genetically diverse mice that mimic our diverse human population, and health will be assessed longitudinally (repeated over time in the same individual) and noninvasively with assays encompassing an array of organs and functional systems. Multiple categories of cellular and molecular measurements (i.e. multi-omics, hence Rejuven-ome) will be collected at several time points before and after intervention initiation to assess both acute changes and long-lasting improvements, enabling us to track changes at an individual level. Lifespan measurements will help link molecular and functional improvements to longer life and disentangle which treatments extend vitality (increase healthspan) versus merely extending time in ill-health.

The central goal of Rejuvenome is to determine which combinations of aging-interventions synergize best, resulting in greater rejuvenation than any alone. The hard truth—no matter what appears in mass media—is that currently there exists no treatment to significantly reverse aging in humans. Nonetheless, that is a worthy goal simply because that is the best way to keep people healthy. Even partial successes on this road could have enormous benefits for quality of life and disease prevention. A thorough understanding of individual interventions and how they work across the body could allow for the rational combination of those interventions. Combinations are a critically underexplored research avenue, even though it is widely believed that to have truly significant impacts on health, we must reverse many aspects of aging simultaneously. Nearly everyone agrees that there will be no silver bullet, yet the number of attempts at combined interventions is miniscule. The Rejuvenome is designed for iterative progress: early data from individual interventions will guide 1) the selection of future interventions to test, 2) the optimization of previously tested interventions, and 3) the design of rational combinations of interventions.

Ultimately the Rejuvenome is designed to generate a comprehensive understanding of how aging interventions work from the molecular and cellular level across the body to the functional level of the animal as a whole, an understanding that could pave new avenues for improved or even novel treatments.

At its core, the Rejuvenome is a basic research project, with translational aspirations. Basic research takes time, and the Rejuvenome is not slated for completion for 5 to 7 years. But over those years, all data, results, and conclusions will be made freely available as they are generated, and the project is deliberately flexible, with the ability to incorporate new interventions, new technologies, new analysis methodologies, and new results and ways of thinking from scientists across the field.

It is our hope that at a minimum, by conducting multiple controlled experiments on the most promising aging interventions at the same site, the Rejuvenome accelerates progress toward improving human health and wellbeing. At its best, the Rejuvenome could generate completely novel interventions or combinations with translational applications to humans.

The Rejuvenome is meant to be an open study with continuous feedback from the community. Ideas, suggestions, and discussions are always welcome! To contact us, please email rejuvenome@astera.org. Intervention suggestions can be submitted here.

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