Catalyzing Connections: Uncovering Synergy in Existing Longevity Interventions

To keep up with the world’s rapidly aging population, the National Academy of Medicine (NAM) launched the Healthy Longevity Global Competition, a multi-stage global competition designed to seek out bold, innovative, and breakthrough ideas that challenge the way we think about aging. The Catalyst Award, the first stage of the competition, rewards exciting opportunities that display prospective improvement in the mental, physical, and social well-being of individuals as they age. George Sutphin is one of NAM’s 46 U.S.-based Catalyst Awardees. We hear from George, an Assistant Professor at the University of Arizona, who speaks to the award-winning project seeking a multidisciplinary approach to identify new interventions to combat aging using tools from the fields of biology, genetics, and engineering.

Can you share a little bit about yourself and your team? How did you come to work together? What advantages does your interdisciplinary team bring?

I am an aerospace engineer turned biologist. I have always been on a science-oriented career track, but an interest in space won out in my early college career and I worked on projects related to space propulsion systems and fusion energy. Early in graduate school, a long-standing interest in aging and lifespan extension rekindled and I started reading about the state of aging biology. Before long, I was reading more about the anti-aging world than my own aerospace research, and I decided to change directions. I started working on the genetics of aging in model systems (yeast and roundworms) during my graduate work and moved on to mouse aging during my postdoctoral work.

My laboratory now combines my background as an engineer with tools in roundworm and mouse aging to execute a comparative genetics pipeline to discover novel longevity interventions. We use a combination of robotics, machine learning, and molecular biology to rapidly screen genetic and pharmaceutical interventions in roundworms (Caenorhabditis elegans), study the underlying mechanisms in C. elegans, validate our mechanistic models and lifespan impact in mice, and ultimately translate the most promising interventions into human clinical medicine. Given my background, my lab is inherently interdisciplinary. A biomedical engineer, Samuel Freitas, leads the effort to develop novel robotic imaging platforms to automate lifespan, healthspan, and biomarker analysis in C. elegans and our team of biologists use these and other tools to identify candidate drugs and drug targets, carryout screens, and conduct the mechanistic studies. A technician and former master’s student in the lab, Emily Turner, manages the team that operates the robotic screening system used to evaluate compounds in this work.

Please tell us about your innovative idea/project. Why it is particularly innovative, bold, and/or novel?

We are on the precipice of real anti-aging medicine. Over the past several decades, research into the biology of aging has identified nearly a thousand genetic changes and hundreds of drugs capable of extending lifespan in eukaryotic organisms. The discovery of new pro-longevity drugs is growing at an unprecedented rate. The first clinical trial designed to evaluate the anti-aging potential of a drug—Targeting Aging with Metformin (TAME)—was approved in 2019. The biology of aging is complex, encompassing the progressive deterioration of various molecular systems across cell and tissue types. No single intervention is likely to simultaneously correct the full range of these changes, which is reflected by the fact that only a few interventions extend average lifespan beyond 20-30%. The most impressive longevity enhancement achieved results from targeted combination of two genetic interventions, resulting in lifespan extension in excess of 400% in the roundworm C. elegans. This and other studies suggest that substantial synergy may be achieved through combined therapy. To date, no systematic effort has been made to assess interactions between pro-longevity compounds, largely because standard methods for measuring lifespan are costly in terms of labor, resources, and time. Recent advances in automated data collection and analysis using robotic tools and machine learning have substantially reduced these barriers in invertebrate models of aging. Here we propose a proof-of-concept study using one of these systems to systematically screen drug combinations to identify beneficial additive and synergistic interactions in the context of healthy C. elegans longevity.

What inspired you to develop your project? Was your original goal improving health for people as they age or did that become apparent later on in the process?

The goal of my laboratory is to develop interventions capable of extending healthy lifespan and combating age-associated disease in humans. It has been clear for a long time that single-target interventions are unlikely to have dramatic benefits at extending lifespan, and that combination therapies that target different biological processes and/or different cell types would be necessary to have more substantive impacts. The aging research field is still relatively young and we are now at the point where the science has developed to the point where it makes sense to start looking at combining interventions. One aspect is simply that we now have a sufficient number of interventions (hundreds to thousands) with a diverse enough set of distinct mechanistic targets that systematic screening makes sense. A second aspect is that relatively high-throughput systems for efficiently measuring lifespan in a large number of animals have only really emerged in the past few years. While these systems are important for direct screening of individual compounds, they are particularly important for combinatorial screening, where the number of experiments needed grows combinatorially with added candidates.

How might your innovative idea/project lead to a future breakthrough in the field of healthy longevity?

There are two answers here. First, this is really designed as a proof-of-principle study to demonstrate that we can evaluate new drug combinations in the context of aging at scale. Once we have demonstrated our capability, the goal is to scale this approach to test a much broader set of drugs. Ideally, we will get to a point where we have a core set of compounds that act on distinct molecular processes. When a new drug comes out, we can rapidly test that compound against our core set to see if there is potential for synergy. This will allow us (and the field more broadly) to rapidly prioritize new compounds going forward. Second, the goal of looking at drug combinations comes back again to the complexity of aging. Once we know which pairs of drugs result in synergistic health benefits, we can begin to ask why. By understanding the biology underlying the synergy, we can begin to piece together optimized drug combinations that push back many aspects of aging at the same time. We can then advance these drug combinations to mammalian systems, and ultimately human trials, to have a broad-spectrum impact on a range of age-associated diseases.

NAM is Seeking Applicants for its 2022 U.S.-Based Healthy Longevity Catalyst Awards! LAST CHANCE TO APPLY!
Applications will be accepted from January 17, 2022, through February 28, 2022 at 11:59 pm EST. Applicants from all fields, backgrounds, industries, and specialties are encouraged to complete the unique and simple 2-page application to earn $50,000 USD in seed funding for their innovative projects.

How do you see your project advancing in the future?

Our goal is to demonstrate that our screening method is effective and identify drug combinations capable of creating large lifespan benefits and leverage this demonstration to expand the approach to a much larger panel of drugs. Each synergistic drug pair can then be advanced as a priority candidate for mammalian testing for both longevity and specific age-associated diseases that are implicated by the mechanisms of synergy.

What motivated you to apply to the Healthy Longevity Catalyst Awards? What advice would you have to other prospective applicants?

The philosophy behind the NAM Catalyst is attractive—a relatively short application with a short response time that can jumpstart new and innovative ideas. Traditional funding mechanisms are bogged down in administrative tasks, long applications, and very slow response times. This creates a high “activation cost” that limits the flexibility of researchers to develop new ideas. If you have something new and interesting to try, the NAM Catalyst Awards are a good place to get started.

George Sutphin is an Assistant Professor at the University of Arizona. He is an aerospace engineer turned biologist after rediscovering his passion for aging research. His lab uses tools in systems and comparative biology to understand the complex biology that drives aging.

Researchers with project proposals can apply here in January 2022 when the Catalyst Award Application opens. To learn more about the NAM’s Catalyst Awardees, check out these stories. For more information about the global Healthy Longevity Global Competition, click here. We appreciate your support in advancing innovative solutions to promote health throughout the human lifespan. Email for questions about the award.

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