The ultimate goal of research into the biology of aging is to identify pharmaceutical interventions to increase both lifespan and healthspan of humans. The natural product rapamycin has been shown to significantly extend the lifespans of all model organisms tested including fungi, flies, worms, and mice. However, chronic treatment with rapamycin also causes unwanted side effects including moderate immunosuppression and impaired glucose tolerance and insulin function. Recent research suggests that rapamycin functions by binding and blocking signaling from two independent signaling complexes, mTORC1 and mTORC2. It has been shown that the beneficial effects on lifespan are due to the downregulation of mTORC1 signaling upon binding by rapamycin. On the other hand, the deleterious side effects of rapamycin result from the downregulation of mTORC2 signaling upon rapamycin binding. Thus, an ideal anti-aging pharmaceutical agent would be highly similar to rapamycin, but have high specificity for mTORC1 and little specificity for mTORC2. Radiant Genomics believes that the enormous diversity of natural product gene clusters that can be identified through a combination of bioinformatics and next generation sequencing of metagenomes and individual organisms can now be mined to provide candidate natural rapamycin analogs that may have desired binding properties, bypassing hurdles blocking traditional methods of natural product discovery. To do this, we have developed a synthetic biology platform that has three main pipelines: 1) a method to bioinformatically identify gene clusters that code for natural rapamycin analogs, 2) a method to clone and manipulate these gene clusters into constructs for transformation into a heterologous host, 3) a method to transform these clusters into an engineered host that has been genetically altered to produce selected rapamycin analogs. Then, in collaboration with the Buck Institute for Research on Aging, we will test the binding specificities of these natural rapamycin analogs for mTOR1C and mTOR2C. If we find analogs with the desired properties, future experiments will be initiated using standard animal lifespan assays and other animal disease models through a collaboration with both the Buck Institute and Delos Pharmaceuticals for further drug development. Successful production and characterization of a range of natural rapamycin analogs will provide strong proof of concept that the Radiant Genomics natural product discovery platform will allow scientists to quickly interrogate the natural diversity surrounding a targeted natural product, an impossibility using traditional natural product discovery methods, and would revolutionize the field of natural product discovery.

Public Health Relevance

Research into the aging process of numerous model organisms across the animal kingdom has demonstrated that intervention with certain natural product drugs, such as rapamycin, can significantly delay the effects of aging and the onset of aging related diseases. However, many of these natural product drugs result in unwanted side effects after prolonged exposure. By utilizing synthetic biology and metabolic engineering, Radiant Genomics will develop a platform that can access existing natural diversity and identify both novel and related natural products that demonstrate improved specificity and efficacy against aging and aging-related diseases.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1-ETTN-M (11))
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Murthy, Mahadev
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Radiant Genomics, Inc.
United States
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