Dr. Ringel on Partial Epigenetic Reprogramming & Reversing Cellular Age

This episode of "Translating Aging," produced by BioAge Labs, features an in-depth conversation with Dr. Michael Ringel, Chief Operating Officer of Life Biosciences. Hosted by Chris Patil, VP of Media at BioAge, the discussion explores Dr. Ringel's journey into the longevity field, the science behind partial epigenetic reprogramming, and Life Biosciences' pioneering work in developing cellular rejuvenation therapies. The episode delves into the company's lead candidate, ER100, for treating age-related eye diseases like glaucoma and Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION). It also touches upon broader themes such as the "pipeline in a pill" concept, the potential impact on current and future generations, and the role of investment in advancing longevity biotechnology. This summary is for individuals interested in cutting-edge biotech, the science of aging, potential treatments for age-related diseases, and the strategic landscape of the pharmaceutical industry.

Key Insights

• Partial Epigenetic Reprogramming as a "Holy Grail": Dr. Ringel highlights partial epigenetic reprogramming, specifically using a combination of three Yamanaka factors (OSK), as a highly promising approach to reverse cellular age without inducing pluripotency or cancer risk. This technology aims to restore youthful cellular function and potentially treat a wide range of age-related diseases.
• Life Biosciences' Lead Candidate ER100 Nears Clinical Trials: Life Biosciences is developing ER100, an inducible OSK-based gene therapy, and expects to be the first company to bring a partial reprogramming therapy into human clinical trials. Initial targets are the eye diseases glaucoma and NAION, with promising preclinical data in mice and non-human primates showing vision restoration.
• The Eye as a Strategic First Target: The choice of ophthalmological indications for ER100 is driven by significant unmet medical need, strong preclinical evidence of efficacy in restoring vision, and the eye's suitability for targeted AAV-mediated gene delivery and controlled, inducible therapy.
• "Pipeline in a Pill" - The Geroscience Hypothesis: The episode underscores the geroscience hypothesis, suggesting that interventions targeting the fundamental biology of aging can simultaneously address multiple age-related diseases. This "pipeline in a pill" concept offers transformative potential for patient health and significant economic opportunities for the pharmaceutical industry, exemplified by the broad efficacy of GLP-1 agonists.
• Long-Term Vision and Current Realities: While specific therapies for age-related diseases like those ER100 targets could reach the market in the 2030s, whole-body rejuvenation is a multi-decade endeavor. Significant challenges, particularly in systemic delivery, need to be overcome before such therapies become a reality.
• Evolutionary Biology Informs Therapeutic Strategy: Understanding evolutionary theories of aging, such as the Disposable Soma theory, suggests that aging is a manipulable process. This framework emphasizes the importance of tapping into existing biological mechanisms for rejuvenation, such as those involved in germline immortality or cellular maintenance and repair pathways.
• The Critical Role of Investment and Collaboration: Dr. Ringel emphasizes the need for continued investment from private, philanthropic, and governmental sources to advance the longevity field, citing the "positive externality" of fundamental research that benefits society broadly. He also calls for more talent to enter this burgeoning area of science and medicine.

Dr. Ringel's Path to Longevity and Life Biosciences

Dr. Michael Ringel's interest in aging biology dates back to his youth in the 1970s, when his father introduced him to the concept of caloric restriction. This early curiosity was further solidified during his PhD in the mid-1990s with landmark discoveries like Cynthia Kenyon's work on Daf-2 in worms, which demonstrated a genetic basis for aging and its potential manipulability. After a distinguished 25-year career at Boston Consulting Group (BCG), where he focused on R&D and innovation initiatives for major pharmaceutical companies, Dr. Ringel's passion for longevity science persisted. He advised Life Biosciences starting in 2018 and was involved in a project for a government entity in 2019 assessing the longevity field, which contributed to the formation of the Hevolution Foundation.

Through an extensive scan of technologies, Dr. Ringel became convinced that partial epigenetic reprogramming, the core platform of Life Biosciences, represented the "holy grail" for transforming how we age at cellular, tissue, and organismal levels. This conviction led him to leave BCG and join Life Biosciences as COO, driven by the desire to actively contribute to bringing this transformative technology to fruition and impact patients' lives, rather than remaining on the sidelines.

Understanding Partial Epigenetic Reprogramming

Dr. Ringel explained the foundational concept of cellular age reset, drawing an analogy to how adult organisms produce offspring that are "brand new" at a cellular level. This inherent biological capacity for age reversal was famously tapped into by Shinya Yamanaka, who won a Nobel Prize for inducing pluripotency in adult cells using four transcription factors (Oct4, Sox2, Klf4, and c-Myc, collectively known as OSKM). These induced pluripotent stem cells (iPSCs) not only regain the ability to differentiate into any cell type but are also "de-aged" to a youthful state, a phenomenon also observed in cloning (e.g., Dolly the sheep).

The critical challenge with full reprogramming is that inducing pluripotency in vivo would disrupt existing cell identities and carry a risk of cancer. However, a breakthrough discovery, highlighted in a 2020 Nature paper from Dr. David Sinclair's lab (a scientific co-founder of Life Biosciences), showed that using only three of the Yamanaka factors (OSK, omitting c-Myc) could achieve cellular de-aging *without* taking cells all the way back to pluripotency. This "partial epigenetic reprogramming" was shown to create a more youthful state in cells, tissues, and even organisms (mice) without evidence of tumor formation. Subsequent studies have confirmed these findings, demonstrating extended lifespan in aged mice treated with this approach.

Life Biosciences' Approach and Lead Candidate ER100

Life Biosciences is leveraging the OSK-based partial epigenetic reprogramming platform. Dr. Ringel positions this approach as distinct from, yet potentially complementary to, other longevity interventions like those targeting nutrient-sensing pathways (e.g., mTOR inhibitors, GLP-1 agonists). While caloric restriction mimetics can offer significant healthspan benefits, partial reprogramming taps into a different biological mechanism—the intrinsic cellular ability to reset age—which may offer more profound rejuvenation potential.

Within the nascent field of reprogramming companies, Life Biosciences aims to differentiate itself by being the first to enter clinical trials with its lead candidate, ER100, and by holding strong intellectual property around the OSK factor combination. ER100 is an AAV2-delivered gene therapy designed to express the OSK factors in retinal ganglion cells. A key feature is its inducibility: the therapy is activated only in the presence of doxycycline, a commonly used oral antibiotic. This allows for precise control over the duration of treatment. Patients would receive a single intraocular injection, and then take doxycycline orally to turn the therapy on. If needed, the therapy can be turned off by stopping doxycycline and potentially re-activated later with another course of the oral drug.

Preclinical studies have demonstrated ER100's promise. The original 2020 Nature paper showed that an OSK-based therapy restored vision in mice subjected to optic nerve crush, a glaucoma model, or simply old age. Life Biosciences has since advanced ER100, the human-optimized version, showing vision restoration in non-human primates after laser-induced optic nerve injury. Importantly, Good Laboratory Practice (GLP) toxicology studies, required by the FDA, have shown no serious adverse events at the top line. Life Biosciences anticipates starting human clinical trials for ER100 in early 2025.

The initial indications for ER100 are glaucoma and Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION). Glaucoma is a leading cause of blindness in individuals over 60, often progressing silently until significant vision loss occurs. NAION is an acute condition, essentially a stroke of the optic nerve, that can cause sudden blindness in one eye and has no current treatments. It is the leading acute cause of blindness in people over 50.

Strategic Considerations and Future Directions

The decision to target eye diseases first was strategic. Dr. Ringel cited the large unmet medical need, the compelling preclinical data showing vision restoration, and the eye's status as an "immune-privileged" and accessible site for AAV-mediated gene delivery. The ability to directly inject and target retinal ganglion cells with AAV2 vectors makes it an attractive starting point.

Beyond ophthalmology, Life Biosciences is exploring other age-related diseases where epigenetics plays a role and where delivery is feasible, although specific next targets are not yet disclosed. This aligns with the "geroscience hypothesis," which posits that targeting the aging process itself can ameliorate multiple age-related diseases simultaneously. Dr. Ringel referred to this as a "pipeline in a pill." He drew parallels to GLP-1 agonists, which were initially for diabetes and weight loss but are now showing efficacy in chronic kidney disease, heart failure, and potentially neurodegenerative conditions and some cancers. This broad applicability, he argued, makes aging-focused therapies incredibly valuable both for society and for pharmaceutical companies. He suggested that pharma companies that "missed the GLP-1 train" should pay close attention to the longevity field, focusing on fundamental medical need and technical feasibility rather than just current market sizes.

Timelines, Investment, and Broader Perspectives

Dr. Ringel provided a realistic timeline: the first therapies like ER100 might reach the market in the 2030s, assuming successful clinical development. However, whole-body rejuvenation is a much longer-term prospect, likely a multi-decade proposition. Key challenges, particularly in achieving safe and effective systemic delivery of reprogramming factors to all necessary organs in the correct amounts, must be solved first. While he hopes such advancements might benefit the current generation, the primary mission is to help humanity, irrespective of personal benefit.

He emphasized the critical role of investment in the longevity biotech field. Fundamental discoveries, he explained, create "positive externalities"—broad societal benefits that extend far beyond the direct profits for the initial inventor. Therefore, philanthropic and government funding are essential to complement private investment, which might otherwise underfund such foundational research. This is particularly true for a field like longevity, which has the potential to address a vast spectrum of human suffering.

Dr. Ringel also touched upon the importance of evolutionary theories of aging, such as the "Disposable Soma" theory. This perspective suggests that aging is not an immutable inevitability but rather a programmed process that can be manipulated. It underscores the strategy of tapping into existing, evolutionarily conserved biological mechanisms for repair and rejuvenation, such as those that ensure germline immortality or mediate the switch between growth/reproduction and maintenance/repair in response to environmental cues. This contrasts with views that see aging as purely an accumulation of damage, which might imply it's harder to reverse.

In closing, Dr. Ringel encouraged young researchers, entrepreneurs, investors, and pharmaceutical companies to engage with the longevity field, highlighting its immense potential for scientific discovery, societal benefit, and therapeutic innovation.

Conclusion

Dr. Michael Ringel's insights paint a compelling picture of a rapidly advancing field. Partial epigenetic reprogramming, particularly using the OSK factors championed by Life Biosciences, stands out as a deeply promising approach to address the root causes of cellular aging. The upcoming clinical trials for ER100 in glaucoma and NAION represent a significant milestone, potentially ushering in a new era of therapies that don't just manage symptoms but aim to restore youthful function to aged or damaged tissues.

The broader implications are profound. If the geroscience hypothesis holds true, and interventions like partial reprogramming can indeed act as a "pipeline in a pill," the impact on human healthspan and the treatment of numerous age-related diseases could be revolutionary. While whole-body rejuvenation remains a distant goal, the focused efforts on specific diseases today are paving the way for a future where aging is a far more malleable process, significantly enhancing the quality and potentially the length of human life.