Why evolution designed us to die fast, & how we can change that – Jacob Kimmel

Overview

Jacob Kimmel, co-founder of NewLimit, explores the biological and evolutionary reasons behind aging, the potential for reversing it through epigenetic reprogramming, and the challenges of drug discovery. The conversation delves into why evolution hasn't optimized for longevity, the mechanics of gene delivery, and the promise of building general-purpose biological models to accelerate medical breakthroughs.

Notable Quotes

- Evolution hasn't optimized for longevity. Ergo, it should be, relatively speaking, easy to intervene and provide health. – Jacob Kimmel, on why aging is a solvable problem.

- If you can prevent even just a couple of hospital visits over a lifetime, you shift healthcare costs dramatically. – Jacob Kimmel, on the economic impact of anti-aging therapies.

- Transcription factors are evolution's levers on the genome. By pulling on those same levers, we can engineer profound changes in biology. – Jacob Kimmel, on the power of transcription factors.

🧬 Why Evolution Didn’t Optimize for Longevity

- Evolution prioritizes reproductive success over individual longevity. High hazard rates in early human history (e.g., predators, disease) meant few lived long enough for longevity to be selected for.

- Aging may act as a regularizer for population turnover, ensuring resources are allocated to younger, fitter individuals.

- Evolutionary constraints, such as limited mutation rates and population sizes, focused optimization on immediate survival rather than long-term health.

🦠 Why Humans Didn’t Evolve Antibiotics

- Antibiotics are metabolites produced by bacteria and fungi in an evolutionary arms race. Humans lack the population size and mutation rates to compete in this microbial warfare.

- Pathogens evolve rapidly, making it difficult for mammals to maintain effective antibiotic defenses.

- Ancient remnants of pathogen-host battles, such as the TRIM5-alpha gene, show how evolution prioritized immediate threats over long-term solutions.

🧪 Epigenetic Reprogramming to Reverse Aging

- Aging is linked to the degradation of the epigenome, which regulates which genes cells use. By remodeling the epigenome, cells can regain youthful functionality.

- NewLimit focuses on identifying transcription factors (TFs) that can reprogram aged cells to a younger state without altering their identity or causing harmful side effects.

- Unlike Yamanaka’s iPSC reprogramming, which resets cells to an embryonic state, NewLimit aims for partial reprogramming to preserve cell type while reversing age-related decline.

🚀 Delivery Mechanisms: The Bottleneck

- Current delivery systems like lipid nanoparticles (LNPs) and viral vectors are limited in targeting all cell types.

- Future solutions may involve engineering immune cells (e.g., T-cells) to act as delivery vehicles, patrolling the body and releasing therapies only where needed.

- While full-body delivery remains a challenge, rejuvenating specific tissues (e.g., liver, immune cells) could still yield systemic health benefits.

📊 Breaking Eroom’s Law with Virtual Cells

- Drug discovery costs have risen exponentially, with diminishing returns. A virtual cell model could reverse this trend by predicting the effects of gene perturbations at scale.

- NewLimit is building a specialized model to predict how transcription factors affect cell aging, with potential to expand into broader applications.

- The pharma industry has largely externalized early-stage R&D to biotech startups, which are better positioned to innovate rapidly.