Jacob Kimmel on Dwarkesh Patel: Why Evolution Ignored Aging

For most of human and primate history, daily mortality from infection, predation, and accidents was so high that few individuals reached ages where late-life health mattered for selection, so genomes accumulated little signal to extend lifespan or preserve fluid intelligence into old age.

Kimmel argues there is no single ‘aging gene’; instead multiple regulatory layers, especially epigenetics, degrade over time—and because evolution never deeply optimized lifespan, there may be relatively tractable “low-hanging fruit” for interventions compared to traits evolution did optimize hard.

Four Yamanaka factors can revert adult cells to embryonic stem cells, proving that a tiny set of transcription factors can reset both cell type and age; NewLimit aims to find safer combinations that make old cells functionally young without changing their identity or triggering tumors.

Because there are roughly 1,000–2,000 TFs and combinatorial space is ~10^16, exhaustive lab screening is impossible; NewLimit uses single-cell transcriptomics and models (initialized with protein language models) to learn how TF combinations move cells in “state space” and to predict which combos rejuvenate cells.

Lipid nanoparticles and AAV vectors only reach certain tissues well, so initial reprogramming therapies will likely focus on tractable cells like hepatocytes or immune cells—but because organs are highly interconnected, rejuvenating one (e.g., liver or bone marrow) can yield systemic health benefits.