Joe Rogan Experience #1349 - David Sinclair

The Horvath epigenetic clock reads chemical marks on DNA (especially cytosine methylation) to estimate biological age and mortality risk. Early human data (e.g., a small metformin–HGH–DHEA trial) suggest those epigenetic markers can be shifted toward a younger profile, implying aging itself is at least partially reversible.

Sinclair’s lab links aging to declining NAD and sirtuin activity. He takes NMN (an NAD precursor) and high-dose resveratrol (with fat for absorption) to stimulate cellular defense pathways, improve mitochondrial function, and mimic benefits of fasting and exercise—though he stresses human longevity proof is still lacking.

Some studies show metformin improves metabolic health and potentially lifespan, but it can dampen exercise-induced mitochondrial adaptations and performance. Sinclair’s pragmatic strategy is to “pulse” metformin—avoiding it on hard training and recovery days, using it on sedentary days—to try to capture metabolic benefits without athletic tradeoffs.

Senescent cells accumulate with age and secrete inflammatory factors that damage tissues and promote disease. In mice, genetically or pharmacologically removing these cells (senolytics) delays multiple aspects of aging and improves function; human trials (e.g., for osteoarthritis) are already under way.

Using viral vectors and a subset of Yamanaka factors, Sinclair’s group has rejuvenated old mouse retinas and even regrown damaged optic nerves, restoring vision and resetting epigenetic age. They aim to move this into human eye trials within a few years, with longer-term ambitions for spinal cord and other tissues.