134: Why Your Cells Age (And What You Can Do About It) with Dr. Ben Bikman

Bikman argues that while protein-derived amino acids also activate mTOR, they do so in a transient manner that is necessary for muscle maintenance. Insulin, however, provides a strong sustained mTOR signal. In a modern diet where people eat carbohydrates frequently, mTOR stays chronically elevated, crowding out cellular repair. By cutting carbs, insulin falls, mTOR activity drops, and cells can re-enter the repair state more often. He emphasizes that this strategy avoids the risks of protein malnutrition and is far more effective than obsessing over protein restriction for longevity.

Bikman positions fasting as a natural, drug-free way to achieve the longevity signaling that people seek from rapamycin. He stresses that the combination of reduced mTOR activation (from lower insulin and amino acid levels) and increased AMPK activity (from cellular energy deficit and BHB) drives cellular housekeeping. He doesn't prescribe a specific fasting protocol but ties it closely to carbohydrate restriction as two sides of the same coin.

Bikman discusses research showing BHB stimulates the autophagic lysosomal pathway, confirmed in rodent brains on ketogenic diets. He suggests that supplementing with BHB (go BHB) can be used alongside or as an alternative to strict dietary ketosis to activate AMPK and promote cellular cleaning. He contrasts this favorably with rapamycin, noting it activates pro-longevity pathways without gonadotoxicity or immunosuppression.

Bikman acknowledges the impressive mouse lifespan data but emphasizes the gap between rodent models and human outcomes. He details the human side-effect profile from transplant medicine: in men, decreased testosterone, disrupted spermatogenesis, elevated LH/FSH indicating primary gonadal failure, and structural testicular damage; in women, ovarian cysts and amenorrhea. While some effects may reverse upon discontinuation, the gamble of enduring such harm for an unproven human longevity benefit is, in his view, unjustified. He recommends using dietary and lifestyle interventions that tap into the same AMPK/mTOR pathways without toxicity.

Bikman directly challenges the 'protein restriction for longevity' movement. He references rodent data where cutting protein to 5–10% of calories extended lifespan ~20%, but argues that a safe, warm cage environment does not replicate human demands for muscle strength to prevent falls and maintain independence. He contends that sufficient protein is necessary to stimulate mTOR in muscles periodically for repair and growth, while the real problem is the chronic background mTOR activity driven by high insulin from constant carbohydrate intake. He believes this approach harmonizes longevity signaling with quality of life.

Bikman points out that insulin activates mTOR through the PI3K-AKT pathway, and when cells are treated with insulin versus leucine, mTOR stays higher and remains active longer with insulin. Moreover, the average Western diet is ~50% carbohydrate and only ~15% protein, with frequent eating keeping insulin elevated all day. He acknowledges that amino acids are necessary for insulin-stimulated mTOR activation (citing Drummond's group), but emphasizes that insulin provides the sustained signal while amino acids provide an acute trigger. Thus, cutting carbohydrates and reducing insulin fundamentally changes the mTOR landscape without needing to restrict protein — which he thinks is dangerous because adequate protein is needed for muscle and bone mass. His view: focusing on protein restriction to control mTOR is 'laughable' when the elephant in the room is chronic carbohydrate intake.

Bikman notes that this age-related decline in AMPK sensitivity means the cellular 'fuel gauge' becomes less sensitive, which then impairs the cell's ability to switch into repair and clean-up mode. This feeds a vicious cycle of accumulated damage and reduced stress resistance. While he does not detail the molecular mechanisms of this decline in this lecture, he frames it as a key reason interventions that boost AMPK — such as fasting, ketosis, or metformin — become increasingly valuable with aging to restore the balance toward autophagy and repair.

Bikman explains that this Nature paper identified PEN2 as a metformin target that inhibits the lysosomal v-ATPase, triggering AMPK activation through a pathway that does not require cellular energy deprivation. This allows metformin to activate AMPK at clinically relevant doses without drastically altering ATP levels. He ties this to metabolic benefits like reduced hepatic acetyl-CoA carboxylase activity (less fat synthesis) and increased fatty acid oxidation, which helps reverse fatty liver. He presents this as an example of how AMPK activation can be achieved pharmacologically, but notes that the same pathway can be triggered by ketones without a prescription.

Citing a recent paper in Cells, Bikman explains that BHB stimulates the autophagic lysosomal pathway via AMPK activation. The lysosome is the organelle that degrades damaged mitochondria and protein aggregates during autophagy. This effect has been confirmed in rodent brain tissue under ketogenic diets. He argues that entering ketosis through carbohydrate restriction or fasting, or supplementing with exogenous BHB, sends a dual signal: lowering insulin reduces chronic mTOR activation, while BHB simultaneously activates AMPK and drives autophagy. This natural lever, he says, mimics the cellular repair benefits sought from rapamycin without the gonadal toxicity.