Biologist Martin Picard and biophysicist Nirosha Murugan propose that an overload of electrons from food in mitochondria could explain diabetes, depression and aging
Biologist Martin Picard and biophysicist Nirosha Murugan propose that an overload of electrons from food in mitochondria could explain diabetes, depression and aging
The authors presented their principle of energetic resistance on October 6, 2025, in a theoretical paper in Cell Metabolism, describing it as a heuristic that brings together findings from previous research. On October 20, 2026, Scientific American covered the principle in an article by Rowan Jacobsen.
Type two diabetes and epilepsy have little in common, yet both often respond to fasting. Diet also affects depression, obesity and heart disease. Picard and his colleagues suggest that many chronic diseases share an underlying vulnerability: cells struggle to extract energy from food and use it.
Electrons from food pass through a chain of carriers in mitochondria to oxygen, providing energy for ATP synthesis. The authors compare this flow to an electric current: some resistance is necessary, but with too little resistance, energy passes through without being put to use. When the supply of electrons exceeds the chain’s capacity to carry them, the flow backs up and resistance becomes excessive. Electrons leak from the chain and react with oxygen at the wrong sites, forming reactive oxygen species, highly reactive particles that damage nearby molecules. Damaged mitochondria become less efficient at conducting electrons, leading to more reactive oxygen species and further damage.
The authors begin with a puzzle in mitochondrial disease. These conditions are usually attributed to an ATP shortage, yet findings from Picard’s group suggest that many people with mitochondrial defects maintain ATP levels comparable to those of healthy people while using more energy. A 2023 study found that energy expenditure roughly doubled in human cells with impaired cellular respiration.
The authors argue that ATP levels alone cannot explain the harm caused by mitochondrial defects and propose a formula. Modeled on the Joule–Lenz law, it makes resistance proportional to fuel reserves and load, and inversely proportional to the square of the capacity to transfer electrons from food to oxygen. According to the formula, doubling this capacity reduces resistance fourfold. Resistance could be reduced by limiting the fuel supply, as fasting does, or by increasing the capacity to carry electrons: after exercise, the body builds new blood vessels and mitochondria.
The authors propose GDF15, a protein released by stressed cells, as a marker of resistance. “This is how cells tell other cells, ‘I don’t feel well,’” Picard explains. High GDF15 levels cause malaise and nausea. In Picard’s 2024 model, in which the brain conserves the body’s energy, this signal acts as a brake: aging cells alert the brain to their growing energy demands, the brain suppresses lower-priority processes, and the person feels tired and moves less.
If GDF15 reflects resistance, its levels should rise with excess fuel and load and fall with greater capacity to carry electrons. The authors tested this prediction using UK Biobank data, which included blood protein measurements from more than 52 thousand people. On average, GDF15 levels were higher in people with high blood sugar and lower in those who were more physically active.
Picard says that diabetes is treated with drugs and insulin to overcome insulin resistance. He proposes a different explanation for that resistance: cells may resist taking up glucose because their mitochondria cannot handle the fuel supply and the cells need a break.
Matt Kaeberlein, former director of the University of Washington’s Healthy Aging and Longevity Research Institute, describes mitochondrial dysfunction as one of the hallmarks of aging. He notes, however, that health depends on more than mitochondria: “If you’re going to claim that everything starts with mitochondrial dysfunction, I think most people would disagree.”