June 1st, 2026
In a sense, exercise is damaging. It places stress on cells, but we have evolved to react to that stress and damage with greater maintenance, repair, and a shift of cell metabolism into a more beneficial state. That a mild or short term stress results in a long term benefit is called hormesis, and it is the case for near all forms of stress. There is a point at which any form of cellular stress or metabolic disarray tips over from net benefit to net harm, a dose-response curve that looks quite similar at the high level for cold, toxins, heat, lack of nutrients, exercise, and so forth. This remains the case once you move past the source of the stress and start picking apart the biochemical changes in cell activity and cell signaling generated in reaction to that stress.
Today's open access paper looks at HMGB1 in this context of stress and hormesis relating to exercise. HMGB1 is variously regarded as devil or angel in different scientific papers, and this does tend to be the case for many of the components of a stress response. HMGB1 can produce both benefits and harms, and the dose is everything when it comes to how the balance of outcomes affects health. So HMGB1 promotes cellular senescence in bystander cells when secreted by senescent cells as a part of the senescence-associated secretory phenotype, for example. But HMGB1 also reverses some losses of DNA structure in aged cells and increases stem cell activity to accelerate regeneration. This sort of characteristic can make stress response emulation a difficult class of therapy to bring to the clinic, as optimal doses (or even whether more versus less HMGB1 is beneficial!) might vary widely from species to species and from individual to individual within a species.
