Hormesis, cell death and aging

Abstract

Frequently, low doses of toxins and other stressors not only are harmless but also activate an adaptive stress response that raise the resistance of the organism against high doses of the same agent. This phenomenon, which is known as "hormesis", is best represented by ischemic preconditioning, the situation in which short ischemic episodes protect the brain and the heart against prolonged shortage of oxygen and nutrients. Many molecules that cause cell death also elicit autophagy, a cytoprotective mechanism relying on the digestion of potentially harmful intracellular structures, notably mitochondria. When high doses of these agents are employed, cells undergo mitochondrial outer membrane permeabilization and die. In contrast, low doses of such cytotoxic agents can activate hormesis in several paradigms, and this may explain the lifespan-prolonging potential of autophagy inducers including resveratrol and caloric restriction.

Figure 1. Autophagy and hormesis

In baseline conditions, autophagy contributes to the maintenance of cellular homeostasis by removing potentially dangerous mitochondria (or other damaged organelles) and by ensuring the disposal of protein aggregates. This might have anti-aging effects and prolong healthy lifespan by elevating the threshold of damage required for the induction of cellular dysfunctions or death. In this scenario, while high doses of agents that stimulate both autophagy and cell death (e.g., BH3 mimetics) would be toxic (A), low doses of the same agents might provoke a hormetic response and hence favor the adaptation of cells to stress (B). MOMP, mitochondrial outer membrane permeabilization.