Hormesis in aging is defined as the life supporting beneficial effects resulting from the cellular responses to single or multiple rounds of mild stress. Application of hormesis in aging research and interventions is becoming increasingly attractive and successful. The reason for this is the realization that mild stress-induced activation of one or more stress response (SR) pathways, and its consequent stimulation of repair mechanisms, is effective in reducing the age-related accumulation of molecular damage. For example, repeated heat stress-induced synthesis of heat shock proteins has been shown to have a variety of anti-aging effects on growth and other cellular and biochemical characteristics of normal human skin fibroblasts, keratinocytes and endothelial cells undergoing aging in vitro. Various mild stresses that have been reported to delay aging and prolong longevity in cells and organisms include thermal shock, irradiation, heavy metals, pro-oxidants, electromagnetic field, hypergravity, exercise and food restriction.
A crucial aspect of the stress response (SR) is that it is not monotonic with respect to the dose of the stressor, rather it is almost always characterized by a nonlinear biphasic relationship. Several meta-analyses performed on a large number of papers published in the fields of toxicology, pharmacology, medicine, and radiation biology have led to the conclusion that the most fundamental shape of the dose response is neither threshold nor linear, but is U- or inverted U-shaped, depending on the endpoint being measured.
Detailed molecular mechanisms that bring about the hormetic effects are being increasingly understood, and comprise a cascade of stress response and other pathways of maintenance and repair. Although the extent of immediate hormetic effects after exposure to a particular stress may only be moderate, the chain of events following initial hormesis leads to biologically amplified effects that are much larger, synergistic and pleiotropic. Hormetic strengthening of the homeodynamic space provides wider margins for metabolic fluctuation, stress tolerance, adaptation and survival. Hormesis thus counter-balances the progressive shrinkage of the homeodynamic space, which is the ultimate cause of aging, diseases and death. Healthy aging may be achieved by hormesis through mild and periodic, but not severe or chronic, physical and mental challenges, and by the use of nutritional hormesis incorporating mild stress-inducing molecules called hormetins.