Aging, adaptation and maladaptation.

Aging is accompanied by a dysregulation of adaptive processes. On the one hand, physiological adaptation mechanisms such as learning and memory, immune system plasticity and exercise-dependent muscle remodeling are blunted. On the other hand, several maladaptive processes increase with age including cancer, pathological cardiovascular remodeling and metabolic dysregulation. With increasing age the quotient of beneficial adaptation (Ab) to harmful adaptation (Ah), Ab/Ah, decreases. The adaptation-maladaptation framework of aging entails that there are age-related pathological phenotypes that are the result of activation of physiological adaptation mechanisms (e.g., maladaptation as a result of misdirection of adaptive cascades and molecular damage incurred by adaptation processes) and their occurrence over time might, to some degree, be inevitable. Aging might hence result from the organism's inability to solve the adaptation-maladaptation dilemma. The present work explores the concept of counteracting aging through adaptation and proposes that interventions such as exercise, environmental enrichment and dietary restriction work in counteracting aging because they increase the ratio Ab/Ah by both raising Ab (e.g., by inducing metaplasticity in cells, meaning they raise the adaptability of cells to future stimuli) and decreasing Ah (e.g., through desensitizing certain potentially harmful adaptive mechanisms). Molecules whose aging-related expression changes can explain aspects of dysfunctional adaptation such as CREB and certain immediate early genes are examined and it is delineated how a better understanding of the dynamical organization of adaptation cascades could elucidate the seemingly complex role of adaptation in driving aging as well as protecting against it.