Activity-Dependent Induction of Younger Biological Phenotypes

In several mammalian species, including humans, complex stimulation patterns such as cognitive and physical exercise lead to improvements in organ function, organism health and performance, as well as possibly longer lifespans. A framework is introduced here in which activity-dependent transcriptional programs, induced by these environmental stimuli, move somatic cells such as neurons and muscle cells toward a state that resembles younger cells to allow remodeling and adaptation of the organism. This cellular adaptation program targets several process classes that are heavily implicated in aging, such as mitochondrial metabolism, cell-cell communication, and epigenetic information processing, and leads to functional improvements in these areas. The activity-dependent gene program (ADGP) can be seen as a natural, endogenous cellular reprogramming mechanism that provides deep insight into the principles of inducible improvements in cell and organism function and can guide the development of therapeutic approaches for longevity. Here, these ADGPs are analyzed, exemplary critical molecular nexus points such as cAMP response element-binding protein, myocyte enhancer factor 2, serum response factor, and c-Fos are identified, and it is explored how one may leverage them to prevent, attenuate, and reverse human aging-related decline of body function.