Homeostatic conflict as a driver for brain aging.

Mammalian tissue function depends on the balance between proliferative, mitotic cell populations and irreplaceable post-mitotic cells. Throughout life, aging progressively disrupts cell type balance and thus tissue function through opposing forces on different cell types. Aging promotes the aberrant proliferation or entry into pro-inflammatory senescent states of mitotic cells, while contributing to the functional erosion and, in vulnerable populations, loss of post-mitotic irreplaceable cells. The divergent age-associated vulnerabilities of mitotic and post-mitotic cells caused by aging generate a case of homeostatic conflict, in which tissue maintenance simultaneously demands the elimination of damaged mitotic cells and the preservation of irreplaceable ones. We examine the concept of homeostatic conflict using the aging brain as an example, and illustrate how the senescence-prone glia expand and acquire SASP-rich transcriptional states, while post-mitotic neurons undergo widespread loss of molecular identity and cell death, resulting in cell type imbalance and consequently tissue dysfunction. Based on the observed homeostatic conflict, we then devise potential context-sensitive therapeutic strategies by combining interventions that protect from ferroptosis to selectively protect irreplaceable cells with interventions that eliminate maladaptive ones to resolve the age-associated cell type imbalance and thus the underlying homeostatic conflict. We present homeostatic conflict as a concept that goes beyond the reductionist view in which numerous isolated processes promote aging in isolation, and provides a logical framework that integrates multiple processes and explains how their interaction drives age-associated dysfunction in a manner instructive to the development of pharmacological combination strategies.