Cell-autonomous vs. non–cell-autonomous aging. Two models for impaired tissue repair are suggested: target cells of aging are shown in gray and senescent cell are shown in blue. In the cell-autonomous case, senescence (or apoptosis) of a progenitor with self-renewal capacity leads to impaired tissue regeneration in old animals. In the non–cell-autonomous case, however, a support cell supplies a factor (X), which is critical for the maintenance of tissue repair. X could be a hormone (e.g., estrogen) acting at a distance or cell-cell interactions (e.g., costimulatory signals from antigen-presenting cells) acting in a paracrine manner. In this model, aging results from the functional loss (e.g., by senescence) of the support cell, which may not be detectable in the tissue of interest.