The Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis

Abstract

It is widely accepted that senescent cells accumulate with aging. They are characterized by replicative arrest and the release of a myriad of factors commonly called the senescence-associated secretory phenotype. Despite the replicative cell cycle arrest, these cells are metabolically active and functional. The release of SASP factors is mostly thought to cause tissue dysfunction and to induce senescence in surrounding cells. As major markers for aging and senescence, p16INK4, p14ARF/p19ARF, and p21 are established. Importantly, senescence is also implicated in development, cancer, and tissue homeostasis. While many markers of senescence have been identified, none are able to unambiguously identify all senescent cells. However, increased levels of the cyclin-dependent kinase inhibitors p16INK4A and p21 are often used to identify cells with senescence-associated phenotypes. We review here the knowledge of senescence, p16INK4A, p14ARF/p19ARF, and p21 in embryonic and postnatal development and potential functions in pathophysiology and homeostasis. The establishment of senolytic therapies with the ultimate goal to improve healthy aging requires care and detailed knowledge about the involvement of senescence and senescence-associated proteins in developmental processes and homeostatic mechanism. The review contributes to these topics, summarizes open questions, and provides some directions for future research.

Keywords: SASP; aging; development; endothelial cells; metabolic function; senescence; stem cells.

Figure 1

Schematic illustration of detection of p16INK4A, p14ARF/p19ARF, p21, and SAβG in selected murine organs during development. P16: p16INK4A; p19: p14ARF/p19ARF. During development, p16INK4A, p14ARF/p19ARF, p21, and SAβG not only mark senescent cells. p16INK4A, p14ARF/p19ARF, and p21 proteins are expressed in distinct cell types during different developmental stages. Expression of the individual proteins correlates with lower expression of proliferation markers in agreement with their classical function as cell cycle inhibitors, with apoptosis, and cellular differentiation. These fundamental processes contribute dynamically to tissue remodeling and morphogenesis during embryonic development.