Telomeres, stem cells, senescence, and cancer

Abstract

Mammalian aging occurs in part because of a decline in the restorative capacity of tissue stem cells. These self-renewing cells are rendered malignant by a small number of oncogenic mutations, and overlapping tumor suppressor mechanisms (e.g., p16(INK4a)-Rb, ARF-p53, and the telomere) have evolved to ward against this possibility. These beneficial antitumor pathways, however, appear also to limit the stem cell life span, thereby contributing to aging.

Figures

Figure 1

The p53 and Rb pathways. p53 activity is predominantly regulated at the protein level. In the unstressed state, p53 is rapidly degraded by MDM2; a process which is inhibited by ARF. Also, p53 can be stabilized by N-terminal serine phosphorylation in response to genotoxic stresses, and this phosphorylation inhibits its interaction with MDM2. p53 activation potently induces either growth arrest or apoptosis depending on cellular context. The antiproliferative activity of p53 in part results from p21 expression, which is a p53 transcriptional target. Rb is inactivated by phosphorylation as a result of the cyclin-dependent kinases CDK4 and CDK6. Hypophosphorylated Rb binds E2F and represses proliferation. CDK activity is inhibited by both p16INK4a and p21.

Figure 2

Telomere structure. Telomeres are present at chromosome ends. They consist of linear arrays of repeat sequences that are 5–15 kb in humans but considerably larger in mice. Telomeres also harbor a G-rich 3′ overhang that is important for the adoption of proper secondary structure.

Figure 3

Bridge-fusion-breakage. Under normal circumstances, the chromosome ends are protected by telomeres. When normal cells develop telomere shortening, they undergo growth arrest or apoptosis in a p53- or p16INK4a-dependent manner. In cells with checkpoint inactivation, however, fusion between telomere-free ends leads to the formation of dicentric chromosomes, which are then broken during anaphase. These breakages produce non-reciprocal translocations and broken chromosome ends that are substrates for further fusion events.

Figure 4

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.