p21 and the cancer-aging hypothesis.

The telomere–telomerase hypothesis is the science of cellular aging (senescence) and cancer

p21 and the cancer-aging hypothesis ..

Herein, we provide an overview of the emerging knowledge of telomere dysfunction and how it relates to possible links between aging and cancer.">

Telomeres, p21 and the cancer-aging ..

Our new molecular understanding of cancer and aging is a major tool in this effort, for two reasons. First, we are beginning to develop molecular surrogate markers of aging and future cancer risk. Such markers will revolutionize medical advice regarding nutrition and wellness. Amazingly, physicians have very little hard evidence to support a given dose of vitamin supplements, exercise, or diet; and most wellness therapeutics of proven benefit are directed toward a measurable predisease state like hypercholesterolemia or hypertension. By examining markers such as telomere function or p53 / p16INK4a expression in a given tissue, however, we may be able to better predict the future onset of cancer and/or aging, and likewise determine the beneficial or harmful effects of a therapeutic intervention with regard to these surrogate endpoints.

There are two important caveats to this sort of analysis. First, only surviving cells are considered in these molecular characterizations of aged tissues. Therefore, one would not expect to detect telomere shortening and p53 expression in cell types where these stimuli are proapoptotic. Nonetheless, apoptotic loss of stem cells may play an important role in organismal aging. Additionally, it is possible that alterations in telomere structure, which can potently induce senescence and apoptosis (–), occur in vivo. Therefore, alterations in telomere dynamics may contribute to a decline in tissue function even in the absence of an overall decrease in telomere length.

9 citations Telomeres, p21 and the cancer-aging hypothesis.

In addition to senescence, it is worth noting that cancer-related stimuli such as oncogene activation, DNA damage, and telomere shortening can also induce an entirely distinct anticancer mechanism, namely apoptosis. Apoptotic loss of progenitor cells in response to such stimuli has been clearly demonstrated in animal models; for example, mice with shortened, dysfunctional telomeres demonstrate increased apoptosis in germ cells of the testes and crypt cells of the intestine (–). In these systems, an increase in apoptosis correlates with tissue atrophy and other phenotypes associated with premature aging. The role of p53 in mediating apoptosis is well-documented (, ), and this activity seems its major anticancer function in certain animal models (, ). Correspondingly, p53 loss greatly attenuates the apoptotic phenotype seen in proliferative organs in the setting of telomere dysfunction in animal models (). While loss of p53 in these animals affords resistance to the effects of telomere dysfunction, these mice also demonstrate a marked increase in epithelial tumor formation (, ), reinforcing the view that aging and cancer are closely linked in this model system. Therefore, telomere shortening and p53 activation modulate two potent anticancer mechanisms: senescence and apoptosis. While the molecular biology of this fate-decision is incompletely understood, the specific response appears to depend on many variables including cell type, genetic context, and proliferation state. Although a role for p16INK4a in inducing apoptosis has been suggested (–), the issue of whether p16INK4a also has senescence-independent anticancer functions in vivo remains an area of active investigation.

01/09/2007 · Introduction

To be sure, adult mammals require extensive proliferation and tissue replacement to survive. Even in the absence of pathology, the intestinal lining replaces itself entirely on a weekly basis, and the bone marrow produces trillions of new blood cells daily. An obvious cost of this massive and obligate proliferation, however, is that even under physiological conditions, it is presumed that stem cell genomes are showered with somatic mutations, some of which may target cancer-relevant genes. In accord with this view is the remarkable observation that roughly 1% of neonatal cord blood collections contain significant numbers of myeloid clones harboring oncogenic fusions such as the AML-ETO fusion associated with acute leukemia (); similarly, as many as one in three adults possess detectable IgH-BCL2 translocations, which are commonly associated with follicular lymphoma (). As the prevalence of these cancers is far lower in the general population, it would appear that potent tumor suppressor mechanisms function to monitor and constrain the growth and survival of these aspiring cancer cells. In humans, three principal and overlapping tumor suppressor barriers appear to be operative; they are represented by the p16INK4a–retinoblastoma protein (p16INK4a-Rb) pathway, the ARF–p53 pathway, and telomeres. The combined effect of these tumor suppressor mechanisms is to place a limit on the replicative life span of cells in the compartment capable of contributing to tissue regeneration (hence termed stem cells). In this Perspective, we will discuss these tumor suppressor mechanisms and the hypothesis that their anticancer roles come at the cost of a decline in stem cell number and their proliferative reserve, thereby compromising tissue repair and promoting the aging phenotype. We will detail the human and murine data in support of this hypothesis, and discuss the implications of the intimate link between cancer and aging.