Aging-associated changes in hematopoiesis and leukemogenesis: what's the connection?

Abstract

Aging is associated with a marked increase in a number of diseases, including many types of cancer. Due to the complex and multi-factorial nature of both aging and cancer, accurate deciphering of causative links between aging and cancer remains a major challenge. It is generally accepted that initiation and progression of cancers are driven by a process of clonal evolution. In principle, this somatic evolution should follow the same Darwinian logic as evolutionary processes in populations in nature: diverse heritable types arising as a result of mutations are subjected to selection, resulting in expansion of the fittest clones. However, prevalent paradigms focus primarily on mutational aspects in linking aging and cancer. In this review, we will argue that age-related changes in selective pressures are likely to be equally important. We will focus on aging-related changes in the hematopoietic system, where age-associated alterations are relatively well studied, and discuss the impact of these changes on the development of leukemias and other malignancies.

Figure 1. Proposed Links between Aging and Cancer

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Figure 2. Conventional and Adaptive Oncogenesis Models for Tumorigenesis

Conventional View (top): Aging primarily contributes to increased cancers by facilitating the accumulation of oncogenic mutations (red cells), including activating mutations in oncogenes or genetic/epigenetic inactivation of tumor suppressor genes. Adaptive Oncogenesis Model (bottom): The ability of an oncogene to induce cancer is context specific. In a healthy population, the ability of cells to effectively compete for niche space is high due to optimal progenitor cell fitness. Thus, this competition is inherently tumor suppressive. However, if cellular fitness decreases as a result of aging or environmental insults, the acquisition of an oncogenic mutation could be adaptive due to its ability to correct or circumvent defective cellular function. In this context, these cells would be selected for leading to carcinogenesis (oncogenically mutated and cancer cells are shown in red).

Figure 3. Alterations in the hematopoietic system associated with aging

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Figure 4. Aging, Cancer, and Selection of the Fittest. (A) Predominant Model. (B) Adaptive Oncogenesis Model

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