Aging of the Hematopoietic System

Abstract

The design of biological systems is not expected to be better than strictly needed for survival and reproduction under a particular set of circumstances. DNA itself is an unstable molecule that can accumulate a perplexing diversity of lesions arising from environmental agents (ranging from UV light and ionizing radiation to tobacco smoke), normal cellular metabolism (in particular, reactive oxygen species derived from oxidative respiration and lipid peroxidation) and spontaneous disintegration. [1]. The energy that an organism devotes to the prevention and repair of such DNA lesions is not spent on reproduction and other vital functions and is therefore subject to selective pressures. In multicellular organisms, the need to maintain genetic integrity varies between cell types and cell death is an additional option. Selective pressures on DNA damage responses and DNA repair pathways in relation to the need to maintain the genetic integrity in a particular cell type has resulted in cell-type specific differences in the sensitivity to DNA damage and the type of response that is triggered by a given level and type of DNA damage. This is illustrated in mammalian cells by the differences in response to lethal levels of DNA damage between e.g., human lymphocytes (apoptosis) and fibroblasts (senescence). HSCs are very sensitive to radiation [2] indicating a (very) low tolerance of DNA damage. Differences in DNA damage responses and DNA repair pathways between mammalian cell types greatly complicate studies on the role of such pathways in normal aging. Furthermore, because the number of cell divisions and the time before reproduction varies widely between mammalian species, it seems reasonable that DNA damage and repair pathways will show species-specific differences as well.