Stem Cell Replicative Stress and Clonal Exhaustion

In humans, the process of aging is characterized by a gradual decline in the functional capacity of multiple tissues, either directly precipitating age-associated diseases or increasing the risk of an individual developing disease, such as in the case of persistent infections or cancer. In regenerating organs, the process of aging is likely driven by the progressive depletion of adult stem cell populations that are responsible for maintaining tissues throughout the lifetime of an organism. One mechanism thought to be a primary cause of progressive adult stem cell depletion with ongoing time, is the accumulation of DNA damage in the stem cell compartment and the subsequent response to this insult. As well as potentially driving the loss of adult stem cells, DNA damage in this cell population is the likely mechanism behind the sequential acquisition of transforming mutations that lead to malignant transformation. Critically, to date, no one has identified the universal physiologic source of DNA damage in adult stem cells that leads to age-associated functional decline and transformation. An in depth interrogation of the mechanism via which adult stem cells acquire DNA damage under physiologic conditions and subsequently respond to this insult is therefore warranted in order to understand the aging process and how this is a critical factor in determining risk of developing cancer and other age-associated diseases. Historically, almost all studies of DNA damage and it’s relevance to aging of stem cells either compare young versus aged cells and/or characterize the DNA damage response to artificial experimental agonists such as ionizing radiation, chemotherapy, serial bone marrow transplantation or in vitro culture. Although these approaches have been valuable in furthering our understanding of the relationship between DNA damage and stem cell biology, their physiologic relevance is debatable. The comparison of young versus aged cells assesses the consequences of cellular aging as opposed to the cause of aging, and non-physiologic experimental conditions of DNA damage evaluate a cellular response to an agonist of a type and magnitude that adult stem cells are unlikely to encounter in a normal lifetime. We have recently developed an in vivo model of DNA damage in hematopoietic stem cells (HSCs), which is precipitated by exposure of mice to agonists that mimic physiologic stress such as infection and chronic blood loss. These stress agonists drive HSCs out of their homeostatic quiescent status, resulting in de novo DNA damage as a consequence of increased replicative stress associated with dynamic changes in HSC energy metabolism. Importantly, this stress-induced DNA damage results in a phenotype of cumulative HSC attrition and a myeloid differentiation bias, which is akin to accelerated aging. In the setting of a clinically relevant mouse model of defective DNA repair (Fanconi anemia), stress hematopoiesis leads to a premature collapse of the entire hematopoietic system, fully recapitulating the progression of this disease in Fanconi anemia patients. Such a model is an ideal platform to study the response of HSCs to physiologic DNA damage and will allow us to better understand how environmental stress stimuli such as infections can impact upon both the rate of aging of tissues and the incidence of malignant transformation. This may have important clinical implications relevant to the study of age-related hematopoietic defects in patients.