Knowing how an organism’s tissues handle stress throughout life is key to understanding ageing and disease. Stems cells of the blood system seem to tackle metabolic stress by means of a process called autophagy.
Stem cells in adult tissues function to replace lost, damaged or diseased cells throughout an organism’s life, thereby helping to maintain tissue health. But what protects the rare, long-lived stem cells from a lifetime of exposure to cellular and environmental stressors such as inflammation, radiation and metabolic alterations?
Aautophagy, a process of cellular self-cannibalization, is one mechanism that haematopoietic stem cells of the blood system use to protect themselves during times of metabolic stress, when nutrients are limited. When cells are starved of nutrients, the tissue’s stem cells must choose whether to live or die. The options are committing suicide by apoptotic cell death, or self-preservation through autophagy, whereby cells recycle damaged or dispensable proteins and organelles into basic components to support cellular growth.
Autophagy is thought to be a major factor in ageing. Loss of autophagy in tissues such as the brain, liver and heart leads to an increase in age-related disorders, including neurodegeneration, metabolic syndromes and cardiac dysfunction. Conversely, factors that stimulate autophagy abrogate these problems and have been linked to greater longevity. It has therefore been hypothesized that reduced autophagy contributes to the diminishing stem-cell function that occurs with age. No study, however, has investigated the direct role of autophagy in adult stem-cell function.
Warr et al. explore this question in both young mouse haematopoietic stem cells (HSCs) and in more-differentiated HSC progeny, including progenitor cells of the immune cells granulocytes and macrophages. The authors find that little or no autophagy occurs in freshly isolated young HSCs, but that this process can be rapidly induced when the cells are exposed to metabolic stress both in vitro and in vivo. Moreover, when autophagy is inhibited during such metabolic stress, young HSCs rapidly die through apoptosis, indicating that autophagy is crucial for their survival. By contrast, granulocyte–macrophage progenitor cells show higher baseline levels of autophagy, but no shift under starvation conditions. Autophagy can be stimulated in several ways, including through inhibition of the signalling molecule mTOR and activation of stress-induced transcription factors such as FoxO3 and p53. Warr and colleagues find that the primary driver in HSCs is FoxO3, with little contribution from mTOR or p53.(Nature 494, 317–318 (21 February 2013) doi:10.1038/nature11948)