Stem Cell Aging
Much of age-related morbidity in mammals may be determined by the influence of aging on stem cell function. We have found that stem cells from the hematopoietic and nervous systems undergo strikingly conserved changes in their properties as they age, including declining self-renewal capacity.
We have identified a network of heterochronic gene products that regulates stem cell maintenance throughout life while also regulating the temporal changes in stem cell properties required to match the changing growth and regeneration demands of fetal and adult tissues. For example, Hmga2 expression declines while let-7 expression and Ink4a expression increase with age, reducing stem cell frequency and function in multiple tissues. By deleting Ink4a from mice, we partly rescued the decline in stem cell function with age and enhanced the regenerative capacity of aging tissues. Networks of proto-oncogenes and tumor suppressors thus change throughout life to balance tissue regeneration with tumor suppression. Proto-oncogenic signals dominate during fetal development when tissue growth is rapid but cancer risk is low, and tumor-suppressor mechanisms are amplified during aging when there is little tissue growth but cancer risk is high.