Novel Insights into Regulation of Stem Cell Aging by Aging of the Niche and Alterations in Systemic Factors

Many tissues of the major organ systems, including the skin, intestine and hematopoietic system, are composed of short-lived cells that require continuous replenishment. This replenishment is assured by somatic stem cells. Stem cells were initially thought to be endowed with unlimited self-renewal (rejuvenation) capacity and thus assumed to be exempt from aging. This would result in a fully intact (young) stem cell compartment in chronologically aged organisms. However, evidence accumulating over the past decade has now proven that there is a measurable and successive functional decline in hematopoietic, intestinal and muscle stem cell activity from adulthood to old age, resulting in a decline of stem cell function in aged humans and mice. As stem cell activity is necessary to replenish lost differentiated cells, it has been hypothesized that aging of stem cells results in impaired tissue homeostasis in aged individuals, which might ultimately limit lifespan. In 1978, Schofield proposed the ‘niche’ hypothesis to describe the physiologically limited microenvironment that supports stem cells. This hypothesis has been confirmed in multiple stem cell systems from distinct organisms over the last decade, and is thus now regarded as a central theme in stem cell biology. One of the major questions in the field – and one which is an ongoing debate – is the extent of the contribution of stem cell-intrinsic versus -extrinsic (niche)/systemic factors to stem cell aging, which is important in the light of reversion/rejuvenation. While distinct aspects of aging are intrinsic to stem cells, over the recent years, the aspect of aging of the niche or even the more general influence of systemic factors on altered phenotypes associated with aged stem cells has become more and more appreciated. As this chapter demonstrates, such novel concepts (microenvironemental/systemic influence on stem cell aging) hold true for different organisms as well as different types of stem cells, rendering them a critical theme in aging of stem cell compartments. This chapter summarizes the presentations at the Else KrÖner-Fresenius Symposium on the Molecular Mechanisms of Stem Cell Aging that focused primarily on elucidating the intrinsic/extrinsic contributions of aging and alterations of stem cell-niche interactions as well as systemic influences on stem cell aging. It includes presentations and novel insights into this matter in Drosophila and mice given by Dr. Thomas A. Rando, Dr. Amy J. Wagers, Dr. Hartmut Geiger, Dr. Ting Xie and Dr. D. Leanne Jones.