As multicellular organisms age, there is a gradual loss of tissue homeostasis and organ function. Throughout life, populations of adult stem cells maintain many tissues, such as the blood, skin and intestinal epithelium. Therefore, it is likely that the decrease in tissue homeostasis can be attributed to an age-related decline in the ability of stem cells to replace damaged cells. Although cell autonomous changes occur as the organism ages that result in the inability of stem cells to proliferate or self-renew, or of daughter cells to differentiate along a specific lineage, local and systemic changes can also affect the ability of stem and progenitor cells to function properly.
A number of evolutionary theories attempt to provide a rationale for why we age and, ultimately, die (Box 1
). Germline stem cells are probably subjected to different evolutionary pressures when compared with somatic stem cells given the very different roles the germline and soma play in the survival of species1
. However, ageing cannot be interpreted as simply a product of stem cell dysfunction. Likewise, longevity is not simply determined by the functionality of the tissues maintained by stem cells. Conditions such as neurodegeneration and cardiomyopathy are not thought to be consequences of somatic stem cell dysfunction. Furthermore, genotoxic and proteotoxic damage that accumulates in post-mitotic differentiated cells can also contribute to disease progression or lead to loss of tissue homeostasis, particularly when such cells provide a support function for tissue stem cells2–4
. Ultimately, understanding how and why we age must integrate mechanisms of both stem cell and post-mitotic cell ageing and the interplay between the two.
BOX 1. Evolutionary theory and stem cell ageing
Many evolutionary theories have been proposed to explain the very existence of ageing of metazoans. They specifically try to reconcile the inexplicability — from an evolutionary perspective — of having a genetic ‘programme’ for ageing with the undeniable influence of genetics on longevity, and the phenotypes of ageing resulting from evolutionarily selected programmes for development, growth and adult homeostasis98
. The ‘disposable soma theory’ posits that selective pressures require a trade-off of resource utilization between somatic maintenance and reproduction. For example, to maximize reproductive success, organisms may have been selected to modulate the trade-off between somatic maintenance and reproduction based on environmental conditions, favouring reproduction during a time when resources are plentiful, but investing more in survival pathways and somatic maintenance when resources are scarce and reproductive success may be limited99
. Ageing is then the result of declining homeostatic mechanisms owing to inadequate investment in defence mechanisms to sustain an organism past the period of fertility. As stem cells contribute to somatic homeostasis, they will have been under similar selection pressures as the rest of the soma, and thus will have evolved differently to germline stem cells, despite their similarities.
An intriguing theory that may explain some features observed in aged stem cells is the ‘antagonistic pleiotropy’ theory, which posits that evolution selects for genes that are beneficial in early life even if they are detrimental later100,101
. p53 and mammalian target of rapamycin (mTOR) are notable examples of genes falling into this category1,102
. Many of the genes considered to exhibit antagonistic pleiotropy are tumour suppressors, beneficial by suppressing cancer early (and later) in life but potentially driving ageing by the very mechanisms by which they suppress cancer. The study of these genes with regard to age-related changes in stem cell function is important to understand how abnormal stem cell fate, including malignant transformation or senescence, can influence tissue ageing and, potentially, organismal longevity.
The interesting overlap between the biology of ageing and the biology of stem cells has been reviewed extensively3,5–8
. To the extent that stem cell ageing is itself an important factor in organismal ageing, it may be possible to develop therapeutic approaches to age-related diseases based on interventions to delay, prevent or even reverse stem cell ageing. Therefore, understanding the basic properties of stem cells as they age, and the mechanisms that promote or prevent stem cell ageing, have significant implications for regenerative medicine and the goal of extending ‘healthspan’. In this review, we highlight emerging model organisms that have begun to reveal general principles of stem cell ageing, and we present the emerging paradigms that characterize age-related decline in stem cell functionality.