In summary, the process of ageing affects the stem cell, the cells of the microenvironment, and the integrity of stem cell-microenvironment interactions. Potential mechanisms for cell-intrinsic changes include the initiation of altered gene expression programs in the stem cell due to accumulated damage, epigenetic modifications, or both. The aged HSC microenvironment may be compromised by accumulation of damage or senescent cells in the stem cell niche. The combined changes cause aged HSCs to interact with the aged microenvironment differently than young HSCs in a young microenvironment. It is easy to see that the resulting changes in stem cell number with age, skewed lineage representation in the peripheral blood, diminished immune response, diminished homing efficiency, reduced stromal cell adherence, and increased propensity for tumorigenesis contradict theories of an "immortal stem cell" in the adult. The effects of age on adult stem cells result in a loss of tissue homeostasis and probably lead to broad functional declines in adult tissues with advancing age, making functional stem cells one of the limiting factors in healthy ageing.

Acknowledgements We gratefully acknowledge the excellent editorial assistance of Paula Thomason.

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