Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a

Stem-cell ageing is thought to contribute to altered tissue maintenance and repair. Older humans experience increased bone marrow failure and poorer haematologic tolerance of cytotoxic injury. Haematopoietic stem cells (HSCs) in older mice have decreased per-cell repopulating activity, self-renewal and homing abilities, myeloid skewing of differentiation, and increased apoptosis with stress. Here we report that the cyclin-dependent kinase inhibitor p16(INK4a), the level of which was previously noted to increase in other cell types with age, accumulates and modulates specific age-associated HSC functions. Notably, in the absence of p16(INK4a), HSC repopulating defects and apoptosis were mitigated, improving the stress tolerance of cells and the survival of animals in successive transplants, a stem- cell-autonomous tissue regeneration model. Inhibition of p16(INK4a) may ameliorate the physiological impact of ageing on stem cells and thereby improve injury repair in aged tissue.