Quiescence of Stem Cells in Aging as a Double Edged Sword

Stem cells spend much of their time in the quiescent stage of the cell cycle, resting without replication in a state of lower metabolic activity. The open access review paper here is an interesting look at why quiescence is both helpful and problematic in the context of the contribution of stem cell dysfunction to aging and age-related disease. The purpose of stem cells is to support the surrounding tissue by providing a supply of daughter somatic cells to replace losses and repair damage. Stem cell populations decline in this activity with aging, due to a mix of cellular damage, a fall in numbers, and increasing quiescence. To the degree that the latter of these issues is dominant, it should be possible to find ways to push stem cells back into greater activity. Indeed, many present approaches to regenerative medicine aim at this goal.

The quiescence stage of stem cells has beneficial and adverse effects on stem cell aging. Stem cell quiescence delays stem cell aging by reducing DNA replication, metabolic activity, gene transcription, and mRNA translation, since all of these activities are accompanied by induction of molecular damage. Stem cell quiescence comes at the cost of impaired expression of repair factors in quiescence and increased vulnerability in response to stem cell activation requiring the concerted and faithful activation of multiple molecular circuits controlling biosynthetic processes, repair, and metabolic activity.

Aging-associated increases in stem cell-intrinsic accumulation of molecular damage as well as stem cell-extrinsic alterations (e.g., chronic inflammation, niche cell defects) contribute to the deregulation of quiescence maintenance and increasing vulnerability during exit from quiescence. Epigenetic alterations occur during aging in quiescent and activated stem cells and lead to aberrant expression of developmental genes resulting in alterations of quiescence maintenance, self-renewal, and differentiation.

In conclusion, quiescence protects stem cells against molecular damage but comes at the cost of aging-associated failure in the correct regulation of quiescence maintenance and exit. Activation of quiescent stem cells - an essential process for organ homeostasis/regeneration - requires concerted and faithful regulation of multiple molecular circuits controlling biosynthetic processes, repair mechanisms, and metabolic activity. Thus, while protecting stem cell maintenance, quiescence comes at the cost of vulnerability during the process of stem cell activation.

Link: https://doi.org/10.1016/j.tcb.2019.05.002

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