Declining stem cell function is undoubtedly an important contribution to degenerative aging and age-related mortality. Tissues require the supply of new somatic cells that is generated by stem cells in order to replace losses, repair damage, and maintain function. Unlike stem cells, somatic cells are limited in the number of times they can divide. Turnover of somatic cell populations is a central aspect of near all multicellular life, and the small populations of tissue-specific stem cells are vital to continued function in an environment in which somatic cells must be periodically replaced. The goal of human rejuvenation will require the restoration of youthful stem cell function, through some combination of replacement, alteration of cell behavior, or repair of damage.
Stem cell exhaustion is the result of multiple types of aging-associated damages and it is one of the phenomena responsible for tissue and organismal aging. Many mammalian tissue-resident stem cells display a substantial decline in replicative function as they mature. The renewal ability of human tissues declines with aging of stem cells altering their capacity to differentiate in different types of cells. Moreover, age-related loss of self-renewal in stem cells leads to a reduction in stem cell number. Nevertheless, it may be possible to generate therapeutic approaches to age-related diseases based on interventions to delay, prevent, or even reverse stem cell aging.
Understanding how stem cells age may help understanding the normal aging process at the organ level, specifically in tissues with continuous regeneration. These processes are influenced by various cell-intrinsic and cell-extrinsic pathways. Indeed, recent discoveries have revealed a complex interaction among cell-intrinsic, environmental, and systemic signals linked to stem cell function loss during aging.
Researchers have worked to understand the main mechanisms with in vitro and in vivo experiments. The principal causes of stem cells aging are accumulation of toxic metabolites, DNA damage, proteostasis, mitochondrial dysfunction, proliferative exhaustion, extracellular signaling, epigenetic remodeling, and loss of quiescence. Many of these aging mechanisms are in common with differentiated cells but stem cell exhaustion, or the quantitative and qualitative loss in stem cell function with time, has a more important impact on tissue aging compared to differentiated cells and has been postulated as one of the aging causes. Adult stem cells perform a critical function in tissue homeostasis by repairing and regenerating tissues throughout life. They maintain practically all tissues and organs, including the forebrain, bone, and muscle, and stem cell exhaustion, defined as a drop in stem cell number and function, is documented in essentially all tissues and organs maintained by adult stem cells. Furthermore, age-related alterations in hematopoietic stem cell differentiation result in fewer adaptive immune cells being produced.
Understanding how stem cell aging affects distant tissues and overall health span is just the tip of the iceberg. This line of research is important because it lays the groundwork for stem cell-based treatments to help people live longer lives. Stem cell rejuvenation may reverse the aging phenotype and the discovery of effective methods for inducing and differentiating pluripotent stem cells for cell replacement therapies could open up new possibilities for treating age-related diseases.