Introduction
Stem cells maintain tissue homeostasis by self-renewing and differentiating into mature cells needed for tissue growth, renewal, and repair in the skin, blood, muscles, intestines, and certain regions of the brain. Neural stem cell activity is more restricted than the continual cell replacement seen in blood and intestinal tissue.
Aging can weaken stem cell regenerative abilities, a phenomenon known as stem cell exhaustion, contributing to impaired wound healing, muscle loss, weakened immune function, and progressive decline in organ performance.Understanding this decline requires examining damage within stem cells, changes in their surrounding tissues, and the experimental approaches being studied to preserve regenerative function.
What is stem cell exhaustion?
Stem cell exhaustion refers to the progressive decline in stem cells’ capacity to self-renew, maintain tissue homeostasis, and generate specialized cells over time. As stem cells grow older, they can become less responsive to external stimuli and accumulate molecular damage.
The balance between quiescence, a reversible resting state, and activation can also become disturbed. Quiescence normally helps preserve stem cells; excessive activation can deplete some populations, while deeper quiescence can make others harder to activate for repair. This phenomenon affects numerous tissue-specific stem cell types, such as muscle satellite cells responsible for muscle regeneration, hematopoietic stem cells involved in blood and immune system functions, and neural stem cells that generate new neural cells in restricted brain regions.
Stem cell exhaustion reduces the body’s capacity to maintain tissues in the blood, skin, and gastrointestinal tract. This affects healing and tissue integrity, making recovery from injury less efficient as people age. Changes vary by tissue: functional impairment can occur, even when stem cell numbers remain stable or increase.
Age-related impairments in muscle satellite cells, the body’s muscle-residing stem cells responsible for repairing muscle injuries, reduce muscle regeneration and can contribute to declining muscle function. Blood stem cells can exhibit reduced self-renewal and altered differentiation, shifting toward myeloid cell production, including granulocytes and monocytes, at the expense of lymphoid cells, including B- and T-cells.
Their measured numbers often increase with age, particularly in mice, even as their function per cell declines. These changes contribute to immune aging, including reduced production of cells needed for adaptive immune responses.
Bone regeneration is also affected. Aging mesenchymal stem and progenitor cells in bone marrow show reduced proliferation and a shift toward fat cell formation at the expense of bone-forming osteoblasts. These changes contribute to reduced bone formation and osteoporosis, along with increased bone resorption and other age-related factors.
The connection between stem cell exhaustion and other hallmarks of aging
Because many stem cells persist throughout an individual’s lifetime, they can accumulate molecular damage. Persistent deoxyribonucleic acid (DNA) damage, oxidative stress from excess reactive oxygen species (ROS) production, mitochondrial dysfunction, and epigenetic changes progressively impair tissue maintenance and repair.
Telomeres, the protective structures at chromosome ends, can shorten during repeated cell division and sustain oxidative damage. Stem cells can express telomerase, which helps maintain telomeres; however, this does not fully prevent age-related shortening in several stem cell populations. Critically short or uncapped telomeres can activate DNA damage responses that trigger senescence or cell death.
Epigenetic changes such as DNA methylation, histone modifications, and alterations in chromatin structure also disrupt gene expression programs that regulate stem cell identity, self-renewal, and differentiation. These changes affect gene expression without altering the underlying DNA sequence.
Cellular senescence links accumulated damage to declining regeneration. Senescence is a stable state of cell cycle arrest that differs from reversible quiescence. Senescent cells can impair regeneration through both loss of proliferative capacity and their effects on neighboring cells.