Age-Related Cellular Senescence Harms Stem Cell Function
The growth in number of senescent cells with age is an important mechanism of degenerative aging. Many studies in mice have demonstrated rapid rejuvenation and reversal of many different aspects of aging and age-related conditions via selective destruction of senescent cells in aged tissues. Here, researchers review what is known of the way in which the age-related expansion of the senescent state in cell populations impedes stem cell function in older individuals. Stem cells support tissues by generating a supply of daughter somatic cells to replace losses, as well as via signaling that is important to regenerative capacity. As stem cell activity declines so too does tissue function and health.
Several cellular settings have been identified where senescence induction seems to exclude stem cell activity, thereby suggesting a functional competition between the two processes. One such example are mesenchymal stem cells (MSCs) used in therapy. Many of the potentially beneficial MSC properties are attributed to their ability to grow as high-density monolayers known as MSC sheets, which however can rapidly acquire senescence features under sustained high-density conditions. Another case of functional competition between senescence and stemness relates to bone marrow mesenchymal stem cells (BMSCs) which constitute a lifelong reservoir for somatic cell generation, and are shown to be significantly useful in bone regenerative medicine. It has, however, been observed that BMSC osteogenic differentiation is inhibited by senescence, thereby limiting the BMSC regenerative potential.
A considerable body of evidence where documented antagonism between senescence and stemness is pivotal for physiological homeostasis refers to muscle tissue. Muscle tissue regeneration relies heavily on satellite cells, a quiescent adult stem cell population whose regenerative capacity declines upon aging. Stellite cells from geriatric populations fail to retain their quiescent state under normal conditions, which extensively impacts their self-renewal and regenerative properties. Resting satellite cells in geriatric mice switch to a pre-senescence state thereby losing quiescence, a process driven by p16INK4A derepression. Thus maintenance of quiescence in adults, in fact, relies on repression of senescence.
Given that senescence is intrinsically characterized by proliferation arrest, while stemness refers to an inherent self-renewal capacity and production of differentiated progeny, the two cellular states are often perceived as mutually exclusive. Indeed, in this review we present an accumulation of evidence where the establishment of senescence may impose a barrier to stemness during natural processes such as aging, and upon reversing this functional competition (e.g. via genetic or pharmacological interventions) cell fate may change, as shown in multiple cell types and tissues such as MSCs, muscle satellite cells, dental pulp stem cells, or pancreatic β-cells.
Interestingly extensive functional synergy between the two states is widely observed in cancer, because the "dark side of senescence" may promote tumorigenic traits through senescent cell paracrine activity or even escape from the senescent state itself. Such activity was found to occur at least in B-cell lymphomas, liver, colon, and lung cancer.