Senescent cells are created and destroyed constantly throughout life, but their numbers accumulate with age, a growing imbalance that is probably primarily caused by immune system aging. The immune system is responsible for removing those senescent cells that do not undergo programmed cell death, but it becomes ever less competent with age. A lingering population of senescent cells is clearly responsible for causing significant harm to cell and tissue function, largely via the secretion of inflammatory, pro-growth factors. Here, researchers think a little more deeply about how this harm progresses.
Here, based on recent research evidence from our laboratory and others, we propose a mechanism - Senescence-Associated Cell Transition and Interaction (SACTAI) - to explain how cell heterogeneity arises during aging and how the interaction between somatic cells (SomCs) and senescent cells, some of which are derived from aging somatic cells, results in cell death and tissue degeneration. Recent genomic analysis reveals a remarkable heterogeneity of cell types during aging. Such cell heterogeneity gives rise to not only senescent cells but also other types of cells including progenitor and stromal cells.
Adult mesenchymal stem cells (MSCs) constitute a small percentage of cells responsible for repair upon tissue damage. The increase in senescent cells is tightly associated with repeated activation of adult MSCs, where they reach replication capacity and become senescent. In response to stress signals, differentiated SomCs may lose their identity and de-differentiate into MSC-like cells for repair. Such epigenetically re-programmed MSCs are subject to cell senescence triggered by replicative, mechanical, and inflammatory stress signals. Although in small numbers, senescent MSCs manifest the senescence-associated secretory phenotype (SASP), spread inflammation, and signal surrounding somatic cells in the tissue microenvironment. Thus, senescent MSCs may accumulate during aging by cell proliferation, transition, and senescence, and accelerate catabolism and death of somatic cells through cell interactions. Important signaling molecules mediating the SACTAI process include pro-inflammatory cytokine IL-1β, IL-6, IL-8, growth factor TGF-β, and morphogen Sonic Hedgehog, which at least partially overlap with SASPs.
SACTAI is a proposed two-step mechanism for aging-associated tissue degeneration and somatic cell death. In the first step, a few adult SomCs, in response to mechanical, inflammatory, or replicative stress signals, undergo proliferation, MSC transition, and senescence, resulting in senescent MSCs (snMSCs). This cell transition and senescence process results in a heterogenous cell population, which enables heterotypic cell interactions with each other. During the second step, snMSCs interacts with SomCs via SASPs. Such cell senescence-associated signaling contributes to cell death and tissue degeneration in age-related diseases. The newly discovered SomC transition to snMSC during aging may explain the fibrosis, abnormal ossification (calcification), and inflammaging phenotypes often associated with aging tissues. The identification of the multi-step mechanism of SACTAI provides an opportunity to develop potential drugs to intervene during different stages of age-related disease pathogenesis.