Review: Drugs that remove senescent cells must account for cell type and tissue
Review: Drugs that remove senescent cells must account for cell type and tissue
On September 2, Masayoshi Suda, Tamar Tchkonia, and James Kirkland published a review in Geromedicine on senescent cells in obesity. They explain why senolytics, drugs that remove senescent cells, have different effects on different cell types.
Senescent cells stop dividing after damage or another form of stress, but they continue to alter their surroundings. They release a set of signaling molecules known as the SASP. Some of these signals sustain inflammation, while others contribute to tissue growth and repair.
In cell cultures treated with senolytics, 30–70% of senescent cells remained resistant. These cells released fewer inflammatory signals, including CXCL1, CXCL5, and CXCL8, but more PDGF-AA, a growth factor involved in wound healing. The review authors propose that this difference reflects the mechanisms that protect cells from programmed cell death. The inflammatory component of the SASP makes a cell more dependent on these protective mechanisms, while senolytics temporarily disable them.
In the adipose tissue of mice with obesity, the differences also depend on cell type. The proteins p16 and p21 help stop cell division, and researchers assess them alongside other markers of cellular senescence. Adipocyte progenitors and immune cells expressing p21 produced more inflammatory signals. In the endothelium, the cellular lining of blood vessels, the p16-expressing cell subtype was more inflammatory. These cells more often showed evidence of DNA damage and contained the inflammatory proteins TNFα and IL-6.
The significance of each marker also changes with time after stress. In irradiated mice, p21 was more commonly activated after one month, whereas cells expressing p16 accumulated by the fourth month. Removing these cells was beneficial only at this later timepoint. In another experiment, p16-positive immune cells helped mice survive severe infection and irradiation. Tissue type, the source of stress, and timing together determine whether a cell is harmful or necessary for the organism.
In humans, the endothelium accounts for about 1–1,5% of body mass, but it lines the entire vascular network. Endothelial cells are continuously exposed to excess glucose, fatty acids, and other metabolic signals in the blood. The SASP produced by senescent endothelial cells triggers inflammation and induces secondary senescence in neighboring cells. Inflamed cells of other types then reactivate the endothelium, sustaining a cycle of inflammation in adipose tissue.
In a genetic mouse model, a drug specifically removed p16-positive senescent cells of endothelial origin. After the intervention, mice with obesity had less fat mass and lower lipid accumulation in adipose tissue, better glucose tolerance, and increased expression of eNOS, an enzyme involved in nitric oxide production in blood vessels.
The choice of senolytic must account for cell type, tissue, and the source of stress. In this model, the vascular lining was the target because its inflamed senescent cells connect the blood with adipose tissue.