Inflammatory Mid-Old Cells in Tissues are Restored to More Youthful Function by Recombinant SLIT2

Researchers here note the existence of what they call "mid-old" cells, cells in tissue stroma that are on the path to becoming senescent, are not yet entered into the senescent state, but nonetheless produce constant inflammatory signaling that is disruptive to tissue structure and function. The researchers find that these cells respond positively to delivery of recombinant SLIT2, diminishing their bad behavior. In very old mice, this treatment resulted in improved muscle mass and function and greater animal activity. This is an interesting finding, and will need further investigation and replication to rule out other mechanisms resulting from SLIT2 delivery. For example, this behavior of mid-old cells could be a bystander effect of senescent cells, and SLIT2 is in some way removing those.

Senescent cell accumulation in tissues is a well-known driver of organ aging and the overall aging process. Multiple studies have consistently revealed the accumulation of senescent cells with the progression of aging. Accumulated senescent cells play a significant role as they cause a halt in the proliferation of functional cells, ultimately resulting in organic dysfunction. Moreover, senescent cells significantly affect the surrounding microenvironment by inducing sterile chronic inflammation through the secretion of senescence-associated secretory phenotypes (SASPs), which are known as "inflammaging" phenomena.

While it has been known that the accumulation of senescent cells in the tissues of the elderly is related to tissue aging, it does not constitute the majority of cells within the tissue. Moreover, it is understood that non-senescent cells within the elderly tissue still proliferate. However, the reason for the decline in organic function in the elderly as they age remains unclear. Therefore, we hypothesized that there might be a subset of cells in an intermediate stage of the cellular senescence process within the tissue, significantly impacting and ultimately leading to organic dysfunction in the elderly. Here, we propose the existence of intermediate stage cells that are neither youthful nor senescent. We termed these cells as "mid-old cells."

Here, we found that the major population of stroma fibroblasts or smooth muscle cells are mid-old status. Moreover, we investigated the cellular characteristics of mid-old fibroblasts and smooth muscle cells in vitro and in vivo, leading us to propose mid-old cells as a new potential target for anti-aging therapy. Upregulation of pro-inflammatory genes (IL1B and SAA1) and downregulation of anti-inflammatory genes (SLIT2 and CXCL12) were detected in mid-old cells. n the stroma, SAA1 promotes development of the inflammatory microenvironment via upregulation of MMP9, which decreases the stability of epithelial cells present on the basement membrane, decreasing epithelial cell function. Remarkably, the microenvironmental change and the functional decline of mid-old cells could be reversed by a young cell-originated protein, SLIT2. Our data identify functional reversion of mid-old cells as a potential method to prevent or ameliorate aspects of aging-related tissue dysfunction.