Grosse L, Wagner N, Emelyanov A, Molina C, Lacas-Gervais S, Wagner KD, Bulavin DV. Defined p16High Senescent Cell Types Are Indispensable for Mouse Healthspan. Cell Metab. 2020 Jul 7;32(1):87-99.e6. doi: 10.1016/j.cmet.2020.05.002. Epub 2020 Jun 1. PMID: 32485135.
DOI: 10.1016/j.cmet.2020.05.002
Summary
As we age, our bodies accumulate a type of cell known as senescent cells, which are essentially cells that have stopped dividing and functioning properly. These aging cells are linked to various diseases and the overall aging process. There has been a theory that removing these senescent cells might help extend our lifespan.
To explore this, researchers developed two new mouse models that specifically target a common marker of aging cells, p16Ink4a. They tracked how these cells accumulate with age and found that this process picks up speed when the mice are about 10-12 months old. The majority of these aging cells were found in the blood vessels of the liver and, to a lesser extent, in certain immune and fat cells.
However, when these aging cells were actively removed, it disrupted the normal barriers between blood and tissue. This led to scarring and damage in the liver and surrounding vascular areas, which actually worsened the health of the mice. This suggests that while these senescent cells can contribute to aging, they also play critical structural and functional roles in the body, particularly in blood vessels. Therefore, simply removing these cells isn’t enough; finding ways to either slow their development or replace them might be a more effective strategy in managing aging and maintaining health as we grow older.
Scientific Abstract
The accumulation of senescent cells can drive many age-associated phenotypes and pathologies. Consequently, it has been proposed that removing senescent cells might extend lifespan. Here, we generated two knockin mouse models targeting the best-characterized marker of senescence, p16Ink4a. Using a genetic lineage tracing approach, we found that age-induced p16High senescence is a slow process that manifests around 10-12 months of age. The majority of p16High cells were vascular endothelial cells mostly in liver sinusoids (LSECs), and to lesser extent macrophages and adipocytes. In turn, continuous or acute elimination of p16High senescent cells disrupted blood-tissue barriers with subsequent liver and perivascular tissue fibrosis and health deterioration. Our data show that senescent LSECs are not replaced after removal and have important structural and functional roles in the aging organism. In turn, delaying senescence or replacement of senescent LSECs could represent a powerful tool in slowing down aging.