Aging is a physiological process characterized by progressive loss of integrity, impairment in tissue/organ function and increase susceptibility to age-related diseases. Cellular senescence, a state of permanent cell cycle arrest, is thought to be one of the causative processes of tissue aging and age-related disorders. Fibroblasts, which constitute a principal component of connective tissue rich organs, play a pivotal role in organ homeostasis and aging. We previously showed that senescent fibroblasts profoundly accumulate in the skin during aging. Under some transient conditions in mammals and amphibians with high regenerative potentials, senescent cells can be successfully removed by cells of the innate immune system such as Natural Killer (NK) cells. We here wanted to understand whether senescent fibroblasts in aging skin are resistant to removal by NK cells or, alternatively, NK cells themselves are compromised to remove senescent fibroblasts. Using a newly developed NK cell mediated killing assay, we found that NK-92 cell line and primary human and mouse NK cells preferentially kill senescent fibroblasts, while primary NK cells isolated from old human donor (~70 years) or old mice (~700 days) are profoundly less efficient in killing senescent fibroblasts as opposed to those isolated from young human donor (~23 years) and young mice (~100 days), respectively. Of note, there is no change in the absolute number of NK cells in peripheral blood and skin between young and old healthy individuals. Furthermore, at the synapse between target cells and NK cells the release of granzyme B is significantly reduced in aged NK cells. This is relevant as granzyme B, the effector molecule, which through pores formed by perforin on the target cell membrane enter the target cell to initiate their apoptosis. These data contribute to advancing our understanding of mechanisms underlying senescent cell accumulation, and may be exploited for future senolytic therapies.

ESDR223 - Impaired clearance of senescent fibroblasts from aging skin: Role of compromised natural killer cells

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING