Cellular senescence is an irreversible state of cell cycle arrest caused by stress injury or certain physiological processes. Senescent cells not only directly affect the normal functions of tissues and organs, but also continuously secrete a variety of inflammatory factors to cause tissue and organ damage, causing a variety of age-related diseases, fatty liver, liver fibrosis, diabetes and other diseases. It has become a consensus in the field that the removal of senescent cells can alleviate or even treat aging-related diseases. However, how to remove senescent cells safely, effectively and accurately is currently a difficulty that needs to be overcome.
NKG2D ligands (NKG2DLs) include MICA, MICB and ULBP1-6, which are highly expressed in tumor cells. Currently, a large number of them are used as therapeutic agents. Targeted tumor treatments have entered clinical trials, and no serious side effects have been found. In the human body, NKG2DLs are also the switch for senescent cells to trigger NK cell killing. Therefore, in anti-aging research where safety is the primary consideration, NKG2DLs is undoubtedly an ideal target for eliminating senescent cells.
August 17, 2023, from the Frontier Science Center for Disease Molecular Networks, West China Hospital of Sichuan University/State Key Laboratory of Biotherapy/National Elderly The Zhao Xudong team of the Medical Clinical Research Center published a paper on NKG2D-CAR T cells selectively eliminate senescent cells in aged animal models as a cover article in Science Translational Medicine. The article elaborated on the effectiveness and safety of NKG2D-CAR T cells targeting NKG2DLs. Anti-aging drugs, effectively clearing senescent cells in macaques, and improving aging-related histology, imaging indicators and motor function indicators in mice.
The researchers first demonstrated that NKG2DLs were significantly upregulated in senescent cells induced by various stresses, and then used the NKG2D extracellular domain as The target recognition domains, 4-1BB and CD3ζ, construct NKG2D-CAR T cells that recognize NKG2DLs for costimulatory signals. In vitro experiments show that NKG2D-CAR T significantly kills senescent cells induced by DNA damage, replication failure, oncogene activation or tumor suppressor gene inactivation in a dose-dependent manner, and releases high concentrations of cytokines, perforin and granzymes.
In order to study the anti-aging effect of NKG2D-CAR T cells, researchers constructed mNKG2D-CAR T cells for mice cells and used to treat irradiation-induced aging mice and naturally aging mice. Compared with the control group, mNKG2D-CAR T cells significantly reduced the number of senescent cells in mice, alleviated weight loss, fat loss and osteoporosis caused by aging, and improved the mice's physical functions and enhanced exercise capacity. During the treatment process, no treatment-related adverse reactions were seen in the mice.
Human and macaque NKG2D is highly conserved, with only two amino acid differences in its extracellular domain. After confirming that human NKG2D-CAR can also recognize macaque NKG2DL, the researchers isolated T cells from aging macaques and infected them with human NKG2D-CAR virus to prepare hNKG2D-CAR T cells for autologous reinfusion to further evaluate the effectiveness and effectiveness of hNKG2D-CAR. safety. Although CAR-T slowly expands in the body after reinfusion, cytokines are always maintained at low levels. After two months of treatment, the expression of senescent cell markers in the macaques was significantly reduced, proving that NKG2D-CAR T cells can eliminate senescent cells in the macaques. More importantly, NKG2D-CAR T cells did not produce severe treatment-related side effects in aging macaques. The research results lay the foundation for the clinical application transformation of NKG2D-CAR T anti-aging.