“Senolytic Vaccination Improves Normal and Pathological Age-Related Phenotypes and Increases Lifespan in Progeroid Mice”, Masayoshi Suda, Ippei Shimizu, Goro Katsuumi, Yohko Yoshida, Yuka Hayashi, Ryutaro Ikegami, Naomi Matsumoto, Yutaka Yoshida, Ryuta Mikawa, Akihiro Katayama, Jun Wada, Masahide Seki, Yutaka Suzuki, Atsushi Iwama, Hironori Nakagami, Ayako Nagasawa, Ryuichi Morishita, Masataka Sugimoto, Shujiro Okuda, Masanori Tsuchida, Kazuyuki Ozaki, Mayumi Nakanishi-Matsui, Tohru Minamino2021-12-10 (senolytics; similar)⁠:

Elimination of senescent cells (senolysis) was recently reported to improve normal and pathological changes associated with aging in mice^1,2. However, most senolytic agents inhibit antiapoptotic pathways³, raising the possibility of off-target effects in normal tissues. Identification of alternative senolytic approaches is therefore warranted.

Here we identify glycoprotein nonmetastatic melanoma protein B (GPNMB) as a molecular target for senolytic therapy. Analysis of transcriptome data from senescent vascular endothelial cells revealed that GPNMB was a molecule with a transmembrane domain that was enriched in senescent cells (seno-antigen). GPNMB expression was upregulated in vascular endothelial cells and/or leukocytes of patients and mice with atherosclerosis.

Genetic ablation of Gpnmb-positive cells attenuated senescence in adipose tissue and improved systemic metabolic abnormalities in mice fed a high-fat diet, and reduced atherosclerotic burden in apolipoprotein E knockout mice on a high-fat diet. We then immunized mice against Gpnmb and found a reduction in Gpnmb-positive cells. Senolytic vaccination also improved normal and pathological phenotypes associated with aging, and extended the male lifespan of progeroid mice.

Our results suggest that vaccination targeting seno-antigens could be a potential strategy for new senolytic therapies.

…To investigate the effect of vaccination on normal aging, we administered Gpnmb vaccine to middle-aged mice (50 weeks old) and examined their performance in the open field test before vaccination and 20 weeks after vaccination (70 weeks old). In the control group, both total movements and the average speed of movement decreased with age, but these age-associated changes were statistically-significantly ameliorated by Gpnmb vaccination (Figure 4c). To investigate the effects of Gpnmb vaccine on the lifespan, we vaccinated Zmpste24 KO mice (a model of Hutchinson-Gilford progeria syndrome) at 10 weeks of age and evaluated their survival. In the control group, all of the mice died by 30 weeks of age. In contrast, mice, especially male mice, administered Gpnmb vaccine showed a better survival rate, even when the vaccine was administered at 10 weeks of age (Figure 4d). Likewise, administration of Gpnmb vaccine statistically-significantly extended the median lifespan of Zmpste24 KO mice, especially male mice, compared with mice treated with control vaccine (male and female mice, 21.1 ± 0.85 weeks versus 25.3 ± 1.10 weeks (p < 0.01); male mice, 21.7 ± 1.27 weeks versus 27.1 ± 1.53 weeks).

See Also:

• “The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice”

• “Targeting p21^Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity”

• “Targeting cellular senescence prevents age-related bone loss in mice”

• “Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice”

• “An aged immune system drives senescence and ageing of solid organs”

• “Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease”

• “Procyanidin C1 is a natural agent with senolytic activity against aging and age-related diseases”

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