Anti-aging vaccine
Can vaccines directly affect the aging process and age-related diseases and eliminate them? In an article published in the journal Nature Aging, a Japanese research group from the Juntendo University Graduate School of Medicine and the Niigata University Graduate School of Medical and Dental Sciences demonstrated that a vaccine that eliminates aging cells associated with age-related diseases, prolongs the lifespan of mice with premature aging. Vaccination against aging cells also reduces the severity of atherosclerosis and normalizes metabolism in mice.
Aging cells accumulate in various tissues with age or in response to metabolic stress. For example, in the atherosclerotic plaque of a person, aging endotheliocytes (cells lining blood vessels) are determined to perform their functions imperfectly and produce pro-inflammatory factors of the secretory phenotype associated with aging (senescence-associated secretory phenotype, SASP). Both of these changes accelerate the development of atherosclerosis. Visceral adipose tissue shows signs similar to aging in patients with type 2 diabetes mellitus and contributes to the formation of insulin resistance.
Senolytics – agents against aging cells – reversibly restore age-related disorders and diseases and prolong life expectancy in elderly mice. Laboratories around the world are actively studying their effectiveness. Nevertheless, concerns remain about the safety and specificity of the senolytics known to date. In addition, not all aging cells contribute to the aging of the body and diseases, some of them are necessary and contribute to tissue repair. Thus, more specific treatments are required that would effectively eliminate unwanted aging cells without affecting a useful subgroup of these cells.
To develop a specific senolytic therapy with fewer side effects, the researchers applied an approach targeting antigens expressed by aging cells. They identified the membrane protein Gpnmb (glycoprotein of non-metastatic melanoma protein B) as a molecular target for senolytic therapy. Gpnmb levels in endotheliocytes and leukocytes of patients and mice with atherosclerosis were abnormally high.
To prove that Gpnmb could be a target, the researchers genetically removed the cells expressing this protein. This slowed down the aging process of adipose tissue. Moreover, the elimination of these cells in mice fed fatty foods improved systemic metabolic parameters and reduced atherosclerotic load.
The authors then developed a peptide vaccine targeting Gpnmb using fragments of it. The introduction of this vaccine to mice led to a decrease in the number of aging cells, stopped atherogenesis caused by high fat content in the feed, and eliminated metabolic dysfunction.
The senolytic vaccine improves the characteristics of atherosclerosis in mice. Two images show the aorta of mice fed with a high fat content, which received a vaccine against Gpnmb (Gpnmb vac) or control vaccine (Cont vac). The aorta was examined for the presence of atherosclerotic plaques (red).
To study the effect of vaccination on normal aging, the researchers administered the Gpnmb vaccine to middle-aged mice (50 weeks) and evaluated the results in an open field test before vaccination and 20 weeks after vaccination (when the rodents turned 70 weeks old). In the control group, both the total number of movements and the average speed of movements decreased with age, but these age-related changes were significantly improved in the experimental group.
The senolytic vaccine increases motor activity in mice. Animals at the age of 50 weeks were injected with a Gpnmb vaccine (Gpnmb vac) or a control vaccine (Cont vac). The graphs show the change in the total number of movements (left) and the average speed (right) from 50 to 70 weeks.
To investigate the effect of the Gpnmb vaccine on life expectancy, the authors injected it into mouse models of Hutchinson–Guilford progeria syndrome (premature aging) at the age of 10 weeks and assessed their survival. In the control group, all mice died by 30 weeks of age, and mice, especially males who received the Gpnmb vaccine, showed better survival. Similarly, vaccination significantly increased the average life expectancy of mice with progeria, especially males, compared to mice who received the control vaccine.
Senolytic vaccine increases life expectancy in mice with progeria. Survival charts demonstrate the life expectancy of mice who received the Gpnmb vaccine (Gpnmb vac) or the control vaccine (Cont vac) at the age of 10 weeks.
This study also compared the Gpnmb vaccine with several senolytics (a combination of dasatinib+quercetin, navitoclax). It is noteworthy that the groups receiving dasatinib+ quercetin or navitoclax showed a decrease in aging-characteristic changes in adipose tissue at week 16 of life, but these effects decreased by week 24. On the contrary, the Gpnmb vaccine consistently improved the phenotypic changes characteristic of aging in visceral adipose tissue. The same results were observed when assessing insulin resistance: dasatinib+ quercetin or navitoclax improved the indicator, but by the age of 24 weeks the effect disappeared, and the Gpnmb vaccine, on the contrary, retained its effect on glucose metabolism until 24 weeks of age. Finally, navitoclax treatment significantly reduced the number of white blood cells and platelets and increased the bleeding time.
The results of this voluminous study show that compared to known senolytic compounds, a new vaccine may be the best option, and vaccination against Gpnmb may become a potential strategy for new treatments for age-related disorders, especially metabolic dysfunction and atherosclerosis.
Article M.Suda et al. Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice published in the journal Nature Aging.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru