Vaccines have been on the mind of almost everyone for the last two years. Undoubtedly, vaccines have led to a near incalculable benefit to the human species by reducing or eliminating debilitating or fatal infectious diseases, but can vaccines be used to fight age-related disease and, ultimately, to extend lifespan? Research published in Nature Aging suggests that such a promising strategy could be a reality.
Cellular senescence has gained a great deal of attention as a key driver of biological aging. Thought to be in part a protective mechanism, cellular senescence prevents dysfunctional cells from dividing, limiting the replication of potentially harmful cells. However, over time these individual non-proliferating cells accumulate and secrete a number of adverse inflammatory chemical signals. This phenomenon has been dubbed the senescence-associated secretory phenotype (SASP); it results in chronic inflammation and instigates multiple age-related diseases. In addition to the hallmark inflammatory secretions, the cells also express unique protein profiles. These proteins can be utilized as an effective means of targeting senescent cells for removal, a process known as senolysis. One such protein, Gpnmb, has been found to be enriched in senescent cells.
Immuno-therapies, whereby an intervention utilizes the organism’s immune system to extirpate damaged or unwanted cells, have shown success in combating certain cancers and are being developed to treat the age-related accumulation of senescent cells. In addition to being abundant in senescent cells, Gpnmb is a transmembrane protein—a portion protrudes from the surface of the cellular membrane. Transmembrane proteins are ideal targets for immuno-therapeutic approaches as the external portion is readily recognized by the immune system. Researchers generated peptides from the extra-cellular domain of the Gpnmb protein and combined it with an immunogenic carrier protein, keyhole limpet hemocyanin, creating a seno-antigen—a protein specifically overexpressed in senescent cells that the immune system can recognize and generate antibodies against. This leads the immune system to identify Gpnmb-expressing senescent cells as “non-self” and ultimately ends in their removal through the process of antibody-dependent cellular cytotoxicity.
Having successfully generated a vaccine against the extra-cellular domain of the Gpnmb protein and demonstrating its ability to induce an antigenic response, researchers turned to animal models of discrete age-related pathologies to determine if such an approach could reduce senescent cell burden.
High-fat diet models lead to obesity and increased adiposity, resulting in multiple comorbidities and decreased lifespan. Adipose tissue has recently been shown to be a significant depot of senescent cells and a key driver of the SASP, accelerating metabolic dysfunction and an advanced aging phenotype. Mice subjected to a high-fat diet treated with the Gpnmb vaccine showed a reduction in markers of senescence in their visceral adipose depots and improvements to glucose metabolism.
As a model for atherosclerosis, ApoE mutant mice exhibit increased lipid deposition, as well as increased senescent cells, in the aortic endothelium. These lipid deposits develop into plaques, resulting in arterial hardening and constriction—cardiovascular events. The presence of senescent cells has been attributed to increased rigidity and inflammation of these blood vessels, two hallmarks of cardiovascular disease seen in aging. Similar to the high-fat diet model, treatment with the Gpnmb vaccine reduced senescent cells in the aorta, and treated animals showed reduce incidence of atherosclerotic plaques.
In a separate experiment, the physical activity of “middle-aged” wild-type mice was measured using an open field test. The mice, vaccinated at 50 weeks of age, showed significantly higher levels of activity when compared to non-vaccinated controls 20 weeks later, suggesting that a reduced senescent burden contributes to a more youthful phenotype in the context of normal aging.
In addition to these discrete models of disease, progeroid models are often used to assess an intervention’s ability to combat premature aging. Progeroid models exhibit many of the same characteristics of aging, including elevated levels of senescent cells, resulting in a phenotype with multiple age-related pathologies and extremely short lifespans. In this study, Zmpste24 KO mice (a progeroid model for Hutchinson-Gilford syndrome) were vaccinated at 10 weeks of age. Lifespans of both male and female vaccinated mice were significantly extended, demonstrating that this therapy attenuates underlying causes of accelerating aging and might have a similar effect of increasing the lifespan of normal aging organisms.
Although these results are promising, more work needs to be done to further understand what effects such an approach may have on non-senescent cells expressing Gpnmb. Historically, the majority of life-extending interventions have focused on lifestyle; however, this technique, as well as a growing number of similar approaches, offer interventions that may be delivered in a clinical setting to slow or reverse underlying impetuses of aging.