New therapeutic strategy targets old cells to prevent ageing

Researchers from Japan have developed a vaccine against senescent cells using a protein that is only expressed by these cells. They used this vaccine to eliminate senescent cells in mice and observed significant improvements in both the normal and disease-causing effects of aging. According to corresponding author Professor Tohru Minamino from the Juntendo University Graduate School of Medicine, who has studied cellular senescence for over two decades, “With age and metabolic stress, cells become senescent and lose function. We wanted to find an effective and efficient way to get rid of these cells and improve overall tissue function.”

Professor Minamino and the rest of the team set out to first identify the proteins expressed only by  senescent cells. Using a technique called transcriptome analysis, they examined gene expression in senescent human cells and found that glycoprotein non-metastatic melanoma protein B (GPNMB) was expressed at high levels in senescent cells. This protein also had high expression levels in cells obtained in patients with atherosclerosis, a senescence-related disease involving plaque build-up and blockage in arteries. These findings confirmed that GPNMB was a senescence-specific protein, i.e., a “seno-antigen.”

The research team went on to understand the effects of eliminating GPNMB-expressing cells using a set of genetic tools. They created mouse models with a genetic modification that allowed them to selectively target and eliminate GPNMB-expressing cells. They found that the elimination of GPNMB-expressing cells in these mice considerably reduced molecular markers of ageing and metabolic abnormalities. Moreover, these mice also showed improved atherosclerotic symptoms.

Encouraged by these findings, the research team developed a vaccine specific for GPNMB. “We found anti-ageing or ‘senolytic’ effects after eliminating GPNMB-expressing cells. But genetic elimination is not feasible in humans. Hence, a vaccine that could target GPNMB and destroy only GPNMB-expressing cells was developed,” explained Professor Minamino.

Next, they tested the effectiveness of this vaccine in three mouse models: normal young mice with a high-fat diet, normal older mice (50 weeks old), and a mouse model of progeria—a disease that causes accelerated ageing. They found a reduction in metabolic dysfunction in normal mice immunised with the senolytic vaccine. Moreover, they found that the older mice who received the vaccine showed fewer age-related motor and functional impairments. Most importantly, progeroid mice who received the anti-GPNMB vaccine showed longer survival durations, and male progeroid mice, in particular, showed an extended lifespan.

Together, the findings from their experiments confirmed the effectiveness of the anti-GPNMB senolytic vaccine in preventing the physical, metabolic and disease-causing effects of senescence. Their results highlight the exciting potential of seno-antigen-based vaccines in new senolytic therapies.

According to Professor Minamino, this is but a small step in a long journey ahead.

“Our study has demonstrated the possibility of a new anti-senescence strategy. We speculate that there are many more seno-antigens that are produced by other kinds of senescent cells. With more research, we will be able to provide individualised anti-senescence therapy for patients depending on the prevalence of different types of senescent cells in their body,” said the professor.