An Anti-Senescence Vaccine Increases Mouse Lifespan

In a new study, late-life treatment with a three-element senolytic vaccine led to lower senescence markers and a 12% increase in median lifespan in female B6 mice. However, short-lived controls complicate the picture [1].

Helping the immune system kill “zombie cells”

Cellular Senescence

As your body ages, more of your cells become senescent. Senescent cells do not divide or support the tissues of which they are part; instead, they emit potentially harmful chemical signals, collectively known as the senescence-associated secretory phenotype (SASP), which encourages nearby cells to enter the same senescent state. Their presence causes many problems: they degrade tissue function, increase chronic inflammation, and can even eventually raise the risk of cancer and other age-related ...
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Cellular senescence is a double-edged sword. It plays important roles in early development, wound healing, and cancer surveillance, but when senescent cells are not cleared by the immune system and instead start to accumulate in tissues, they contribute to aging and disease.

To make the aging immune system more effective against senescent cells, scientists have experimented with anti-senescence (senolytic) vaccines [2]. The idea is simple: teach the immune system to recognize a protein associated with these cells and eliminate cells displaying it. Execution, however, has been trickier.

A new study from a group of Chinese scientists, published in Advanced Science, describes a senolytic vaccine consisting of three main elements that is aimed at dendritic cells, the immune cells that collect proteins, process them, and display fragments to T cells. The antigen is Gpnmb, a protein previously used in experimental senolytic vaccination. A special piece of CpG DNA acts as an adjuvant via the receptor TLR9, which recognizes this DNA as a microbial-like alarm signal and promotes T cell activation against the antigen. Finally, the CK5 protein scaffold packages the ingredients into nanoparticles that get absorbed by the cells.

The researchers assembled the three components into nanoparticles approximately 90 nanometers in diameter. They then generated dendritic cells from the bone marrow of young mice. Along with CK5, the team used a different scaffolding protein, K36.

Improved immune responses and senescence markers

Both nanoparticle vaccines improved antigen uptake and dendritic-cell activation compared with simpler formulations. Dendritic cells exposed to the nanoparticle vaccines stimulated greater CD8 T-cell proliferation. However, the CK5-based vaccine released Gpnmb into the dendritic cells’ cytosol more effectively than its K36-based counterpart.

This led the researchers to investigate CK5 separately. A gene expression analysis showed that treating dendritic cells with CK5 reduced expression of Aurora kinases A and B, proteins best known for regulating cell division.

Previous research has linked Aurora-kinase inhibition to reduced activity of PI3K/AKT signaling – a pathway associated with senescence [3]. This led the scientists to investigate whether CK5 can actually alleviate cellular senescence. To test the connection, they compared CK5 with K36 and danusertib, an Aurora-kinase inhibitor. D-galactose was used to produce senescence-like stress in cultured dendritic cells.

When the researchers compared the two vaccines, the CK5-based formulation reduced activation of PI3K/AKT and the senescence-associated markers p16, p21, and p53 while preserving cell viability. The treated cells also showed signs of improved metabolism: increased oxygen consumption and extracellular acidification.

The AI model AlphaFold3 predicted interactions between CK5 and each of the two Aurora kinases. However, this in itself does not prove the proposed mechanism.

A lifespan increase that comes with a caveat

The researchers first tested this vaccine’s health effects in mice fed a high-fat diet from four weeks of age, who were then vaccinated at 60 weeks. The CK5 vaccine elicited stronger responses from dendritic cells and CD8 T cells than the comparator groups, which included vaccines lacking one of the elements, and a K36-based vaccine. More CD8 T cells expressed interferon-γ and granzyme B, molecules associated with immune activation and cytotoxic capacity. The researchers then asked whether those T cells could effectively kill targets. Indeed, T cells collected from CK5-vaccinated mice killed more senescent Gpnmb-high cells in culture.

In the mice, vaccination reduced senescence markers in visceral fat and improved liver fat accumulation. The authors report approximately 50% lower senescence-associated β-galactosidase staining relative to the comparator groups (this experiment did not include untreated controls).

Importantly, glucose tolerance and insulin responses also improved. Body weight and food intake did not differ significantly between groups. This makes reduced eating or weight loss less likely explanations. Median lifespan reached 91 weeks, compared with 79-83 weeks in the comparator groups.

Then came the most important test: effect on lifespan in naturally aged mice. Normally fed mice were vaccinated at 75 weeks of age. The CK5 vaccine and the K36-plus-danusertib combination both strengthened immune responses, reduced senescence markers in fat tissue, and improved glucose regulation. Neither significantly changed food intake or body weight.

Mice that received the CK5 vaccine had a 12% longer median lifespan than untreated controls. This is a strong result considering how late in life the intervention started. However, two important caveats apply: the lifespan experiments were fairly small, with 10 mice per group, and the controls were relatively short-lived for this mouse strain (C57BL/6). Short-lived controls are a known issue in mouse lifespan experiments [4], although this does not necessarily invalidate the results. More rigorous studies are needed to test this intriguing proof of concept.

Literature

[1] Q. Song, X. Du, W. Dong, Y. Wang, X. Wang, and Q. Yin, A Bi-Adjuvant Senolytic Nanovaccine Modulating Dendritic Cell Senescence Ameliorates Aging-Related Metabolic Dysfunction. (2026). Advanced Science

[2] Wu, R., Sun, F., Zhang, W., Ren, J., & Liu, G. H. (2024). Targeting aging and age-related diseases with vaccines. Nature Aging, 4(4), 464-482.

[3] Astle, M. V., Hannan, K. M., Ng, P. Y., Lee, R. S., George, A. J., Hsu, A. K., … & Pearson, R. B. (2012). AKT induces senescence in human cells via mTORC1 and p53 in the absence of DNA damage: implications for targeting mTOR during malignancy. Oncogene, 31(15), 1949-1962.

[4] Pabis, K., Barardo, D., Gruber, J., Sirbu, O., Malavolta, M., Selvarajoo, K., … & Kennedy, B. K. (2024). The impact of short-lived controls on the interpretation of lifespan experiments and progress in geroscience–Through the lens of the “900-day rule”. Ageing Research Reviews, 101, 102512.