Could a vaccine approach to removing harmful senescent cells that accumulate with age be an alternative to senolytic drugs, which destroy them? Some researchers certainly believe it might and have published a new mouse study showing just that.
What are senescent cells?
As you age, increasing numbers of your cells enter into a state known as senescence. Senescent cells do not divide or support the tissues of which they are part; instead, they emit a range of potentially harmful chemical signals that encourage nearby healthy cells to enter the same senescent state. Their presence causes many problems: they reduce tissue repair, increase chronic inflammation, and can even eventually raise the risk of cancer and other age-related diseases.
Senescent cells normally destroy themselves via a programmed process called apoptosis, and they are also removed by the immune system; however, the immune system weakens with age, and increasing numbers of senescent cells escape this process and begin to accumulate in all the tissues of the body.
By the time people reach old age, significant numbers of these senescent cells have built up, causing chronic inflammation and damage to surrounding cells and tissue. Senescent cells only make up a small number of total cells in the body, but they secrete proinflammatory signals including, cytokines, chemokines, and extracellular matrix proteases, which, together, form the senescence-associated secretory phenotype, or SASP. The accumulation of senescent cells is thought to be one of the reasons we age.
A vaccine-based approach to senescent cells
Today, we want to highlight a new study that is taking a slightly different approach to senescent cell accumulation in the form of a vaccination [1]. These researchers demonstrate that a vaccination against a cell surface marker is a viable approach to dealing with the senescent T cells present in fat tissue.
The researchers in the study we are talking about today show that vaccination against a surface marker present on the surfaces of senescent T cells living in fat tissue can spur the rest of the immune system to see them as a problem and seek and destroy them. This should be beneficial given the level of evidence that excessive fat tissue produces an increased amount of senescent cells, and as a result, an elevated level of systemic inflammation from the secreted SASP, which disrupts metabolism and impairs healthy tissue function.
A vaccine would provide a constantly active way to remove senescent cells, but that might not be ideal in humans. This is because cellular senescence is a useful process and is only a problem during aging, which is when they accumulate, get out of control, and become harmful. Cellular senescence is a safety net against cancer, and it facilitates wound healing and tissue repair when it functions correctly. If a vaccine were to target all senescent cells and immediately remove them, this could be problematic for wound healing and regeneration. Therefore, removing all senescent cells using a constantly active mechanism such as a vaccine may not be wise unless we are certain that the targeted cells serve no useful function.
However, it should be noted that due to the heterogeneity of senescent cell populations, the surface marker that this vaccine uses only appears on a subset of these cells, so the treatment would be unlikely to target all senescent cells at once; this is much like the present use of senolytics, which target different pathways used by subsets of senescent cells. In other words, it is unlikely that a single senolytic or vaccine could target all senescent cells at once due to their diversity in characteristics, such as surface markers and pro-survival pathways used to evade apoptosis.
The heterogeneity of senescent cell populations is a hot topic for researchers in recent months and there is even a SASP Atlas, which aims to comprehensively categorize the various secretions that the various senescent cell types make [2]. There is also the excellent HAGR cellular senescence database CellAge, which is charting the interactions, gene expressions, and complexities of senescent cells. Databases like this will, without a doubt, help researchers make the most informed decisions about future targets for senescent cell removal, including vaccines.
Senotherapy targeting for senescent cells is designed to attenuate age-related dysfunction. Senescent T cells, defined as CD4+ CD44high CD62Llow PD-1+ CD153+ cells, accumulate in visceral adipose tissues (VAT) in obese individuals. Here, we show the long-lasting effect of using CD153 vaccination to remove senescent T cells from high-fat diet (HFD)-induced obese C57BL/6J mice. We administered a CD153 peptide-KLH (keyhole limpet hemocyanin) conjugate vaccine with Alhydrogel (CD153-Alum) or CpG oligodeoxynucleotide (ODN) 1585 (CD153-CpG) and confirmed an increase in anti-CD153 antibody levels that was sustained for several months. After being fed a HFD for 10–11 weeks, adipose senescent T cell accumulation was significantly reduced in the VAT of CD153-CpG-vaccinated mice, accompanied by glucose tolerance and insulin resistance. A complement-dependent cytotoxicity (CDC) assay indicated that the mouse IgG2 antibody produced in the CD153-CpG-vaccinated mice successfully reduced the number of senescent T cells. The CD153-CpG vaccine is an optional tool for senolytic therapy.
Conclusion
It is possible to make the case that removing senescent and dysfunctional T cells from fat tissue could be useful, as such damaged immune cells likely serve no useful purpose and instead add to systemic inflammation. As we learn more about the heterogeneity of senescent cell populations, it may turn out to be the case that there are other populations of senescent cells that are not useful in any way and could have surface markers that allow a vaccine-based approach to destroy them as well. However, that would need to be tested in further studies to establish this.
Would a vaccine approach to clearing senescent cells be superior to periodic senolytic treatment to purge the cells? That remains to be seen, although the direction of the research here is certainly intriguing and gives some food for thought.
Literature
[1] Yoshida, S., Nakagami, H., Hayashi, H., Ikeda, Y., Sun, J., Tenma, A., … & Rakugi, H. (2020). The CD153 vaccine is a senotherapeutic option for preventing the accumulation of senescent T cells in mice. Nature communications, 11(1), 1-10.
[2] Basisty, N., Kale, A., Jeon, O., Kuehnemann, C., Payne, T., Rao, C., … & Schilling, B. (2019). A Proteomic Atlas of Senescence-Associated Secretomes for Aging Biomarker Development. bioRxiv, 604306.
