King’s College in London, UK has been awarded a grant to investigate the role of senescent cells, which accumulate as we age, in the context of the heart and how using a therapy to remove them influences its ability to recover from injury.

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. These senescent cells are a key process in the progression of aging [1-2].







Senescent cells only make up a small number of total cells in the body, but they secrete proinflammatory cytokines, chemokines, and extracellular matrix proteases, which, together, form the senescence-associated secretory phenotype, or SASP. The SASP is thought to significantly contribute to aging [3] and cancer [4]; thus, targeting senescent cells and removing them has been suggested as a potential solution to this problem.

Seek and destroy

One of the proposed solutions to the problem of harmful senescent cells is to remove them from the body so that they can no longer secrete their harmful cocktail of inflammatory signals.

A few years ago, a new class of drugs known as senolytics were discovered; these drugs cause senescent cells to enter a kind of self-destruct sequence and destroy themselves without harming nearby healthy cells.

Various animal studies have shown that removing senescent cells improves tissue repair and delays age-related disease, and some studies show that it increases the healthy lifespan of mice.







A grant to test senolytic therapies

Heart Research UK has awarded King’s College a grant of over $160,000 to test senolytic drugs on senescent heart cells in order to further our understanding of how aging affects these cells in the surrounding healthy tissue and how therapeutically removing them might improve heart tissue health.

Led by Dr. Georgina Ellison-Hughes, the team will be growing senescent cells in culture alongside healthy heart cells, seeing how their presence and harmful SASP influences tissue repair. They will also be testing senolytic drugs on the senescent cells to see if destroying these cells and removing the SASP that they produce is beneficial to the growth, survival and ability of heart cells to repair heart tissue.

Should the tests prove positive, as they have in various tissues in mice, it could lay the foundations for senolytic therapies being developed and used to treat age-related heart disorders and injury from strokes and heart attacks. It could also find application in helping the heart recover and repair following chemotherapy, which is harmful to healthy heart cells as well as the cancer cells it seeks to destroy.

Conclusion







Based on the previous research of Dr. Georgina Ellison-Hughes, who has worked with senolytics pioneer Dr. James Kirkland, we know that she has worked with the popular senolytic combination, dasatinib and quercetin [5]. It is not known if this combination will be used in this study, but we would say it is a fair bet. It will be interesting to see if this is the case and if other senolytics are also tested either in tandem or individually.

There is also a plot twist here: from the initial number of drugs found to be senolytic from existing drug libraries, many more have been identified in the last few years, each working slightly differently. This is a good thing because as it turns out, there is more than one kind of senescent cell.

Each senescent cell type evades apoptosis by using a different genetic pathway that allows them to resist destruction. This means that one senolytic drug might destroy a certain population of senescent cells, but another would be needed to destroy others using a different pathway that the first drug does not target. It seems increasingly likely that a “senolytic cocktail” will be required in order to remove enough senescent cells to make a truly effective senescent cell therapy.

The good news is that other researchers are busy building a comprehensive database of senescent cells and SASP characteristics, which will help guide the research community in refining future senolytic therapies.

In closing, all of this sounds great, and it is wonderful to see once again that targeting the root causes of aging in order to improve health and prevent age-related diseases is entering the mainstream, but there are some challenges ahead.







Literature

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[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217. [2] van Deursen, J. M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439-446. [3] Freund, A., Orjalo, A. V., Desprez, P. Y., & Campisi, J. (2010). Inflammatory networks during cellular senescence: causes and consequences. Trends in molecular medicine, 16(5), 238-246. [4] Coppé, J. P., Desprez, P. Y., Krtolica, A., & Campisi, J. (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual review of pathology, 5, 99. [5] Lewis‐McDougall, F. C., Ruchaya, P. J., Domenjo‐Vila, E., Shin Teoh, T., Prata, L., Cottle, B. J., … & Tchkonia, T. (2019). Aged‐senescent cells contribute to impaired heart regeneration. Aging cell, 18(3), e12931.