The breaking news today is that yet another research group has entered the field of senescent cell clearance to treat aging. Therapies that remove senescent cells are known as senolytics, and they have been a hot topic for the past year or so. Before we talk about the new study, let’s take a look at what senescent cells are and how they contribute to aging.

What are senescent cells?

Cellular senescence is one of the hallmarks of aging and is one of the various processes that cause us to age. As you grow older, an increasing number of your cells enter into a state known as senescence. These senescent cells no longer divide or support the tissues of which they are part; instead, they spew out a cocktail of harmful chemical signals that cause inflammation and drive an aging process.

This proinflammatory collection of proteins, cytokines, and signals is known as the senescence associated secretory phenotype (SASP). The SASP blocks various important cellular processes, prevents stem cells from repairing damaged tissue efficiently, and is implicated in the development of age-related diseases[1-2].

If that was not bad enough, SASP from senescent cells can also encourage nearby healthy cells to become senescent, initiating a downward spiral of increasingly poor tissue repair. This means that a small number of these cells can have a dramatic effect.







It has been suggested that because the number of senescent cells increases with aging that senescence contributes to aging. However, this is not quite as simple as it first appears and downplays what the likely primary purpose of cell senescence is.

Senescence is a safety measure built into cells to prevent the propagation of damaged cells, allowing them to enter apoptosis (cell death) and have the immune system dispose of them. Therefore, senescence is, generally speaking, a good thing, as it keeps us safe from damaged cells causing cancer and promotes healthy tissue repair.

However, there is a tipping point of this safety valve. Clearing away unwanted senescent cells is the job of the immune system, and replacing the lost cells requires stem cells to repopulate the tissue. As we age, the ability of the immune system to clear these cells begins to fail, and they begin to accumulate; this, in turn, increases inflammation, reducing the ability of stem cells to replace losses. Thus begins the downward spiral.

At this point, cell senescence ceases to be a safety valve and switches to becoming an active driver of aging. Senescent cells are also involved in the wound healing process, but they only require a very small number of cells to achieve this[3].

Inflammaging







Senescent cells also contribute to another hallmark of aging, altered intercellular communication, by driving the background of chronic low-grade inflammation sometimes known as “inflammaging”. This comes from a variety of sources, including cell debris, microbial burden, activation of the pro-inflammatory NF-kb pathway, and the pro-inflammatory signals from senescent cells.

Inflammaging is different to acute inflammation in that it is a constant, low-grade level of chronic inflammation; many age-related diseases have a link to this inflammation, making it a significant risk factor to our health as we age. Inflammaging contributes to the loss of regenerative capacity of tissues and stem cells, and it is closely linked to the other hallmarks of aging, as it is an integrative process aggravated by the other primary processes.

So, what can we do about senescent cells?

It has been suggested that the most direct approach to the accumulation of senescent cells is to periodically destroy them, reducing their numbers to manageable levels. Thankfully, the number of senescent cells that accumulate with age is not enormous: they only make up a small percentage of cells in tissue even in late old age. As mentioned previously, even a small number of these cells can play havoc, and removing them periodically to help compensate for the failing immune system seems to be a potentially viable approach.

Senolytic therapies that can remove senescent cells have been tested on animals in previous studies, with some showing an increase in the healthy period of life and even maximum lifespan [4]. Other studies have shown that senolytics have the potential to treat age-related diseases, such as heart disease [5-6] and osteoarthritis [7].







In other studies, just removing thirty percent of senescent cells showed significant reductions to age-related decline. These results suggest that it is feasible to selectively ablate senescent cells using senolytics in order to alleviate the symptoms of aging and promote health as we grow older [8-9].

New study uses another approach

The researchers in this new study have approached the problem of senescent cells in a slightly different manner than that used by the various senolytic drug candidates that have been tested so far [10]. The advantage with this new approach is that it potentially has fewer side effects, which are often a problem with small-molecule approaches. The approach used in this study directly targets one of the mechanisms that senescent cells use to avoid apoptosis, and, fortunately, this mechanism does not affect healthy cells.

This has the advantage that the drug can be delivered system-wide, and it will only affect senescent cells, in contrast to other drugs with senolytic properties, such as Navitoclax, that have some potentially serious side effects and risks. Navitoclax and a number of other similar senolytics work by targeting the bcl-2 family of proteins (in particular bcl-1, bcl-w and bcl-xl) that prevent the cell from entering apoptosis.

The researchers in this new study instead focused on FOXO4 (Forkhead box protein O4 is a protein encoded by the FOXO4 gene) and its influence on p53 (a gene that codes for a protein that regulates the cell cycle). Senescent cells increase expression of FOXO4 to escape apoptosis, and the researchers have chosen a peptide to disrupt this mechanism. By disrupting the crosstalk between the two, the team was able to induce apoptosis in senescent cells; this achieves a similar result to other approaches but with seemingly none of the side effects.







Conclusion

There is certainly more research to be done, and some academics are calling for further studies. The researchers who performed this study believe that they have concluded their mouse work and are ready to start planning the next step. Dr. Keizer told the BBC news website: “In terms of mouse work, we are pretty much done; we could look at specific age-related diseases e.g. osteoporosis, but we should now prepare for clinical translation”.

While preparations for human clinical trials begin, it could be some years before such a therapy is available to us due to the time these studies take. Thankfully, other companies such as Unity Biotechnology are already well on the road to launching human clinical trials for senolytics in the near future.

Even better, companies like Oisin and CellAge are following up with more sophisticated approaches, using plasmids and synthetic biology, respectively. It is excellent that we have so many approaches to the same common problem, because in science, things do not always work out as planned.

This is why supporting early-stage research for aging is so important. The more different ways we have to tackle senescent cells, the better the chance that one or more of them will translate to a therapy for humans. As the saying goes, never put all your eggs in one basket. As always, we are optimistic but remain cautious until the data from larger-scale studies is in.







Literature

[1]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, 99–118.

[2]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.

[3]Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., … & Hoeijmakers, J. H. (2014). An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Developmental cell, 31(6), 722-733.

[4]Baker,van Deursen Kirkland et al (2011) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders, Nature 479, 232–236







[5]Roos, Zhu, Tchkonia, Kirkland et al (2016) Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice DOI: 10.1111/acel.12458

[6]Childs, B. G., Baker, D. J., Wijshake, T., Conover, C. A., Campisi, J., & van Deursen, J. M. (2016). Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science, 354(6311), 472-477.

[7]Xu, M., Bradley, E. W., Weivoda, M. M., Hwang, S. M., Pirtskhalava, T., Decklever, T., … & Lowe, V. (2016). Transplanted senescent cells induce an osteoarthritis-like condition in mice. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, glw154.

[8]Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL. (2013) Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest. 2013 Mar;123(3):966-72.

[9]Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., … & O’Hara, S. P. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658.







[10]Baar, Marjolein P. et al.(2017). Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell , Volume 169 , Issue 1 , 132 – 147.e16