Senolytics: Overview

Senolytics: removing senescent cells

As your body ages increasing amounts of your cells enter into a state of senescence. Senescent cells do not divide or support the tissue they are a part of, but instead emit a range of potentially harmful chemical signals, these encourage other nearby cells to also enter the same senescent state. Their presence causes many problems: they degrade tissue function, increase levels of chronic inflammation, and can even eventually raise the risk of cancer.

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 these senescent cells escape this process and build up. By the time people reach old age significant numbers of these senescent cells have accumulated in the body and cause havoc further driving the aging process.

Our research focuses on the destruction of these stubborn “death resistant” cells from the body in order to reduce inflammation and improve tissue function. The evidence to date supports this approach and now we wish to apply the therapy to robust lifespan studies to see if we can improve healthy life span and extend maximum lifespan in already aged mice.

What follows is an introduction into some of the research that proposes to seek out and destroy these senescent cells to promote healthy longevity.

 

Senolytics: A brief history

 

The health and lifespan of mice have been demonstrated to improve by the removal of senescent cells using a transgenic suicide gene (Baker, D. J., et al) and later experiments showed the same could be achieved using small molecules. Senolytics are a relatively new class of drugs that focuses on the removal of senescent cells.

 

Senescent cells comprise a small number of total cells in the body but they secrete pro-inflammatory cytokines, chemokines, and extracellular matrix proteases, which together form the senescence-associated secretory phenotype or SASP. The resulting SASP is thought to significantly contribute to aging (Freund, Campisi, et al, 2010) and cancer (Coppé, Campisi, et al, 2010) and thus Senolytics and removal of SASP is a potential strategy for promoting health and longevity.

It was discovered through transcript analysis that senescent cells have increased expression of pro-survival genes, consistent with their resistance to apoptosis (Zuh et al., 2015). Drugs targeting these pro-survival factors selectively killed senescent cells. Two such drugs were Dasatinib and Quercetin which were both able to remove senescent cells but were better in differing tissue types. However it was discovered that a combination of the two drugs formed a synergy that was significantly more effective at removing some senescent cell types (Zuh et al., 2015).

In other studies whilst only removing thirty percent of senescent cells there were improvements to age related decline. These results suggest the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of aging and promoting healthy longevity (Tchkonia et al., 2013; Kirkland et al., 2014; Kirkland and Tchkonia, 2015).

Even more recently a further study demonstrated the benefits of senolytics for certain aspects of vascular aging (Roos, Zhu, Tchkonia, Kirkland et al, 2016). This is the first study to confirm that clearance of senescent cells improves aspects of vascular aging and chronic hypercholesterolemia, and could be a viable therapeutic to reduce morbidity and mortality from cardiovascular diseases.


Dasatinib and Quercetin are already approved for use by humans too so the application of these drugs or improved drugs based on them could be developed relatively quickly.However to date the combination of Dasatinib and Quercetin has yet to be tested in relation to its potential to increase maximum healthy lifespan. Current Senolytic studies have focused only on health improvements rather than the long term effects (either bad or good) of this type of approach. The MMTP aims to address this missing and vitally important question, can Senolytics promote healthy longevity.

 

Literature

 

  • 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.
  • Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, Palmer AK, Ikeno Y, Hubbard GB, Lenburg M, O'Hara SP, LaRusso NF, Miller JD, Roos CM, Verzosa GC, LeBrasseur NK, Wren JD, Farr JN, Khosla S, Stout MB, McGowan SJ, Fuhrmann-Stroissnig H, Gurkar AU, Zhao J, Colangelo D, Dorronsoro A, Ling YY, Barghouthy AS, Navarro DC, Sano T, Robbins PD, Niedernhofer LJ, Kirkland JL. (2015) The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell.  Aug;14(4):644-58.
  • 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.
  • 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.
  • Baker,van Deursen Kirkland et al (2011) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders, Nature 479, 232–236
  • Baker, van Deursen et al (2016) Naturally occurring p16Ink4a-positive cells shorten healthy lifespan nature 16932
  • Roos, Zhu, Tchkonia, Kirkland et al (2016) Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice DOI: 10.1111/acel.12458