Our friends at H+ magazine have kindly published an MMTP article about senolytics and our research. Inflammation caused by Senescent "death resistant" cells is a significant driver of the aging process and our work in this field could help speed up progress and understanding in this area. Next to stem cells this type of therapy has the potential to dramatically improve health and potentially even maximum lifespan.
Senolytics: Seek and Destroy!
By Steve Hill
As you 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 are destroyed 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 (Darren et al., 2011) 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?
Who are the MMTP?
The Major Mouse Testing Programme is a non-profit project that aims to speed up the pace of progress up by rapidly testing longevity interventions – meaning research which would have taken decades via traditional funding channels can be done much faster using crowdfunding.
It is also plausible that some interventions, when combined could have a greater synergy than the individual compounds, this has certainly been the case with Dasatinib & Quercetin. It is likely there are more synergies to be discovered and this is where the MMTP plans to push forward, not only testing single interventions but also combinations to seek out these powerfulcombinations.
We have opted to test with mice partly due to the costs involved and mouse studies are also considerably easier to organize and are the usual starting point prior to moving into human clinical trials. Organisations such as the FDA and EMA for example also usually require substantial animal data prior to approving any clinical trials involving people so this is another reason for choosing to begin here.
Another compelling reason is that mice, humans and most other animals suffer this same senescent cell burden as they age, so there is good reason to believe such therapies could translate directly to people and have similar potential benefits.
There is a considerable disconnect with many people when it comes to the link between basic research, animal testing and drugs and therapies reaching people. Most people are not interested in mice because it is not considered “sexy” science and it is not something they can benefit from right away. This is a considerable barrier to progress as no animal data means new drugs and therapies will never enter human clinical trial. So whilst it might not be the most glamorous science it is certainly a vital one and should be something those interested in healthy longevity should support.
We are using an innovative testing system that allows us to maximize our data and statistical evaluation, enabling us to use smaller groups of mice and combine data coming from different concentrations used.
This reduction in the number of animals also helps our commitment to the 3Rs (Replacement, Reduction and Refinement) of animal research which is a central consideration of our work.
We are launching our crowdfunding campaign on www.lifespan.io in April 2016 to raise the funds we need to begin this important longevity research work. You can check out our website and we are also active on various social media including facebook, twitter and linkedin.
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