Testing compounds to remove dysfunctional cells to extend maximum lifespan and healthspan
According to modern science, aging is the accumulation of damage that the body cannot completely eliminate, due to the imperfections of its protection and repair system. The good news is that the processes that constitute aging, are amenable to medical intervention. We can slow down or even reverse some aspects of aging by the application of different therapies, preventing or blocking some of these processes.
One of these processes is called cell senescence or simply cell aging.
Senescent cells are removed by the immune system, however the immune system weakens with age and increasing numbers of these senescent cells accumulate. These “Death resistant” senescent cells accumulate in the body with age and secrete toxic signals causing inflammation and damage to organs and tissues, increasing risks for cancer and other diseases of old age. This is why these cells are often called “good citizens but bad neighbors”. They remain partially functional, but their presence does more harm than good.
A new class of drugs known as Senolytics have recently demonstrated the ability to remove senescent cells to improve health. However the potential of senolytics to increase health and lifespan beyond current maximums remains unknown. This is what we at Major Mouse Testing Program want to investigate - with your help!
Why is this study of particular interest?
It was discovered, that senescent cells have increased expression of pro-survival genes, consistent with their resistance to natural cell death - apoptosis. Drugs targeting these pro-survival factors selectively killed senescent cells and improved health. 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.
Venetoclax has also recently been discovered to be senolytic in nature and is a therapy we wish to explore as part of our combination testing. In cancer therapy Venetoclax has shown to work well with Dasatinib so we are interested in seeing if this can be applied to clearing senescent cells too. In recent studies by removing senescent cells there were improvements to age related decline and improvement of healthy lifespan. Recent confirmation that clearance of senescent cells is beneficial for cardiovascular health and lowers high cholesterol levels in the blood suggests that Senolytics may be a viable therapeutic approach.
We have opted to treat already naturally aged mice in our tests. Mice will be 16-18 months old (equivalent to a human of approximately 60 years old). This has two advantages, we speed up research, and also demonstrate the feasibility of translating Senolytics to already middle aged or older humans.
Dasatinib and Venetoclax are also already approved for use in humans (to treat specific diseases, but not for delaying aging unfortunately), and Quercetin is a readily available supplement so the application of these drugs or improved versions based upon them to prevent and postpone age-related damage to health could be developed relatively quickly. So far senolytics have only been proven to reduce the number of senescent somatic cells, but what effect do they have on stem cells? This has not been closely studied, and is a question we intend to fully answer in addition to the implications this presents for lifespan.
It is entirely possible that Senolytics taken alone may not improve lifespan just healthspan, and our initial data may confirm this. However even if this is the case, we should not be discouraged. What we learn in this first phase, paves the way for our next step - combining Senolytics with Stem cell therapy to encourage tissue regeneration.
About our lead researcher
Dr Alexandra Stolzing is our chief researcher and a world class expert in her field, with over fifteen years in the medical research field, and a decade of work in regenerative medicine, Alexandra brings substantial experience to our project. She has worked with stem cell transplants and and is keen to explore new possibilities in the rapidly advancing field of regenerative medicine.