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 systems. 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 through the application of different therapies, which prevent or block some of these processes.
One of these processes of aging is cell senescence.
Senescent cells normally self destruct via a process called apoptosis, but unfortunately not all of them do. These “death resistant” senescent cells accumulate in the body with age and secrete toxic signals. This causes 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, albeit each in different tissue types. Even more excitingly 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.
Recent studies have shown removing senescent cells mitigates age related decline and improves healthy lifespan. Additional studies have shown that clearance of senescent cells is beneficial for cardiovascular health and lowers high cholesterol levels in the blood. This strongly suggests that Senolytics may be a viable therapeutic approach to combat aging.
In our study we have opted to treat already naturally aged mice. These 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 already approved for use in humans to treat specific diseases, 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.
Senolytics and Stem Cells
So far senolytics have only been shown 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 extend maximum lifespan, but rather healthspan. Even if this is the case, it is no reason to 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.