Senolytics and Senescent Cells’ Huge Potential Within Longevity
Last week I attended a conference called Longevity2020 where some of the top researchers and entrepreneurs gave talks on their latest pieces of work.
One talk however, stood out to me for how “against the grain” its topic was. The talk was given by Reason (yes that is his name) who is a founder at Repair Biotechnologies and writer of the blog Fight Aging! His talk was interesting because he said that a lot of the current research that is being done into longevity is only gaining marginal increases into total lifespan. Research into rapalogs, STACS, and other small molecules only add 2 to 3 years of lifespan. The drug discovery and clinical trials of these molecules is where the majority of research is being put into.
He argued what needs to happen is put more research into the root causes of agings which would result in outcomes of much larger lifespan extension.
The types of interventions Reason would like to see are things that effect the primary hallmarks of aging. Things like epigenetic reprogramming would be the holy grail of lifespan extension. The problem is with trying to tackle the primary hallmarks it is hard to get the precision in order to only change those hallmarks to affect aging. For example with epigenetic reprogramming, an issue is that teratomas (a type of tumor made up of several different types of tissue) form which has caused a lot of hesitations towards it.
Contrastly, with the small molecules like rapamycin, metformin, and nicotinamide riboside (NR) they are all pharmacological approaches that target a certain protein. Comparatively, there are a lot less unknowns when taking this approach because small molecules have a smaller impact.
An approach that I see is in the middle of this dichotomy is senescent cell eradication. They have been shown to have larger effects on lifespan than the common approaches but they are farther along in the developmental process than epigenetic reprogramming. There is a lot of basic research being done in senescent cells as well as a group of companies in clinical trials working to get senolytics out to market.
What are Senescent Cells?
To understand what senescent cells are you have to understand the process of cell division. Each time your cell undergoes mitosis and replicates its DNA a bit of the end of a chromosome gets shaved off. The telomeres are sequences of non-coding DNA that protect the real DNA from being shaved off. Eventually all of the telomeres get wiped out and the cell reaches a point called Hayflick’s Limit.
When the cells reach this point it activates a cell state known as senescence. The body does not want to replicate the DNA of the cell anymore because it fears without the telomeres it will create cells with damaged DNA that can cause mutations and even tumors.
These senescent cells however start to release toxins to surrounding cells to tell the immune system to clear it away. These toxins are known as the SASP: Senescence-Associated Secretory Phenotype. Problems occur when the senescent cells are not cleared away immediately and start to build up. The toxins they release can damage nearby cells and cause them to become inflamed or even senescent themselves.
An example of this is when your hair turns grey. If you ever notice when one of your hairs begins to turn grey it is normally the hairs around it start to form a patch of grey hair. The reason behind that is that a senescent cell is releasing the grey pigment through its SASP and nearby cells are also effected become senescent and start to release that pigment.
Numerous types of inflammation have been linked to senescent cells most notably osteoarthritis. The main condition that makes us feel like we are old and the molecular reasoning behind it is connected by senescent cells.
How to Target Senescent Cells
Senolytics are the drugs and therapies that are used to target senescent cells. What these compounds target are the pathways that sustain these senescent cells. Two major pathways are the p53 pathway and p16 pathway. Most of the drugs you see inhibit these pathway in order to eradicate the senescent cells.
Major compounds/therapies that have garnered a lot of attention are Unity Biotechnology’s UBX0101. UBX0101 target osteoarthritis in the knee which immediately sounds very appealing as a target tissue. They are currently in Phase II trials for UBX0101 but also have drugs down the pipeline targeting senescent cells for treating glaucoma.
This is a good table of other senotherapies that have made significant progress.
Another big player to consider is Oísin Biotechnolgies who is taking a different approach to eradicating senescent cells. They are targeting the same pathway p53 but there delivery to inhibit it is through a gene therapy. They are delivering the gene therapy through a lipid proteo-lipid vehicle. To my understanding there are some complications with there technique are a lot of the therapy accumulates in the liver when delivered but time will tell if they will be able to bring there product to market.