Epigenetic alterations are chemical modifications to the proteins that package the DNA, or to the DNA itself. They don’t change the genetic code, but they can change which parts of the code are read. This is what gives different types of cell their ‘identity’, making a brain cell a brain cell and a blood cell a blood cell. Additional epigenetic alterations accumulate throughout life, further changing the way our DNA is read and causing cells to behave in inefficient and harmful ways.
As it turns out, these alterations aren’t permanent. Using a cocktail of molecules called Yamanaka factors, it’s fairly simple to ‘reprogram’ specialised cells to become stem cells, which erases epigenetic modifications and, with them, most signs of ageing. The cost of this reprogramming is that the cell loses its identity – muscle cells stop behaving as muscle cells and so on. More recently, scientists have figured out how to do something called partial reprogramming – a method in which Yamanaka factors are used to erase epigenetic changes, but without resetting their identity. Now, the race is on to safely test partial reprogramming in humans to see whether it can slow or reverse the ageing process.
Back in May, Lifespan.io interviewed Yuri Deigin of YouthBio Therapeutics, a biotech company looking to make epigenetic reprogramming in humans a reality. In case you missed it, here is a summary of the key points, as advances in this area are well worth following.
The Fundamental Importance Of Studying Ageing
- Many people simply don’t realise that ageing is the driver of pretty much all non-infectious diseases (inherited conditions aside).
- People assume that because ageing is normal, it’s not a disease and we can’t affect it.
- Animal experiments suggest otherwise. Ageing is malleable in these organisms, and there should be ways to affect ageing in humans.
- Slowing ageing would be a more efficient way to prevent most deadly diseases than targeting said diseases individually.
How Yuri Deigin Arrived At Epigenetic Reprogramming
- At first, Yuri was very interested in raising public awareness about the study of ageing.
- Yuri learned about partial reprogramming from a 2016 paper which succeeded in extending the lifespans of mice. Yuri was writing a lot about epigenetic ageing at the time.
- Yuri noticed that people didn’t really seem to be making serious efforts to translate partial reprogramming into human therapies, so he decided to get involved.
- In 2020 he met Viet Ly and they founded YouthBio. They have been working with João Pedro de Magalhães and Alejandro Ocampo to explore hypotheses about translation into human therapies.
What Causes Ageing?
- We know that a lot of epigenetic changes drive ageing. The beauty of reprogramming is that if it works, it doesn’t matter what the fundamental causes of these changes are.
- The goal of YouthBio is ultimately to produce a working therapy as quickly as possible, not to study the fundamental science.
- Yuri thinks that ageing is probably programmed and that damage accumulation is also responsible at some level.
- Yuri suspects that patterns of human ageing are due the genes responsible for damage mitigation getting dialled down.
- Harmful genetic sequences like retrotransposons are ‘released from epigenetic jail’ and wreak havoc on the genome. To Yuri, this suggests that ageing has a programmed or non-random element.
- This could be evolutionary, or simply because evolution ‘doesn’t care’ about these changes beyond a certain point.
- YouthBio’s approach is to use gene therapy to deliver reprogramming genes into tissues of interest, then activate them with a small molecule.
- Different organs will probably need different reprogramming factors and definitely different dosing regimens.
- Eventually, they want to move away from Yamanaka factors because they weren’t designed for partial programming.
- Rejuvenation seems to happen before loss of cell identity, so there’s a ‘Goldilocks zone’ of rejuvenation.
- The ideal reprogramming factors would widen that Goldilocks zone for a wider therapeutic window.
The Complexity Of Adjusting Reprogramming For Different Cell Types
- With Yamanaka factors, different cell types need different durations of exposure.
- The next step is to find different factors for different tissues.
- To provide distinct treatment for different organs, we need different gene induction mechanisms that won’t overlap, which is something that YouthBio are working on.
Addressing The Shortfalls Of Tissue-Specific Gene Therapy Delivery
- YouthBio isn’t tied to any specific delivery mechanisms, and will use whatever the best system is at the time.
- Hopefully, delivery systems will improve over the next two years as work on partial reprogramming continues.
- YouthBio is keeping an eye on novel delivery approaches.
How Long Until Partial Reprogramming Is Available To Humans?
- Clinical trails could begin as soon as a therapeutic effect is shown in animals.
- This could happen within the next few years but depends on animal data.
- Timelines will be different for different diseases. Diseases that have no other treatment options may see clinical trials begin earlier.