Summary

Aging is the main risk for pathologies like arthritis, hypertension, and diabetes.  Classical medicine treats the symptoms of age related degeneration.  Germ cell biology can be used to combat aging. 

 

It is Dr. Sebastiano’s belief that epigenetics are the fundamental root of aging.  Methylation changes, chromatin organization, and histone modifications and positioning are some of the possible epigenetic modifications.  By controlling epigenetics we can target multiple pathologies at once.  Germ cells undergo massive epigenetic remodeling after fertilization and during germline differentiation.

 

Cloning and induced pluripotent stem cell methodologies support the idea that epigenetic renewal can lead to complete rejuvenation of a cell.  iPSC cells often utilize full de-differentiation to revert the cell back to an embryonic state.  However, it’s possible to use the yamanaka factors in short bursts to only partially revert a cells epigenetic state.  Plasmids and viral vectors cannot carry out this task – but mRNA can.  It’s safer and the duration of expression can be tuned, unlike plasmid or viral expression.

 

Partial reprogramming appears to affect every hallmark of aging with the exception of telomeres.  It has been demonstrated to work in a variety of naturally aged human cells.  The current method uses 4 days of reprogramming to reverse aging, measured via a litany of biomarker data.  In cooperation with Steve Horvath, methylation patterns were also measured and determined to reverse in age.

 

This principle can be applied to stem cells, such as muscle stem cells, to create long term regenerative effects.  Marco Quarta and Tom Rando collaborated in an experiment to partially deprogram mouse muscle stem cells.  Muscle growth was increased while no tumor formation was observed.  The same experiment was done on human muscle stem cells and similar outcomes were observed.

Presenters

Presentation: Epigenetic Reprogramming of Aging

What is an exciting goal of your field?

  • We are at an inflection point for treating patients using epigenetic reprogramming.

Which enabling technologies would be required to unlock new capabilities?

  • RNA technology, broadly speaking, will be a game changer. For us and for other fields – it was dramatic what it could do in the context of vaccines and the same will be true for us. Delivery solutions will also be crucial. Gene therapy will also be dramatically affected by RNA advances.

What is a challenge that you would like to see solved?

  • In vivo delivery. If we effectively deliver to specific cell types, it will be a dramatic shift in the way we think about regenerative medicine.

There’s widespread acknowledgment that the recipe is tricky – when are we going to move toward more sophisticated recipes based on readouts of information from the cells being rejuvenated?

 

  • We’re using what the technology that allows us to do. AI may play a role to help parse data from the reprogramming process as measured with microbiology tools.
  • There is also the potential for discovering new factors while developing the partial reprogramming procedures.

 

There were papers on applying dedifferentiation methods to facilitate wound healing in muscles. Did you compare dedifferentiation approaches with yamanaka factors?

  • Rejuvenation can be used in two ways – keeping the identity fixed and rejuvenating the cells, or altering the identity slightly but not all the way to a pluripotent stem cell. If you know what defines a neural stem cell, you could potentially provide that cocktail to a neuron to a neural stem cell. Is that changing an age of a cell? That still needs to be figured out. Transdifferentiation – horizontal conversion of one cell into another – doesn’t change the cells age.

 

The telomeres – they don’t seem to be affected by your technique. What does that say about their relationship with aging?

 

  • I don’t think telomere attrition is such a big deal for human aging. It’s a big deal for senescent cells, but they only explain a fraction of the aging phenotypes we see at the systemic level. The mRNA technology is so malleable that if we discover telomeres are important one day we can just transiently express TERT and fix the problem. I think it’s actually good to not see telomere elongation because telomere elongation happens with loss of cell identity so not seeing it is a positive sign for this therapy.

You showed with mRNA that you trend to get younger, but you don’t achieve what stem cells do which is to erase aging. Why was it a trend, instead of an erasure of all aging?

 

  • The goal here is to make the cell younger without losing identity. If they go back too far, they receive signals from too many different sources and head in another trajectory, becoming a tumor. If we could figure out a way to specifically target stem cells in vivo, at that point we could make those stem cells younger and have a long term effect because you would be targeting the cells responsible for long term health of the tissue.

If you just rejuvenated cells from a cell population and stuck them into a normal environment would you see a benefit?

 

  • Unknown, I’m not sure of the answer but it’s probably something we should look into. There are two ways of looking at this – restorative, and preventative. It’s possible to use this technique on cells that are not aged yet in order to prevent future aging. Maybe these factors could be pulsed to prevent cells from going through the aging process.

What could this group do to help you?

  • The network is very important, getting ideas from AI and machine learning is valuable. As an academic, the usual answer is funding, these are expensive experiments that require substantial funding.

Could you expound on how the influx of money could change this field?

  • I’m flattered, because we were one of the first to pioneer this idea. There are hundreds of millions of dollars going into this, and it’s a clear signal that this strategy is worth investigating.