Holistic Rejuvenation – an Integrative Approach

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Allegory of Vanity by Antonio de Pereda, 1611.

Is age truly just a number? Proven strategies for reversing the signs of aging

Picking up on where Dr. Jennifer Pearlman left off (see Part I), eminent Stanford University scientist, Dr. Vittorio Sebastiano, agrees that there are a number of tactics such as exercise, stress management and a nutrient-rich diet that can “very dramatically” impact multiple indications of aging.  Nevertheless, the professor sees a “bottleneck” in these individual approaches in that “they solve the problem from a rather narrow perspective, addressing only a number of hallmarks simultaneously.”

In his lab, Dr. Sebastiano is working on a more holistic approach involving the revolutionary concept of reprogramming the whole epigenome – or entire cell organism.  As the scientist explains, this tackles a very fundamental mechanism of cell homeostasis and by doing that, it impacts most, if not all of the hallmarks of aging. The professor elaborates below.

Homeostasis is a state of balance maintained by living things even in unstable environments. It allows optimal functioning in organisms. All cells must maintain homeostasis to stay alive.

How do you reprogram the epigenome?

That is the work that my lab has pioneered over the past 10 years.  The way we do it is by delivering inside the cell, a cocktail of mRNA that can encode for proteins that go into the nucleus and reset the epigenome.

The epigenome is a program that fundamentally dictates which genes in the cells are turned on and which genes in the cells are turned off.

The cells have two programs – one is the genetic program which we inherit from our parents, which is more of a fixed program (unless there are mutations) and then there is an epigenetic program (epi means “above”) which denotes an extra layer of information that is very plastic, flexible and reprogrammable, that can basically trick the genetic code so that some parts are activated in some cells and inactivated in the same cells.

In time, with age, this code becomes dysfunctional.  But thanks to the fact that it is programmable, we can bring it back to its functional, youthful state through the expression of those mRNAs.

Messenger RNA, or mRNA, is genetic material that instructs the body how to make proteins. Credit: Phys.org

How exactly does this work?

We isolate the cells from the body, keep them in a culture and then we deliver this cocktail inside the cell.  While in vitro, we make sure that the cells are youthful, that they’re safe and then in principle, they could be put back into the patient.  We’re not quite yet at the point of conveying them back into humans.  We have transplanted them into mice but because we’re not at the clinical stage yet, we cannot put them back in people without conducting more safety studies.

Eventually, we would like to do this directly, in vivo, without extracting the cells from the patients at all – just being able to rejuvenate the cells in situ, in the tissue they reside in.

Stanford University Professor Vittorio Sebastiano, PhD, is a leader in the emerging field of cellular reprogramming.

So, for someone with osteoarthritis, for example – can you regenerate cartilage?

Yes, in theory that’s potentially possible.  We have preliminary data showing that could be possible.  It’s just a matter of expanding our studies.

If I understand correctly, what you’re saying is you can basically rejuvenate an entire human being – every part of the body?

In principle, it could be possible.  How far are we from there?  I don’t know because that basically would mean that you would have to regenerate every single cell in the body … which is a very challenging task.

But, another way of looking at it is that some tissues age faster than others.  For instance, some people are more at risk of cardiovascular disease or pulmonary disease.  So, ultimately, it may be necessary to rejuvenate or regenerate just the organs that are aging faster.

That’s one step.  Another is understanding there are some major drivers of aging in the body.  For example, I’m particularly fascinated by this process in women.  We know that aging ovaries have a strong systemic impact.  So, just rejuvenating the ovaries will have a universal effect.

How far away is this mRNA cocktail from being used on humans?

I have a company called turn.bio which is working on clinical-grade products that are built off of this idea of epigenetic reprogramming.  We are starting with dermatology and then we will move into other programs.

We hope to be conducting the safety studies — Phase 1 clinical trials — in 2025.

Tell me more about your work in dermatology.

Turn.bio is developing a delivery solution that could rejuvenate the skin in situ, in the body.  That requires delivering the mRNA inside the cells that you want to target.  We are working on different aspects of skin rejuvenation – from cosmetics to medical aesthetics to indications that are specific to aging.

Turn.bio is at work on an application of its technology to fully restore skin integrity. Credit: turn.bio

Is the skin treatment spot-specific or is this head to toe?

In principle, it could be head-to-toe and again it boils down to the more rapidly-aging areas of skin like facial skin or sun-exposed skin.

But it’s not just about aesthetics.  The skin, which is the largest organ in the body, is also a barrier to pathogens.  So having healthy, youthful skin doesn’t just mean looking better.  It also means being more resilient and more capable of preventing pathogens from entering our body which, on its own, has universal effects like lowering inflammation.  This goes beyond beauty.

Are you targeting the production of more collagen and elastin?

Yes and many other things — improving thickness, wrinkling, water retention, discoloration — all the things that change with age potentially could be reversed.

How much reversal are we talking about?

In some cases, we have seen that we can rejuvenate the cells by almost 20 years.  In others, it’s between one and five.  It depends on the tissue you’re dealing with.  It’s difficult to quantify this because if you don’t know someone’s age, it’s very hard to say “Oh, this skin is 40 years old.”  The same is true for rejuvenating it.

Could epigenetic reprogramming actually be the fountain of youth?

In a way, yes, together with other approaches.  It’s still a good idea to exercise, sleep and eat well.  This is maybe the next frontier and one of the many different things that science will enable in the future.

What happened with COVID accelerated our work.  We now know that delivery of mRNA is possible, safe and scalable.  This has made possible a number of other developing technologies and I think this will really be a game changer going forward.

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