I accidentally made my best friend cry last week…
…on her birthday.
But I can explain!
She was turning sixteen and I did the done thing: I sang her Happy Birthday. Then she burst into tears.
Was it something I said?
Later on, she confessed that it “made her feel old” and that she was “one year closer to being a Grandma!” My reaction was simple…
Who Thinks That Ahead?
A lot of us do. We all fear old age to a certain degree because it’s supposed to be the one fight humankind always loses.
It’s supposed to be.
I’m here to tell you that there may be hope of preventing, or at least slowing down the aging process using Gene Therapy.
Gene Therapy for Human Longevity
August 20, 2019, Professor of Genetics at Harvard Medical School George M. Church contributed a paper: A single combination of gene therapy treats multiple age-related diseases.
Harvard Researchers at the Wyss Institute for Biologically Inspired Engineering targeted four age-related diseases — obesity, type II diabetes, heart failure, renal (kidney) failure — using three adeno-associated virus vectors.
What are adeno-associated virus vectors?
Great question! Think of it like this…
Gene therapy works like a software update. It sends the correct genetic information to target cells. The carrier of this update would be a vector. Common vectors are viruses.
What?
Weird right. But since viruses essentially brainwash cells by inserting their viral DNA into a target cell. However, you can genetically modify the virus to deliver the correct genetic information to the cell instead of it’s own.
Voila!
But wait! There are many different types of viruses. Some viruses have DNA in their head, some RNA. Some of them integrate into the target cells DNA, some don’t. There’s retrovirus, lentivirus, adenovirus, etc. However, the most frequently used viral vector would have to be AAVs. They trigger less of an immune response, they’re easier to manufacture, can infect dividing + non-diving cells (that matters!) and are safer!
Why 3?
So now we know what AAVs are but why would we use three different vectors? Even though all four of these diseases are age-related, you cannot fix them all by just modulating a single genetic pathway.
Sidenote: A genetic pathway is what it sounds like. The pathway starts from a gene being expressed; several reactions then take place to produce a specific product, usually a protein.
So the team created three AAV vectors, each one targeting a different longevity associated gene.
Which 3?
The three genes targeted by the different AAV vectors:
- FGF21 (Fibroblast Growth Factor) Gene
- TGFβ1 (Transforming Growth Factor) Gene
- αKlotho Gene
Higher FGF21 expression helps with metabolism and glucose (sugar) handling. TGFβ1 or sTGFβR2 (soluble form) signalling prevents hypertrophic cardiomyopathy (swelling of the heart), immune recruitment and extracellular matrix formation (collections of enzymes & stuff for structure). αKlotho regulates calcium within the cell and protects the heart and kidney.
FGF21 is produced by the liver and αKlotho in the kidney. TGFβ1 is secreted from several places.
Due to FGF21’s ability with metabolism and glucose, it aids in most metabolic diseases (obesity and type II diabetes). TGFβ1 directs more focus towards heart failure and αKlotho to renal failure.
How Did They Do It?
Many gene therapy methods try to impact independent cell behaviour. For instance, telomere length is a huge thing in longevity…
Essentially, longer telomeres means longer healthspan. Telomeres are maintained by the enzyme telomerase. The production of telomerase requires modifying independent cell behaviour.
The problem is, that’s tedious. And anyways, the proteins the researchers were trying to produce are usually secreted! So instead, they cleverly decided to target the liver since it naturally secrets several proteins. They used the AAV8 species of vector due to it’s highly effectiveness in the liver.
These three AAV vectors were injected as one dose in transgenic (genetically modified) mice. The researchers then verified expression of the genes as follows…
- FGF21 was 17X more present
- TGFβ1 circulation increased 95%
- αKlotho circulation increased 10X
They started by tackling metabolic diseases. Mice were fed a high fat diet for three months experiencing an average weight increase of 50%. This same diet was maintained before, during and after the experiment.
The mice were then infected with the three AAV vectors individually and in combinations. Any mouse which received AAV: FGF21 had obesity completely reversed within 40 days!
To test whether this reversal was due to a higher metabolism, the mice were placed in a metabolic chamber where their activity, food intake, oxygen gas consumption and carbon dioxide production were measured.
Metabolism is directly proportional to cellular respiration (oxygen in, carbon dioxide out). Thus, a higher consumption and production of oxygen and carbon dioxide respectively would indicate a higher metabolic rate.
No increase in activity or decrease in food intake was indicated yet there was an increase in oxygen consumption and carbon dioxide production. The FGF21 gene expression increased the metabolic rate of the mice.
But how about type II diabetes? In order to observe this, researchers observed four things:
- How fast a ball of glucose could be cleared from the blood.
- Cell sensitivity to insulin.
- Ability of liver to produce glucose (pyruvate tolerance test).
- Fasting glucose levels.
There was an enhanced glucose response and recovered insulin sensitivity without affecting the liver glucose production! AAV: FGF21 also reversed diabetes!
So… It Worked?
Yes!
Using AAV: sTGFβR2 and AAV: FGF21, all four diseases could effectively be treated or reversed in a single dose! There was a 58% increase in heart function, a 38% reduction in αsmooth expression (helps reduce swelling of the heart), a 75% reduction in inner kidney degradation and complete reversal of obesity and diabetes in mice fed a high fat diet.
There was even a subsequent 30% increase in lifespan and healthspan!
To Good To Be True?
There are subsequent challenges however. This test worked on transgenic mice but not on non-transgenic mice. In order for this drug to essentially be used on humans, it needs to impact non-transgenic mice.
Additionally, longevity drugs are commonly rejected FDA approval and the process can take over 20 years! But this drug does work to treat age-related diseases which could take some of the heat off.
On top of that, viral gene therapy generally doesn’t receive FDA approval. Viral vectors are viewed as unsafe, even when using AAVs: the safest option. The idea is to consider the risk of not treating the diseases vs the risk of the treatment.
However, thanks to papers such as A Single Combination Gene Therapy Treats Multiple Age-Related Diseases from the Wyss Institute and researchers such as George M. Church, the treatment is looking increasingly favourable.
Essentially, my bestie may still become a Grandma but one who’s still got the looks!
Who am I?
I’m K: an innovator at The Knowledge Society (TKS), founder & CEO of CrossBow Canada and a biotechnology researcher!
