Location, Location, Location: Longevity Pathways to Target with Gene Therapy
So you’re making stew.
Before you serve it, you taste some…oh no.
Something’s off.
You have a problem. There’s either too much or too little of an ingredient. Is it salt, garlic or maybe pepper? The stew tastes bad and you know something’s needed and you can still add things but you don’t know what to add.
Gene expression
Our bodies are like that stew. We’re aging and we know that something is wrong and we can fix it with gene therapy. We just need to understand what proteins (flavors) are missing so that we can express their respective genes!
So let’s get started!
Gene Therapy is arguably the best way to defeat aging. Most age-related issues originate from depleted levels of important proteins. Since genes encode proteins, overexpressing specific genes can raise protein levels.
But how do you overexpress genes?
Good question!
You essentially deliver that gene, into the body using a vector (genetically modified to deliver the gene). Common vectors are viruses and that’s where viral gene therapy comes in. More on how gene therapy works in this article.
Okay but how do you stop gene expression?
This is called inhibiting gene expression. It’s slightly more complicated. You still send genetic information using a vector. However, the genetic information encodes miRNAs (microRNAs) and siRNAs (small interfering RNAs) which will inhibit the target gene expression.
RNA essentially translates DNA to produce proteins.
MiRNA and siRNA both reduce gene expression by meddling with the transcript RNA. MiRNA bonds to the transcript RNA, preventing it from coding for the proteins. SiRNA degrades transcript RNA before it can code for proteins.
& voila! You’ve depressed the gene’s expression!
But how do we figure out which genes to depress? For that, we need to…
Understand aging
Aging is emergent.
This means that aging is progressive. We start ‘dying’ at around 25.
Aging is epigenetic.
If our genome is a keyboard, the epigenome is the keys we are playing. It’s the expression of our genome. It tells us what genes are on, off, and how much they are being expressed. As we age, our DNA gets damaged. When repaired, the genome is the same but the epigenome has changed. This then affects protein production, etc. These changes are frequently age related.
Aging is a metaphenomenon.
There is definitely abstraction in longevity. However, that does not mean it cannot be studied! There is research indicating a potential aging clock within the hypothalamus (part of the brain). I’ll be writing an article in more detail about that next!
So we know that aging keeps getting worse (emergent) and it’s impacts (on the epigenome) leads to our body eventually losing. But then why does it take us so long for us to get age-related diseases? If the process starts on our 25th birthday, wouldn’t we be in the hospital on our 30th?
Repair
No. Because our bodies heal. And that’s the most important ability in longevity. In theory, if we had perfect repairing/maintenance mechanisms, we’d be immortal.
Alas, that is not the case.
However, we do have some top-notch mechanisms in place. The body’s repair mechanisms are called the homeodynamic space. It is the ultimate determinant of a person’s health and ability to survive. It has five main molecular pathways…
#1: Defense against oxidation.
Flashback to your elementary school science class where they taught you about cellular respiration.
Well, unfortunately, they didn’t tell you the full story. There’s something missing in the products of this equation: hydrogen peroxide. Hydrogen peroxide is a free radical, or more accurately a reactive oxygen species (ROS).
Free radicals are missing an electron, so they steal one from a stable molecule. This subsequently makes the previously stable molecule a free radical and damages both molecules. It’s worst when an ROS steals electrons from DNA molecules. DNA damage and repair is eventually what leads to epigenetic changes and aging.
So how do we prevent it? Two words: antioxidants and enzymatic defenses.
…okay three words.
Antioxidants neutralize free radicals. They have an extra electron which they can give away.
To increase the presence of antioxidants we can overexpress these genes: NFE2L2, glutathione peroxidase 2 & 5 & 7, glutaredoxin, selenoprotein P, FOXO, etc.
Enzymatic defenses are essentially different enzymes that accelerate the decomposition of ROSs into stable molecules. The main enzymes used are catalase and superoxide dismutase. To increase the presence of these enzymes we can over express these genes, respectively: CAT and SOD1.
#2: Stress response.
There are mainly two genes related to stress response: COMT and BDNF.
COMT: This gene produces the catechol-o-methyltransferase enzyme. This enzyme helps break down dopamine, epinephrine and norepinephrine.
Epinephrine and norepinephrine, also known as adrenaline and noradrenaline, are hormones and neurotransmitters (chemicals which can stimulate nerves) both involved in the body’s stress response.
Epinephrine/adrenaline increases blood sugar levels and heart rate, to give your more energy. Norepinephrine does that too and also narrows your blood vessels, increasing blood pressure.
High blood sugar, blood pressure and heart rate are very frequently seen in today’s society due to chronic stress. Higher COMT gene expression would produce more catechol-o-methyltransferase, allowing more epinephrine and norepinephrine to be broken down. Our stress response would be less damaging and extreme.
BDNF: This gene encodes the BDNF (brain-derived neurotrophic factor) protein. It represents our ability to tolerate stress by reducing the negative effects of stress on the brain.
Neurons often die prematurely due to stress; the BDNF protein prevents that by inhibiting apoptosis (cell suicide). Free radicals increase under stress; BDNF inhibits free radicals. It also stimulates growth of neural stem cells into new neurons to replace damaged cells.
Several of the negative effects of stress can be opposed with BDNF, increasing our stress tolerance.
Thus, other great genes to target would be COMT and BDNF.
#3: Protein repair.
Remember those free radicals we discussed? When antioxidants and enzymes can’t get to them first, they damage proteins. These proteins then need to be repaired. Of course, the effectiveness of reparation mechanisms reduces with age. At 80, around half of the bodies’ proteins are damaged.
When a free radical oxidizes a protein, the protein it unfolds. This is called denaturation.
That’s where protein chaperones come in. Protein chaperones refold proteins so they can function again. Think of chaperones as parents. They fold the blanket after the messy free radical (you know who) sleeps in it!
Chaperone proteins, also known as heat-shock transcription proteins, are encoded by the heat shock factor (HSF) genes! For proteins that look less like a messy blanket and more like a torn one, you have the protein repair methyltransferase enzyme, encoded by the PCMT1 gene. Thus, over expressing the HSF and PCMT1 genes would increase the amount of protein repair.
#4: Waste removal.
Ideally, in your body, the rate of protein synthesis and degradation should be equal. This is called the turnover rate. Think of your body as a basketball team.
You continue to retire old players and sign new ones to ensure that your team stays fast and agile. That’s called turnover. However, what if fewer people tried out and you had to stick with your old players longer? The team would slow down.
This is what happens as we age. The rate of degradation of proteins gets higher that the rate of synthesis and more and more of our proteins are damaged.
So how do we speed up protein production? There is a hidden layer of genetic code which determines the rate of protein synthesis. Even silent mutations (swapping out an inactive gene) can significantly slow down or speed up the rate of production.
In order to increase rate of synthesis, we’d need to understand this layer more deeply. Thereafter, the tinkering can commence!
#5: Nucleic acid repair.
DNA and RNA are two very important nucleic acids in the body which can often get damaged by ROSs. Most of these ROSs come from cellular respiration which takes place in the mitochondria.
The mitochondria is very important in human longevity because that’s where metabolic processes such as cellular respiration happen. There is a very strong correlation between metabolism and longevity. In fact, metabolism is so important that sirtuins, a family of proteins involved in metabolic regulation, are promoted for anti-aging. The series of genes that encode sirtuins are SIRTs.
So cellular respiration produces ROSs and, if not stopped, ROSs will damage mitochondrial and nuclear DNA.
As seen in this photo, DNA that goes unrepaired leads to a number of age related problems.
So what are our DNA repair mechanisms?
There are different types of DNA repair. Our favorite, most efficient and simple method is direct reversal. This method doesn’t require a template because specialized proteins can just chemically reverse the damage.
When only one of the two strand DNA strands breaks, you can go in with the single-strand mechanisms: base excision repair or nucleotide excision repair. Base excision is essentially substituting the damaged base or nucleotide with the correct one.
Nucleotide excision is for more significant damage. It takes out 12–24 nucleotides, finds the specific damage, removes it, and then replaces that area.
When both strands of DNA break, we go in with double-strand repair. The mechanisms we use in this process are non-homologous end joining and homologous recombination.
Non-homologous end joining (NHEJ) is when DNA ligase (an enzyme which ‘fills the gaps’ in DNA) directly joins the ends of the two DNA strands. Homologous recombination (HR) is different because it needs a template to make that same fix. The difference is best demonstrated in the photo bellow.
Each of these processes use different biochemical pathways and enzymes. Therefore, there are many genes we can express for DNA repair! Some of the enzymes used are endonucleases, exonucleases, ligase, oxoguanine, and glycosylase. The genes which produce these enzymes respectively are HEGs, EXOs, LIG4, OGG and UNG.
That’s It?
Yes. That’s it! Those five things are the ultimate cause for aging. Thus, expressing these genes will promote longevity.
There are several papers testing expression with these different genes (check out my article on Harvard Researchers developing a longevity therapy) where the results are very positive. There is only one question left to ask:
Are we ever going to get to human trials?
This is difficult to say. Lots of viral gene therapies are considered unsafe but progress in this area is being made.
When we do get to human trials, we’d likely test on older subjects to reduce the duration of the study.
In addition, a great strategy is to market the drug as a cure for age-related diseases rather than a longevity. Human longevity drugs often don’t receive FDA approval as aging is not officially a disease. Usually the FDA will weigh the risk of not taking the drug VS the risk of taking the drug. Since there is seemingly no risk or urgency in aging, drugs don’t get approval. However, longevity drugs tackle the root of the problem and subsequently prevent several diseases. Therefore, labeling the drug as a cure for age-related diseases, while still targeting longevity pathways, could get it to the market!
Now it seems we’ve figure out what was lacking in the stew. Now, we just need to get permission to add a little salt!
Genes To Express.
- Prevent oxidation: NFE2L2, glutathione peroxidase 5 & 2 & 7, glutaredoxin, selenoprotein P, FOXO, CAT, and SOD1.
- Improve stress response: COMT and BNDF.
- Increase protein repair: HSF and PCMT1.
- Improve DNA repair: HEGs, EXOs, LIG4, OGG and UNG.
- Increase metabolism: SIRTs.
More On Me!
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References
Longevity Gene Therapy Is the Best Way to Defeat Aging. (n.d.). Retrieved from https://ieet.org/index.php/IEET2/more/konovalenko20140923az
Rattan, S. I., & Singh, R. (2008). Progress & Prospects: Gene therapy in aging. Gene Therapy, 16(1), 3–9. doi:10.1038/gt.2008.166
Sinclair, D. A., & Oberdoerffer, P. (2009). The ageing epigenome: Damaged beyond repair? Ageing Research Reviews, 8(3), 189–198. doi:10.1016/j.arr.2009.04.004
Tanaka, M., Gong, J., Zhang, J., Yoneda, M., & Yagi, K. (1998). Mitochondrial genotype associated with longevity. The Lancet, 351(9097), 185–186. doi:10.1016/s0140–6736(05)78211–8
Yang, Y., Nunes, F. A., Berencsi, K., Furth, E. E., Gonczol, E., & Wilson, J. M. (1994). Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proceedings of the National Academy of Sciences, 91(10), 4407–4411. doi:10.1073/pnas.91.10.4407
