Hallmarks of Aging 1 Genomic Instability
May 13, 2024Genomic Instability - Hallmark of Aging #1
"Please, please write your newsletter about the Hallmarks.....I want to know," asked one of my clients. I couldn't rattle them off by memory, so here is one of them. Genomic Instability is listed as the first Hallmark. This idea of Hallmarks of Aging has been proposed in 2023 and caused a great stir in the research world. The twelve initially proposed hallmarks are genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. Sounds like jargon. I want to turn it into understandable English.
Each cell in our body has enough DNA to reach about 6 feet in length. The process of duplication of cells, activation, and deactivation of genes, and reproduction, all in an environment of toxins and radiation that breaks DNA means a prodigious amount of DNA repair must occur. Any given cell has to decide as to where their energy is going to be allocated: repairing DNA or living longer and reproducing. Sex always wins. We have to reproduce, which means our DNA has to get old.
With all the means of damaging DNA around, our DNA ends up with point mutations, deletions, translocations, telomere shortening, single- and double-strand breaks, chromosomal rearrangements, defects in nuclear architecture, and gene disruption caused by the integration of viruses. I didn't even mention transposons. (What are transposons? That's the process of taking a whole segment of DNA and inserting it into another organism. CRISPR is basically transposon methodology turned into medical intervention)
Once you have taken care of nuclear DNA, you discover there is a whole universe of DNA pieces floating around in the cell water, the cytosol. That cytosolic DNA is not meant to be there, and it arouses an innate immune response called "sterile inflammation". That is inflammation set off without an invading bacteria.
We are meant to have repair mechanisms. Our sirtuin proteins are just that, the caretakers of our epigenome (the markers on the surface of our chromosomes.). The very, very first cell had to have several key elements. DNA that could duplicate itself, some means of assembling a membrane, some means of generating energy, and some means of repairing broken DNA. Every order of living beings on planet earth has sirtuin proteins. Fasting turns them on. Metformin turns them on. Metformin activates SIRT 1 (the first of 7 sirtuin proteins in humans) that essentially mimics the same pathways as calorie deprivation. SIRT1 is energized by NAD or niacin.
Hence, the combination of metformin and niacin helps everyone live a little longer. Provided they get enough NAD. NAD (otherwise known as Vitamin B3 or Niacin) declines with aging. NAD+ declines with age largely due to the activation of CD38, an enzyme activated by the inflammation produced by senescent cells – cells that no longer grow or replicate. In a feed-forward cycle, the decline of NAD+ by CD38 induces the spread of more senescent cells and inflammation.
Genomic instability is a deep rabbit hole with many publications and journals covering it. It's a great way to spend a rainy afternoon if you don't like golf.
www.What will Work for me. I'm on metformin and niacin. I do my intermittent fasting too. I'm surprised to learn that one of the Hallmarks of Aging fits so well with David Sinclair's concept of everyone being one metformin and niacin. David Sinclair has started a large placebo controlled trial to work this out in scientific rigor. It's going to take 7-8 more years to get results. Now I want to know the other Hallmarks and see how we can incorporate their physiology to our advantage. Stay tuned.
References: Cell, Curr Genomics, Cell, NAD.com,
Pop Quiz
1. What are the Hallmarks of Aging? Answer: So far 12 interconnected processes that demonstrate degredation with aging. If we can understand how they fall apart, we gain insight into how to address them.
2. What are the problems with Genomic Instability? Answer. Duplicating DNA and turning genes on and off takes a many stepped process that is intricate to the extreme. Any mistake breaks DNA that has to be repaired. That doesn't always go well. Then there are viruses that insert their DNA into ours. Then there are chomosomes that swap genes back and forth with each other. We are still discovering all the ways it goes wrong.
3. What is "sterile inflammation"? Answer: Our DNA is kept in the nucleus of the cell in a tightly controlled place. When a piece of DNA ends up outside the nucleus in the cellular water, it elicits an immune response. We get inflammation without bacterial invasion...so called sterile inflammation.
4. What are the proteins tasked with caring for our epigenome, the markers on the outside of our chromosomes? Answer: Sirtuins. The most ancient and preserved of all proteins.
5. What does metformin do that helps aging? Answer: Turns on the production of sirtuins, just like fasting does. (Nice to find a way to get around that obnoxious fast.)