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Genetics and Life Extension: A Xanatos Research Focus

Who doesn't want to remain strong, healthy and vital well into their senior years? All of human history has told us that when we age, we become weaker, eventually succumbing to any of a stunning variety of the opportunistic diseases of aging, losing our freedom, strength and dignity in the process. This is a universal tragedy - we know of very few other forms of life that have an experience any different from this.

Something New Under the Sun

News & Useful Links

XANATOS DNA to Protein Transcription Tool

Targeting Telomeres and Telomerase: Studies in Aging and Disease Utilizing CRISPR/Cas9 Technology - Paper

Download the Human Genome (particular attention to Chromosome 5) - FTP site

NCBI Genome Viewer - Online App @ NCBI. Link takes you to Chromosome 5

ASU Telomerase Database

Human telomerase RNA component (TERC), telomerase RNA

Jennifer Kahn: Gene editing can now change an entire species -- forever - TED Talk (TRANSCRIPT HERE)

Structure of the catalytic subunit of telomerase bound to its RNA template and telomeric DNA

iBiology.org - All Talks on Genetics and Gene Regulation


Custom DIY DNA Sequencing - This is THE link to read if you are very skilled in Python and want to synthesize your own proteins and sgRNA using various cloud-based labs. The best desscription of the process I've ever seen in one place. Truly excellent.


Two identically aged mice. The one on the right has its standard telomere complement; the one on the left had its Temomerase enzyme activated. Click the image to read the article.

Telocyte - A Future Beyond Alzheimer's
Synthgo - sgRNA sequencing
Synthgo's fantastic sgRNA design tool
E-Books and White Papers on CRISPR
Other Sequence Design Resources
BioViva Science
The End of Aging - Documentary
Interview with Aubrey de Grey - Podcast
A Deceptively Simple Tweak to CRISPR Makes It 50 Times More Accurate - Article
Reversing Aging - in Dogs - Article

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Biotium DNA LAdder Selection Info
Biotium DNA Ladders

Something came onto the radar of Xanatos Research back in 1996 that had direct, and stunning, implications for Lifespan and Healthspan Extension possibilities. Sections of DNA that were previously thought to be an accumulation of "junk DNA" were instead discovered to be protective and regulatory structures of great importance. These DNA sections were subsequently called "Telomeres". Shorter in elderly populations and people with rapid aging diseases like Progeria, Telomeres were discovered to be the cellular aging clocks of the body. One of the primary mechanisms of cellular aging had been discovered. This was an incredibly significant breakthrough. Concurrent with this discovery was the discovery of an enzyme that, in certain cell cultures, restored lost Telomeres during cell replication. This enzyme was termed "Telomerase". And thus began an unprescedented period of fruitful research into both the age-reversing effects of extending Telomeres, and the methods to do so. This research extended to not only to the reversal of the aging process, but also to potentially stopping cancers in their tracks. Something incredible had been uncovered.

First the Lock, Now for the Keys: Small-Molecule Activators, CRISPR-Cas9 and Gene Therapies Offer Answers

After several years of research, and seeing the effects of activating Telomerase in cell cultures in the body (see studies such as this, on mice - or see image on right), it became obvious that an efficient and safe methodology of activating Telomerase in cell cultures throughout the body was necessary. Initially, the focus was on small-molecule activators, such as cycloastraganol, but they only activated approximately 20% of the Telomerase in cell cultures body-wide. But in 1987, Osaka University researchers Yoshizumi Ishino and his colleagues accidentally discovered what has become known as the CRISPR-Cas9 DNA Editing System (to learn more about CRISPR, view the link at https://en.wikipedia.org/wiki/CRISPR for a good introduction.) In short, the CRISPR-Cas9 system allows us to literally cut and paste DNA sequences using whatever template we generate. It allows us to precisely snip out genes that are less-than-optimal for certain tasks, and substitute gene sequences that perform functions we wish to activate, such as turning on the Telomerase enzyme in cell cultures. And fortunately, it turns out that using CRISPR-Cas9 is very easy, although it is not without its quirks... among which is that while the templating action of the system is very robust, DNA sequences often have VERY similar sequences which are NOT what we want to edit, so research is underway to create systems with double or triple redundancy to ensure that the section edited is exactly what we want to edit. Ultimately, rather than biochemical Telomerase activators, it is likely that an augmented CRISPR-Cas9 system will be the preferred method for full system-wide telomerase activation, perhaps, even into the germline cells themselves.


Single-molecule movie of DNA search and cleavage by CRISPR-Cas9. Atomic Force Microscopy, courtesy of Kanazawa University and University of Tokyo.

While CRISPR-Cas9 looks like a very robust candidate for Telomerase activation, and with a variety of protocols for transferring the edited genetic sequences to the host (Nucleofection, Electroporation, Lipofection, etc.), Genetic Therapies have also been put forward as methodologies to make Telomerase Activation available as a clinical therapeutic technique. One extreme, and it should be duly noted, controversial, example, is BioViva Science's founder Liz Parrish. In September, 2015, Liz flew to Colombia to receive a series of injections of her companies Telomerase Activator and another anti-aging solution designed to combat age-related deterioration of muscle mass. She had to do this in Colombia because regulations in the US prevented her from using her own developed compounds on herself - she could have literally not only lost her professional credentials, but also faced significant punitive legal actions, including jail time. Her subsequent testing - again, not without controversy - seems to have indicated a statistically significant increase in telomere length in the tested cell cultures. While her science seems worthy of consideration, only time will tell if her methods have, in fact, proven out. (Reference articles here, here, and here.)


A Deeper Dive

What are Telomeres?

Image: thymine molecule
Telomeres are structures found at the ends of the chromosomes in every cell in our bodies (and most all other life on Earth). These structures consist of a repeated sequence (roughly 9,000 to 10,000 in a human at conception) of chemicals (Thymine, Adenine, and Guanine- see the images to the right). Telomeres' function may be thought of as "buffers" to protect the genetic coding information of the inner DNA. Until fairly recently, these structures were considered "extraneous" material, and not given much notice. In the 1980's, however, a relationship was noted between telomere length and age of the individual. Further findings showed that those with the rapid aging disease of progeria exhibited severly shortened, or missing telomeres. Researchers began to theorize that they had found the cellular aging clock, and the race was on.


Image: adenine molecule
As research has proven out, when cells divide (which is the normal method that the body uses to rejuvenate and replace tired, worn out cells), a small segment of the telomere strand is lost with each successive division. When, after a lifetime of cellular divisions, the telomeres are exhausted, and the "main" DNA string is exposed, the cell receives a chemical signal. This signal tells the cell that if it divides again, it will express a corrupt DNA pattern, and the cell ceases to divide again, despite the presence of any growth factors. Eventually, as the cell ages well past its normal division point, it breaks down, and is not replaced. Over time, as more and more cells begin to "wink out" in this fashion, and the remaining cells have to fill in and do the job of their missing co-workers, tissues begin to thin out, creating many of the obvious effects of aging. Not so obvious is the fact that the weakened tissues now become potential targets for the opportunistic diseases of aging.


Image: guanine molecule
Now that the mechanisms of cellular aging had been discovered, a mechanism to prevent this needed to be found. And, as it turns out, it was found in the relatively immortal nature of cancer cells. Cancer cells are cells whose genetic code is defective, AND that have somehow switched on an enzyme called Telomerase. The function of Telomerase is to, when it reaches the end of the DNA strand, detect the missing end pieces of the telomere sequences, rebuild them, and reattach them to the strand. In effect, it resets the clock with every successive division.


The work of Geron Corp., and others, including the Whitehead Institute in Boston, MA., had been to discover methods by which the enzyme Telomerase, which is an enzyme that is able to be produced by human cells, but is not normally, may be "switched on", to allow healthy cells to continue to reproduce indefinitely. This research has been successful in-vitro on samples from a number of human tissues. Cells which have a normal replicative lifespan of 50 to 100 generations are still humming along at more that double or triple their natural lifespan, with no sign of mutation or cancerous deviations. The process is not as hard as one might imagine, and once regulatory approval can overcome the climate of uncertainty, clinical applications should begin to enter the marketplace. Major pharmaceutical corporations such as Upjohn and Pharmacia have poured large sums of money into developing this and its sister research, turning OFF telomerase stop cancer in its tracks, in an effort to bring the fruits of this labor into our lives.

While there is no way of knowing exactly how long this breakthrough will extend our lives, if we have discovered this much now, the extra time it buys us may allow us to live with excellent health many, many decades beyond what we would have lived without it, and perhaps past the point of the next significant breakthrough in extending the human lifespan. Perhaps, some of us reading this now may still be alive a hundred years hence.

TELOMERE BASICS
Basic Nucleotide Units Found in DNA, including TELOMERES

Image: thymine molecule in telomeres Image: adenine molecule in telomeres Image: guanine molecule in telomeres
C5H6N2O2

C5H3N4NH2

C5H5N5O

TELOMERES in human beings are a repeating sequence of three of these nucleotide units: Thymine (T), Adenine (A), and Guanine (G), in the sequence:

Image: telomere sequence

Each base unit is connected to a sugar via a beta glycosyl linkage. Both ends of the strands contain telomeres, and both the 3' and 5' strand contain these end sequences. The normal bonding pairs Adenine with Thymine, and Guanine with Cytosine, in a relationship known as complementarity.

Image: cytosine molecule in telomere
The flip side of Telomeres is Telomerase, a combination of RNA (designated hTR for Human Telomerase RNA) and a protein (hTRT, for Human Telomerase Reverse Transcriptase). Telomerase directs the synthesis of the TTAGGG sequence. In effect, it contains a template of complementarity (AAUCCC) that allows it to stamp out telomeres much like a cookie cutter.


Now, you might be asking "What can I do in the meantime to keep my body healthy while I wait to have my telomeres extended?". Well, eat healthfully (eliminate sugar, and sugar substitute; excessive carbs and simple starches as they convert to sugar in the body), get good exercise, have a good outlook on life, and take lots of GOOD vitamins (and load up on Omega Three Fatty Acids) to slow existing damage due to free radicals, homocysteine, etc. Reduce your inflammation load (have your doctor check your C-Reactive Protein levels) and take anti-inflammatory supplements such as Zyflammend (avoid other NSAIDS if possible.) Check out The Life Extension Foundation, (http://www.lef.org) where you can read about the latest life extension vitamins and drugs, as well as research on telomeres and other life-extending therapies.

You may also visit Geron Corporation, (http://www.geron.com), the original researchers that spearheaded this breakthrough. There you will find their current focus of resaerch (currently turning Telomerase OFF in cancer cells and forcing them to literally burn themselves out of existence.)

If you are familiar with searching the Human Genome Databases, try NCBI (http://www.ncbi.nlm.nih.gov), and see if you can discover the next breakthrough in life extension and novel genetic therapeutics...

Resources (to be organized)

Tibolium castaneum TERT structure
Working principle of telomerase
hTR Secondary Structure
Human TR (451 nt)

University of Utah Codon Decoder Chart
University of Utah Codon Decoder Chart


This article was originally written by founder David Julian Xanatos in 1998 and most recently updated in 2018. Sad, but the progress in this field has been remarkably slow. I believe several sectors recognize the staggering implications of this research, and in their defense, we have no idea how to deal with a populus that may live 100, 200... or more years on average. The societal impacts are unfathomable. Just look at the retirement age... how can we realistically have people retiring at 65 or 70, and living on pensions and social security for the next 100 years? It would destroy countries and economies. And add into this Artificial Intelligence and we have a global reality that is utterly alien to what we have grown up with. We should bear in mind that we WILL eventually find a way to integrate these technologies - the strength of their tide cannot be staid forever. In the interim, it is up to each of us individually to keep up to date on discoveries and find if there may be cracks in the wall through which we may quietly pass and participate in this, perhaps most amazing of human discoveries, in as non-disrupting and circumspect a manner as possible. XANATOS is actively pursuing this technology and various methodologies. To this end, updates and links to Telomere news and research findings of Xanatos will be posted at the top of this page periodically.