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Aging: the secret of telomerization

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message 1: by Rui (last edited Oct 20, 2012 05:06AM) (new)

Rui Zambujal (RuiZambujal) | 1 comments Hello everyone

I’m going to give you a glimpse to the abandoned field of telomerization, I think you’ll find it curious.

My name is Rui Zambujal, I’m a Portuguese biologist, and I wrote a book entitled "2009-2049: Forty Years on a Roller Coaster". Chapter 2 has a lot of matter pertaining to medicine, and the following is an excerpt.

Here it is:

The encyclopedia reported:
“In January 1998 the journal Science reported the work of biologists who had developed a method by which they obtained normal human cells, but immortal. Normal human cells die after 50-70 divisions, unlike cancer cells, which divide forever but have nothing normal. This work described in Science showed that if you get the telomeres (the ends of chromosomes, which lose some of their length with each cell division) to remain extended indefinitely, a miracle happens: the limit of divisions of normal cells is exceeded - this mortality is called the Hayflick Limit - and the cells live forever. (Or at least indefinitely, since "forever" is impossible to prove). These investigations were conducted by Calvin Harley, from Geron Corporation, and Woodring Wright and Jerry Shay, from the Southwestern Medical Center at the University of Texas (and staff), and definitely proved that the biological clock of cells is found in the telomeres.”

“This work had been preceded by an unpublished experiment where the biologist founder of Geron Corporation (the first biotech company specialized in aging), Michael West, took cells from the knee of Leonard Hayflick (the dean of biogerontology) and made them immortal. West planned to publish an article (which never came out) entitled The Immortalization of Dr. Hayflick. Hayflick’s cells were probably the first immortalized cells in human history. Quite fitting.”

"Eleven years later, in 2009, the Nobel Prize in Medicine was awarded to the three scientists whose research on telomeres in the organism Tetrahymena and in human cells preceded the work of Shay, Harley and Wright. Biologist Elizabeth Blackburn, her student Carol Greider, and Jack Szostak were contemplated, for their pioneering work, much more revolutionary than what they could imagine when they did the first experiments."

On the big screen they saw video of the scientists, accompanied by photographs of cell cultures. In some, telomeres could be seen shining in the ends of chromosomes.

Continued Superclopedia:
"The work reported in Science was simply to introduce into cells the gene of the enzyme telomerase, whose function is to lengthen telomeres, with the result that the cells remain indefinitely with characteristics of young cells. They produce ‘forever’ antioxidant enzymes and other proteins at the level of young normal cells, maintaining the pattern of gene expression typical of un-aged adult cells".

"Too good to be true? In the middle of the first decade of this century there was a company that didn’t think like that. This company was called Telomolecular, and began to assemble a portfolio of patents, of very good provenance (Stanford University and University of Nebraska), to develop a technique of telomerization (lengthening of telomeres) applicable to the human body. From Stanford University came nanocircles, developed by Eric T. Kool. These are small DNA circles with a nucleotide sequence (letters of genetic code) which complements the sequence that repeats in telomeres (TTAGGG). These little circles unite with telomeres and lead to their lengthening, rejuvenating the cells. In addition to nanocircles, Telomolecular planned to also use telomerase for this elongation".

Following the voice-over they saw drawings of nanocircles and electron microscopy photographs of these molecules, with a photo of the scientist.

"From the University of Nebraska came the technique by which they would carry the telomerizing molecules into the interior of each cell. It was a refinement of a technique already recognized by the FDA whose name was ‘PLGA nanoparticles’. PLGA stands for ‘Poly (Lactic-co-Glycolic Acid)’. PLGA nanoparticles aren’t toxic, don’t cause immune response, are biodegradable and cross the blood-brain barrier, and are an ideal carrying vehicle for molecules too large to be transported by other methods".

"But the work continued in other universities, and at the end of 2009 a team from the University of California at Los Angeles published an article in the journal Nature Nanotechnology describing a new method for the transport of proteins within cells. The method was called ‘nanocapsules’, and consisted of a polymer shell that was covalently linked (1) to the carried protein, and this enclosure could be degradable or non-degradable. It had a high transport efficiency and protected the proteins from attack by proteases (enzymes that break down proteins) of cells and the stomach".

"With such great promises, Telomolecular in the first decade of this century lived a very discreet, too discreet, life: it appeared that they weren’t going anywhere. In 2010 it had already disappeared, and its patents had been purchased by a London company called RCP Therapeutics, which also didn’t seem interested in making waves. But in spite of a journalist class that seemed curiously reconciled with its mortality, the news of so much ambition began running from mouth to mouth, and pressure from investors and prospective customers grew”.

-Fantastic! - Pedro says - still didn’t know these details. That’s why our parents and our grandparents are so different from the film’s characters. This appeared just in time for them.

And they really had been very lucky. In 2020 the first clinical trials were set up, and the most courageous began taking the first telomerization pills. Among these brave souls were Ricardo, Álvaro and Sarah.

(1): a polymeric shell casing is composed of polymers; a polymer is a molecule composed of many identical molecules linked together. For example, cellulose is a polymer of glucose, it’s composed of thousands of glucose molecules linked in a chain. The casing is covalently connected to the protein that it carries because to make that connection it uses covalent bonds, which are the strongest chemical bonds that exist. In a covalent bond between two atoms they share one to three pairs of electrons.

In 2020 Ricardo was 54 and well preserved, but already showing the beginning of a belly announcing a dangerous resistance to insulin. His appearance wasn’t bad (he was a man with dark blond hair and blue eyes, tall and with a pleasant face), but the least one could say is that he had already begun his decline. Álvaro was 8 years younger, so he still had the look of a very well maintained forty-something. Almost as tall as Ricardo (who measured six ft. two in.) he had black hair with light brown eyes. The twins had inherited Álvaro’s curly black hair and Ricardo’s blue eyes. They were lucky boys. Sarah was the same age as Álvaro, with a shapely body beneath a blue-eyed face, and an interesting-looking blond hair similar in colour to Ricardo’s.
When they started telomerization it was Ricardo who naturally saw the biggest changes: a few weeks after his belly began to fade, and some small wrinkles that already had arisen around the eyes were eclipsed. In Álvaro and Sarah, the changes were less pronounced, but the two noticed a weight loss and better looking skin.

Ever since, their appearance remained stable, as did the numbers of the tests that were periodically done.
Álvaro enters the room when the boys were finished viewing the Superclopedia video. Rui asks:

-Hey Álvaro - the twins used their two fathers' first name, given the confusion it would cause if they were both called father - if you never get old, will you ever die?

-To live forever doesn’t seem possible, Rui, since "forever" is a really long time. "Forever" is to live 100,000 trillion years? No, it’s really much, much more than that. It’s infinite, and I don’t think the human soul is designed for such a thing. But it‘s not inconceivable that we can live a good few thousand years. Who knows, we're in uncharted territory, pushing the limits of human nature. What we know is that the experiments on cells and then in animal models give enough reason for hope.

-What animal models? There are animals that don’t die of old-age? – Pedro asks.

-There are animals that apparently don’t have an aging process, such as sharks and lobsters, according to some authors (2), and there is a very long-lived sea bird, called Oceanodroma leucorhoa whose telomeres instead of becoming shorter with age, get longer. And in the end of November 2010 the journal Nature reported the work of a Harvard scientist with a very Portuguese name, Ronald DePinho, who had managed to create the first rejuvenated mice. The mice had an inactive telomerase gene that could be activated by the injection of a given chemical. What DePinho did was allow the animals to grow old and, and when they were clearly degenerated, he activated the dormant telomerase. And the results were incredible. The mice started producing new brain cells, recovered their lost olfactory reflexes, the hair, which had had areas of baldness, rejuvenated and became equal to that of young adult animals ... in the article’s photos, it could be observed that the brains of the telomerized mice were clearly bigger than the atrophied brains of aged rodents. They had elongated telomeres, which led to the reversal of aging in various organs. All this with a treatment of only four weeks.

-Cool! – Rui exclaims – And there were other animal models?

(2): biologist Leonard Hayflick in his book "How and Why We Age"; Hayflick is the discoverer of the Hayflick Limit, which is the observation that normal human cells have a limited number of divisions, after which they age and die.

-Some of the most interesting experiments have been done in a fish called Nothobranchius furzeri, which is the second vertebrate with the shortest life known. The vertebrate with the shortest life is also a fish – an Australian pygmy fish with which it’s harder to work - which is called Eviota sigillata and lives three and a half weeks. A famous experiment (by Italian scientists) was done in Nothobranchius with red wine’s antioxidant resveratrol and an increase of almost 60 percent of life extension was obtained.

-A really lucky fish! – Pedro Paulo observes.

-This fish became an instrument of choice for studying the effects of telomerizing agents because it lives only about thirteen weeks, and so it’s particularly useful to demonstrate increases in life span without having to wait years and years. Moreover it’s a vertebrate such as humans, which is important because all vertebrates have the same nucleotide sequence in their telomeres. The experiments have been very encouraging. Shortly after DePinho's work was published, soon there were researchers who remembered to insert the gene for the inducible telomerase, used in the experiment at Harvard, in Nothobranchius furzeri. That way, they had a technique to control the action of telomerase in all cells of the fish. And the results were very interesting.

-I bet they were! - notes Rui Ricardo – The fishes must still be alive to this day, forty years later.

-And in people studies were also very encouraging: a work of scientists from the National Institutes of Health of America, published in 2009 showed that in women taking a simple multivitamin per day, telomeres were 5.1 percent longer, which corresponded to an increase in life expectancy of 9.8 years. Multivitamins are very important because they are antioxidants and telomeres are very sensitive to oxidative stress (3).

(3): this sensitivity of telomeres to oxidative stress, which "wears" them, was discovered by scientists in the UK (Thomas von Zglinicki and colleagues).

message 2: by Anna (new)

Anna Patterson (romancenovelistannapatterson) | 1 comments Rui wrote: "Hello everyone

I’m going to give you a glimpse to the abandoned field of telomerization, I think you’ll find it curious.

My name is Rui Zambujal, I’m a Portuguese biologist, and I wrote a book en..."

Thought this a nice note on aging. thanks.

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