AGING: THE SECRET OF TELOMERIZATION

Illustration by Cristina Sampaio, published in Expresso

Rui Zambujal

A shorter version of this article appeared in the Portuguese weekly Expresso, June 9, 2007, on page 53 of the main body (opinion page), titled "Luta Contra O Envelhecimento" (Fight Against Aging).

=============================================

It was a moment of illumination in research on aging to find that the biological clocks of our cells reside in the telomeres, the ends of chromosomes. In each cell division, these structures lose some of their length, and that progressive shortening, from a certain point, causes a change in the expression of genes to an aged state; that's when the cell stops dividing and dies. At least at the cellular level the origin of aging had been found.

Since then, researchers have determined that the shortening of telomeres is of crucial importance in many human degenerative processes, such as cardiovascular disease, osteoporosis, atrophy (aging) of the skin, and Werner’s syndrome (a disease of accelerated aging) , for example.

And we seem to have finally gotten to the time of the practical application of these observations. So far, only the introduction of the gene for telomerase (the enzyme that lengthens telomeres) was used, in aged cells, resulting in rejuvenation of cell cultures. In addition, there are small molecules able to make a modest telomerization (lengthening of telomeres). For example, Geron Corporation (an American company), which is one of the most active in research of telomeres, announced recently that it could decrease 2 to 5 times the viral load of HIV in cell cultures of AIDS patients through the use of a molecule (TAT0002) which stimulates the action of telomerase. The CD8+ T cells of the immune system, due to their hyperactivity in combating the virus, are aged and have no replicative capacity (the telomeres of a 40 year-old patient with AIDS are comparable to a person of 90 years); Geron’s molecule renews them.

However, a new company, Telomolecular Corporation (also American), is developing two new methods for lengthening telomeres: using telomerase itself and through DNA molecules called nanocircles. These two molecules are delivered within the nucleus of each cell using a technology with the name of PLGA nanoparticles: Poly (Lactic-co-Glycolic Acid) nanoparticles. The PLGA technology (more specifically a technique called ELMD1) is a technology already well developed and approved by the US FDA (the regulatory agency for medicines). The PLGA nanoparticles are not toxic, do not cause immune response, are biodegradable and cross the blood brain barrier, and are an ideal vehicle for the supply of molecules too large to be transported by other techniques.

Nanocircles were developed by a team of Stanford University led by Eric T. Kool, and consist of circles of DNA complementary to the TTAGGG sequence (the sequence of letters of genetic code that repeats in telomeres). It has been shown in cell cultures that they’re able to rejuvenate aged tissues, serving as a template for the elongation of telomeres. In the near future Telomolecular promises to create a telomerized sheep, which will be named Dolly II in honor of Dolly the cloned sheep, who had excessively short telomeres. We’ll see.[Update 03 July 2010: Telomolecular exists no more. Its patents were sold to a London company called RCP Therapeutics, which leads a very discreet life]

How promising is this new technology? Can we seriously consider a true promise of rejuvenation? The data that have accumulated since 1998 are very promising. In January 1998 the journal Science published an article that described how normal human cells, which have a limited life expectancy of between 50 and 70 divisions (in contrast to cancer cells, which divide without limit), became immortal without becoming cancerous by introducing the telomerase gene. The rejuvenated cells remain quite young (they produce the antioxidants catalase, superoxide dismutase, glutathione peroxidase and other proteins in quantities typical of young cells) without any sign of abnormality (they have a normal number of chromosomes, for example). These experiments, originally conceived by Calvin Harley, from Geron Corporation, and Woodring Wright and Jerry Shay, from the Southwestern Medical Center, University of Texas (and colleagues) were repeated over 800 times at many universities and companies. And the experiments were done on cells relevant to human disease processes such as endothelial cells (from the endothelium of blood vessels, important in atherosclerosis), cells of the retinal pigment epithelium (the cause of macular degeneration, which leads to the loss of vision), and fibroblasts (important in aging skin and other tissues).

More recently (a study published in 2003 in The Lancet) a team led by Richard M. Cawthon measured telomeres in blood cells of 143 adults over 60 years-old. He found that those who belonged to the group of 50% with larger telomeres lived 4 to 5 years longer (4.8 years for women and 4 years for men)than those belonging to the 50% with the shortest telomeres. The authors observed in the latter group a mortality rate 3 times higher for cardiovascular diseases. The 25% with shorter telomeres had a mortality rate 8 times higher for infectious diseases than the 75% with longer telomeres.

Also in 2003, in Neurobiology of Aging, researchers discovered the existence of a strong negative correlation between the length of telomeres in T lymphocytes and the level of mental decline in Alzheimer's patients: the shorter telomeres were in those lymphocytes, the worst was the mental condition of patients. Length of telomeres in T lymphocytes was also inversely correlated with plasma levels of inflammatory cytokine TNF-alpha protein. The researchers speculated that there could be an immune component in Alzheimer's disease.

Closer, in May 2005 in the journal Circulation, researchers found that telomere loss in immune cells is correlated with increased insulin resistance, a condition associated with cardiovascular disease and an early death, and more body fat.

Finally, an interesting animal model: in April 2000, in an article published in Science, Robert Lanza and colleagues showed that cows cloned using a technique that increases the length of telomeres showed a much longer cell youth in comparison to normal cows at the same age: their cells divided in culture over 90 times, much higher than their normal limit (50 to 60 times). The researchers say that these telomerized cows can live 50% more than their normal life expectancy.

According to Telomolecular, there are already commercial applications of telomerization: University of Tennessee-Memphis produces new corneas from old corneal cells, something impossible to do without telomerization because the original cells do not divide enough, and a Dutch company produces skin grafts for burn victims.

What to do to buy time while these technologies are not ready? Telomolecular intends to develop, for the earliest, cosmetic products for skin and scalp; the reason is that the legal process of licensing is much simpler for these products. Experiments in tissue culture have shown that skin cells (fibroblasts) modified to produce telomerase secrete much higher levels of collagen, restoring skin elasticity in a model of aging skin. These experiments, of scientists from Geron Corporation and Stanford University, were published in August 2000 in the journal Experimental Cell Research. The products targeted at the degenerative diseases and aging in general will have to go through a much longer regulatory process.

However, there is something you can do to delay the shortening of your telomeres. In an issue completely dedicated to the biology of aging of the Annals of the New York Academy of Sciences (April 2002), scientists from the UK (Thomas von Zglinicki and his colleague Gabriele Saretzki) concluded that the rate of telomere shortening is dependent on oxidative stress : the weaker the antioxidant defenses of a cell the more quickly telomeres are "spent". Therefore, the strategy is simple: take your antioxidants (vitamins and minerals, and other antioxidants such as resveratrol [update 30/03/2013: resveratrol discontinued, due to bad results], coenzyme Q10 [ubiquinol is better], grape seed extract or alpha lipoic acid), and make the most antioxidant nutrition possible. It is (highly?) possible that this small extra effort will have a potential return of many years of life.

Note: there is a process in organic chemistry called telomerization, but in this article we refer to a biological telomerization, of course.