Tag Archives: Daf-2

Why Do We Grow Old?

May 20, 2010

Original source: “Miks me vananeme?” (Postimees newspaper, 6 February 2010) by Toivo Maimets, University of Tartu (Estonia) Professor of Cell Biology. Translation by Lauri Randveer.

Why do we age? We have probably all asked this question, driven by the desire to understand what goes on inside living organisms that allows no one to escape from aging, as well as by the hope that the knowledge acquired might enable us to slow down the aging process.

Theoretically, how long could a human being live? Scientists think that during the last 100,000 years the maximum human lifespan has remained unchanged, somewhere in the region of 125 years. What has changed, however, is the average life expectancy. Thanks to better hygiene, a decrease in infectious diseases, and the discovery of antibiotics and vaccines, average life expectancy has increased by approximately 27 years within the last century alone.

To understand the nature of aging, we need to study more closely what goes on inside our cells. The human organism contains billions of cells and everything we do – eat, move, think, etc – depends on their activities.

For some time already, scientists have been aware that cells have a finite lifespan, a maximum number of possible divisions. In laboratory conditions human cells can divide about 50 times, after which they lose their ability to replicate and therefore die.

In a 40-year-old human, the same cells are capable of replicating 40 times, whereas those of an 80-year old divide only 30 times. The cells of animals with a shorter lifespan than humans are capable of dividing a smaller number of times.

There is a genetic disease called Werner syndrome, which causes patients to age very rapidly, so that they look like elderly people while still in their teens. The cells of someone suffering from Werner syndrome replicate fewer times than those of unaffected individuals.

As an organism grows older, its cells undergo many changes. Proteins become increasingly modified and mutations in the DNA accumulate. The cells’ resistance to stress – such as fluctuations in temperature, or chemicals and radiation – decreases constantly and the likelihood of cell death increases. One of the causes of these changes is the damage done to cellular macromolecules (DNA, RNA, proteins) by harmful superoxides and other free radicals that are produced in the course of cell metabolism. Cells are equipped with mechanisms to counter such effects by destroying free radicals and repairing damaged macromolecules.

However, these mechanisms can never be absolutely perfect and thus changes accumulate over time. At a certain point, the amount of these changes reaches a critical limit and brings about the death of the cell.

The protective mechanisms of various cells work with varying degrees of effectiveness, which is why we encounter such variation in the longevity of different cells. From the above it is clear that the more active genes are at destroying free radicals and repairing damage, the longer the lifespan of a cell and that of the whole organism.

This has led scientists to describe gene coding for DNA-repairing proteins and free-radical-destroying enzymes (such as superoxide dismutase and catalase) as “longevity genes.” One of the proteins responsible for repairing DNA damage in cells is a product of the WRN gene, which is known to be compromised in patients suffering from the Werner syndrome. The better these genes and the proteins coded by them function, the longer the lifespan of cells and, consequently, the higher the probability that the whole organism lives longer.

Apart from this general mechanism of “accumulating mutations,” special structures on the ends of chromosomes called telomeres have been indicated as having some role in regulating the lifespan of a cell.

Telomeres are regions within the DNA that are synthesized during cell division through mechanisms that differ somewhat from those programming the synthesis of the rest of the cell’s DNA. Last year the Nobel Prize in Physiology and Medicine was awarded to telomere researchers Elizabeth Blackburn, Carol Greider and Jack Szostak.

Telomeres guarantee the integrity of chromosomes by ensuring that DNA is passed on to offspring in its entirety. Blackburn once compared them to the plastic caps at the end of shoe-strings that prevent the strings from unraveling. Telomeres have been found to become shorter with each cell division. After a certain number of divisions, telomeres become so short that they cannot guarantee the stability of chromosomes anymore and the cell dies.

However, various cancer cells have achieved immortality through producing large quantities of telomere-synthesizing enzymes which protect their telomeres from wearing down in the course of divisions.

But this is not all. In addition to mechanisms that regulate the lifespan of individual cells, there appear to be more general control mechanisms in place that regulate the lifespan of the organism as a whole.

University of California researchers Javier Apfeld and Cynthia Kenyo have demonstrated that some genes may regulate the longevity not only of the cell in which the particular gene was produced, but also that of the other cells in the organism.

A gene entitled daf-2 has been identified in the tiny Caenorhabditis elegans worm which, when damaged, considerably extends the longevity of the organism and enhances its stress resistance.

Daf-2 regulates lifespan by preventing the cells from lapsing into a state of inactivity and rest.
Researchers from California were able to demonstrate that a product of this gene also affected neighboring cells where the products of daf-2 were not generated.

Thus, it appears that in addition to a lifespan regulating mechanism that works at a cellular level there is also a “biological clock” which controls the life expectancy of an organism as a whole.

Although we still know only very little about the components and working principles of this “clock,” there is reason to believe that it is a widespread mechanism, which has been preserved in the course of evolution. All of the proteins that have been identified as components of an age-regulating “molecular clock” in the C. elegans worm, have also been found to have analogues in other animals, including humans.

Does our present state of knowledge already enable us to extend the human lifespan? It is, in fact, very easy to extend the longevity of cells. Scientists have identified dozens of genes called oncogenes – since they are especially active in many tumors – which when activated, switch off the mechanisms regulating normal growth and aging in a cell, and the cell then becomes immortal. For example, some of them enhance the synthesis of telomeres; others make cell growth independent of environmental factors. The resulting tumor cells are capable of growing and replicating in vitro infinitely.

On 11 October each year, Henrietta Lacks’ Day is celebrated in Atlanta, USA. Henrietta Lacks was a woman who died in 1951 at the age of 31 due to cervical cancer. Cells from her cancerous tumor were used to create a cell line for medical research.

The HeLa cell line, as it is called after the first letters of her name, is now cultivated in hundreds of laboratories all over the world and has become very important in the research and treatment of cancer, AIDS, polio and many other diseases, by making it possible to compare results from different laboratories. The quantity of HeLa cells grown in labs all over the world today greatly exceeds the amount of the original cells.

Thus, it can be said that in a sense Henrietta Lacks has become immortal – at least at the cellular level. This kind of mortality may be of interest to those religious scholars who believe that a human being may indeed consist of a single cell which has its own unique gene combination. A cell that does not feel any pain and has no self-consciousness or social relations – such as a fertilized ovum. Fortunately, the majority of researchers don’t share this view and hence human immortality remains yet to be achieved.

The mortality of normal cells and the immortality of tumor cells exemplify one important paradox of aging: Immortal cells are generated by tumor cells, which at the same time cause the rapid death of the organism as a whole.

The integrity of an organism is maintained by the coordinated functioning and replication of its cells. This, however, is achieved at the price of the mortality of cells and, consequently, the finite lifespan of an organism.

But nature has found a way out of this paradox, too: The entirety of our genetic information is transferred in the form of DNA to our offspring, who ensure the continuity of this information by passing it on to new generations. Immortality exists, because we survive through our children.