Genome Advance of the Month

The Biology of Living Longer

January 2011

By Jonathan Gitlin, Ph.D.

Science Policy Analyst

The ability to reverse or halt the aging process has long held allure, from early human mythology to Oscar Wilde (The Picture of Dorian Gray [wikipedia.org]) through to Indiana Jones (Indiana Jones and the Last Crusade [wikipedia.org]). It's also been the subject of considerable scientific study.

In January 2011, a paper published in the journal Nature has shown, for the first time, a possible biological mechanism where halting the aging process might be possible. A team of researchers at Harvard, led by Ronald DePinho, has found a way to reverse aging in a mouse by manipulating telomeres.

OK, it's a mouse model of aging, and hasn't been tried in humans, but DePinho's team has been able to reverse the effects of aging and extend lifespan. The Harvard team genetically engineered mice so that the researchers could control the production of an enzyme called telomerase — turning it on and off at will. They used the drug Tamoxifen to flip the switch.

Withhold Tamoxifen and the mice don't make functioning telomerase resulting in significantly shorter lifespans compared to control mice that expressed telomerase normally. The engineered mice also had advanced symptoms of aging: widespread tissue atrophy, especially in fast-growing tissues such as the testes and spleen, as well as degeneration of brain cells. Mice lacking normal telomerase production also had a high degree of DNA damage within their cells, also consistent with aging.

But when telomerase was switched on for four weeks by treating the mice with Tamoxifen, DePinho and his group reversed these symptoms of aging. Now that the mice had telomerase, their telomeres were repaired and lengthened and organs that were atrophied (testes, spleen) recovered in size. The Tamoxifen-treated mice lived significantly longer than untreated telomerase-deficient mice. Detailed analysis of the brains of these mice further confirmed the reversal of aging-related damage once telomerase function had been restored.

To understand how and why this happened, it's useful to know a little bit about telomeres and what they do inside cells. Telomeres are sequences of DNA that act as caps on the ends of chromosomes. Many thousands of bases long, they are made up of repetitive sequences of DNA that don't code for proteins, but are important during cell division. Their role is to prevent the loss of genes from the ends of chromosomes, and also to prevent the ends of two different chromosomes from fusing together. When a cell divides, the telomere acts as a buffer at the end of each chromosome, and any lost DNA comes from the telomere rather than a gene.

Telomeres get shorter with each cell division, and eventually they become too short to work properly, and the cell can no longer divide. As an example, skin cells that came from a newborn baby grown in a lab could divide more than 80 times, but skin cells taken from a 70 year old might only be able to divide 20 times. The telomeres do not get replenished because differentiated or mature cell types, like skin cells, produce little or no telomerase, the enzyme that repairs the damage.

While this is true for almost all the cells in the body, there are some exceptions, such as fetal cells and adult stem cells. These so-called undifferentiated or immature cells produce telomerase all the time are able to extend the telomere after replication, allowing these cells to replicate indefinitely. Cancerous cells can also have active telomerase, allowing them to continue dividing long past the point where other cells would have died, explaining why cancerous cells are considered immortal.

The discovery of how telomeres work, and their roles in aging and cancer, was a major achievement in understanding of how the genome works, and earned Elizabeth Blackburn, Carol Greider, and Jack Szostak the 2009 Nobel Prize in Physiology or Medicine [nobelprize.org]. Now someone has taken this basic research finding and figured out how to apply it to something that everyone cares about.

Clearly, it's a long way from demonstrating a concept in a mouse model to applying it in people, but the finding was sufficiently alluring to have even reached that well-known peer-reviewed broadcast, The Colbert Report, The Colbert Report [colbertnation.org], where DePinho was interviewed about the finding before a live audience.

While these findings are highly exciting, it is still a little soon to say that scientists have cracked the problem of aging. The next step will be to see if it's possible to reverse aging in the cells of normal mice by stimulating or adding telomerase, with any potential testing in humans much further away. As mentioned, cancer cells are able to continue dividing in part due to the abnormal presence of telomerase, so it's quite possible that adding it artificially may cause cancer. Even if it proves possible to reverse human aging without causing cancer, there are many ethical issues that society will need to address regarding extending human lifespans.

January saw several other research papers NHGRI thought interesting enough to highlight. They are as follows:

Shattered chromosomes and cancer. Scientists in the United Kingdom and Baltimore, Md. show that some cancers are a result of widespread genetic rearrangement. Most cancers accumulate mutations as a gradual process, rather than in a single event. It was thought that cells died following DNA damage severe enough to 'shatter' the chromosomes. But occasionally, the damaged cell can repair its DNA, but imperfectly, with localized rearrangements of genes along a particular chromosome. This kind of rapid rearrangement may account for up to five percent of most cancer cases, and as much as 25 percent of bone cancers. Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development

Cell, January 7, 2011 Non-invasive prenatal testing for Down's syndrome. Normally, this is done by amniocentesis, a procedure that is not without risk to the fetus and mother. Down's syndrome is a result of having three copies of chromosome 21 instead of the normal two copies. In this study, Professor Chui and colleagues at the Chinese University of Hong Kong, have shown that it is possible to detect the fetus' extra copy of chromosome 21 just by sequencing and analyzing a sample of the mother's blood. Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study

British Medical Journal, Jan. 11, 2011 Orangutan genome. The Orangutan genome has been sequenced by a consortium of researchers, including those from the NHGRI Genome Sequencing Program (GSP). Interestingly, Orangutans have much more stable genomes than humans or chimpanzees, the other two great apes whose genomes have been sequenced. Comparative and demographic analysis of orang-utan genomes

Nature, Jan. 27, 2011

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