Turning on' Telomerase To Stop Cell Aging: The Quest for Immortality

Telomeres consist of special DNA regions at the ends of each chromosome. Each time a cell divides, it loses part of its telomeric DNA, causing telomere shortening. Apparently, when telomeres become too short, "cell aging" occurs. But there is an enzyme, telomerase, that can reset telomeres back to their youthful lengths, suggesting to Dr. Michael Fossel the possibility of radical extension of the healthy human lifespan in the near future.

Dr. Michael Fossel received his Ph.D in neurobiology and his M.D. at Stanford University, and is currently a professor of clinical medicine at Michigan State University. Dr. Fossel's 1996 book, Reversing Human Aging (William Morrow and Co. Inc.), considers that much or most of normal aging may be due to shortened telomeres. [...]

What are your estimates of the implications of this research on human life span?
Fossel: We should be able to extend the human life span indefinitely. Not infinitely, but indefinitely. It's really any number you want to pick. If I said we could extend the human life span to 1,000 years, people would laugh hysterically. If I said we could extend it one year, people would yawn. So when I say 200 years, it's because I need a number we can talk about that doesn't seem either silly or boring.

Are you saying that there need not be any clear-cut objective limits to the human life span?
Fossel: Let me put that differently. I would say there are at least two kinds of limit to the human life span. One is stochastic: sooner or later, you get hit by a meteor, fall off a ladder, get struck by a car, step on a land mine, or whatever-if you live long enough, whatever it is, one of those things will happen.

In your book, you give some numbers.
Fossel: If your risk remained equal to the risk of 30-year-olds in 1960 in the U.S., as I recall the median life span should be 1,776 years. That's assuming no cause of death other than trauma. More

Telomere length predicts survival independent of genetic influence

Telomeres are DNA protein complexes of repetitive noncodon hexanucleotide sequences at the end of eukaryotic chromosomes that provide protection from recombination and degradation during cellular division (de Lange, 2002). Telomeric DNA structures are inadequately replicated, and as a consequence, telomere length declines in mitotic tissue with each cell division (Olovnikov, 1973). The enzyme telomerase, which prevents telomere shortening, is highly expressed in germline tissue, whereas expression is low or absent in most somatic tissue (Blackburn et al., 1997; Blackburn, 2001).

Progressive shortening of telomeres during cellular replication in vitro eventually leads to loss of chromosomal stability, changes in gene expression within the subtelomeric region, senescence and apoptosis. Shortening beyond a critical length leads to loss of telomere protection and induces cellular senescence (Blasco, 2005). Aberrant activation of telomerase maintains telomere length above the critical threshold, resulting in excessive cellular proliferation and prolongation of cellular lifespan (Blackburn, 2001).

Telomere length in DNA from human blood lymphocytes is inversely related to age (Jeanclos et al., 2000) and is influenced by genetic factors (Slagboom et al., 1994; Bischoff et al., 2005a,b). Individual differences in telomere length can also be explained by differences in expression of telomerase during embryonic development (Okuda et al., 2002), in white blood cell turnover rate, and in accumulated oxidative damage (von Zglinicki, 2002).

Reduction in telomere length has been implicated in the pathology of several diseases, although it is not clear whether increased telomere loss is a marker of poor health status or whether the loss has a direct biological effect on the causal network that underlies human health. Premature aging syndromes, such as congenital dyskeratosis, are associated with accelerated telomere shortening (Aviv et al., 2005; Hofer et al., 2005). In contrast, 80% of human cancers show increased telomerase activity (Kim et al., 1994), resulting in retained telomere length in spite of replication of the tumor cells. There have been previous population-based studies of telomere length that both support and contradict the suggestion that telomere length influences survival in human populations (Cawthon et al., 2003; Martin-Ruiz et al., 2005; Bischoff et al., 2006). Whether causal or not, evidence is growing that telomere length may reflect the biological aging rate of the organism. More

Three Americans share Nobel Prize in medicine

Stockholm: Americans Elizabeth H. Blackburn, Carol W. Greider and Jack W. Szostak won the 2009 Nobel Prize in medicine on Monday for discovering a key mechanism in the genetic operations of cells, an insight that has inspired new lines of research into cancer. The trio solved the mystery of how chromosomes, the rod-like structures that carry DNA, protect themselves from degrading when cells divide.

Chromosome research: The Nobel citation said the laureates found the solution in the ends of the chromosomes—structures called telomeres that are often compared to the plastic tips at the end ofshoe laces that keep those laces from unravelling.

Blackburn and Greider discovered the enzyme that builds telomeres—telomerase—and the mechanism by which it adds DNA to the tips of chromosomes to replace genetic material that has eroded away. More

Finding Clues to Aging in the Fraying Tips of Chromosomes

When Time magazine named Elizabeth H. Blackburn, a cell biologist, one of this year’s “100 Most Influential People in the World,” it listed her age as 44. Enlarge This Image Thor Swift for The New York Times Stress can have effects similar to aging in redcing an enzyme that keeps chromosome tips in shape.

“Don’t think I’m going to ask for a correction on that one,” Dr. Blackburn, 58, a biochemistry professor at the University of California, San Francisco, said in a recent visit to New York City. “If they want to turn back the clock, that’s lovely.”

Dr. Blackburn, a winner of the 2006 Albert Lasker Award for Basic Medical Research, studies aging and biochemical changes in cells that are related to the diseases of old age.

Whatever Dr. Blackburn’s own chronologic age, the buzz in scientific circles is that she is likely to be the next woman awarded the Nobel Prize in Medicine.

Q. What are telomeres and telomerase?
A. Telomeres are the protective caps at the ends of chromosomes in cells. Chromosomes carry the genetic information. Telomeres are buffers. They are like the tips of shoelaces. If you lose the tips, the ends start fraying. Telomerase is an enzyme. In cells, it restores the length of the telomeres when they get worn. As the ends of the chromosomes wear down, the telomerase comes in and builds them back up. In humans, the thing is that as we mature, our telomeres slowly wear down. So the question has always been: did that matter? Well, more and more, it seems like it matters. More

From nursing homes to chromosomes: actually reversing aging

Just as the telomere is the key to the altered pattern of gene expression in aging cells, so too is it the key to resetting gene expression in cells and in reconstituted human skin. Here, as always, the question is not "What causes aging?", but rather "What is the single most effective point to intervene in aging?" The issue is not academic, but concrete. How can we most effectively and efficiently prevent or treat the diseases of aging? In treating arthritis, we could (and do) replace the affected joints, but this is painful, expensive, and not entirely effective. In treating heart disease, we could replace the heart itself, but this is not only painful and expensive, but remarkably risky as well. In treating the genes that underlie these and other age-related diseases, we could - just as with hips and hearts - replace the affected part. But just as in hips and hearts, so too with genes: why not simply make the normal part work the way it was intended to work?

The difference between a young cell and an old cell is not the superoxide dismutase gene, nor should we replace this or other genes. The difference between a young cell and an old cell is that this and other genes are not being expressed in the right amounts and at the right times. All of this can, and has been reset by using telomerase both in the laboratory and in reconstituted skin. More

Partial reversal of aging achieved in mice

Researchers led by Ronald A. DePinho (above), a Harvard Medical School professor of genetics, say their work shows for the first time a dramatic reversal of many aspects of age-related degeneration in mice, a milestone in aging science achieved by engineering mice with a controllable telomerase gene. The projection of chromosomes seen here shows telomeres (highlighted in red) on their ends.

Harvard scientists at Dana-Farber Cancer Institute say they have for the first time partially reversed age-related degeneration in mice, resulting in new growth of the brain and testes, improved fertility, and the return of a lost cognitive function.

In a report posted online by the journal Nature in advance of print publication, researchers led by Ronald A. DePinho, a Harvard Medical School (HMS) professor of genetics, said they achieved the milestone in aging science by engineering mice with a controllable telomerase gene. The telomerase enzyme maintains the protective caps called telomeres that shield the ends of chromosomes.

As humans age, low levels of telomerase are associated with progressive erosion of telomeres, which may then contribute to tissue degeneration and functional decline in the elderly. By creating mice with a telomerase switch, the researchers were able to generate prematurely aged mice. The switch allowed the scientists to find out whether reactivating telomerase in the animals would restore telomeres and mitigate the signs and symptoms of aging. The work showed a dramatic reversal of many aspects of aging, including reversal of brain disease and infertility. More