Those of us with many birthdays under our belts may look spry on some days and appear haggard on others, but is there any gauge for how well we really are aging within?
Elizabeth Blackburn, PhD, is not ready to predict how long you will live. But she and her UCSF colleagues are exploring a feature within cells that is a kind of hourglass. While the hourglass appears to mark cellular aging, she says that we may also be able to turn it upside down.
Within cells, it’s not sand, but rather DNA that is gradually slipping away. The DNA hourglass runs at different rates for different people. Sometimes it runs at different rates within the same individual at different times. And surprisingly, in some cells, in some people, this hourglass may defy time for a spell, running backward with the aid of a key enzyme.
Blackburn is optimistic that we may derive health benefits from medical tests and, perhaps, treatments based on discoveries stemming from this bit of DNA – called the telomere – and the enzyme that acts on it.
Telomeres are appended to the ends of all 46 chromosomes in all of our cells. Once telomeres become too short, cells can no longer multiply to replenish body tissues. The progressive shortening of this chromosome-capping, protective bit of DNA now appears to be associated with risk for certain chronic diseases. Studies even show that people with longer telomeres are more likely to live longer and, arguably even more significantly, to have more years of healthy life.
Already, over the past decade, Blackburn’s research group and others have found links between shorter telomeres and risks for cardiovascular disease, diabetes, some cancers, depression, pulmonary fibrosis, vascular dementia, osteoarthritis and osteoporosis.
“More and more, we are thinking about how telomeres and their maintenance are involved in issues of human health,” Blackburn said during a January 4 seminar talk at UCSF’s Mission Bay campus.
Nobel Prize-Winning Line of Inquiry
Twenty-six years ago, Blackburn, who was then at UC Berkeley, and her then graduate student Carol Greider, now at Johns Hopkins University, discovered a new enzyme that they named telomerase. When active in cells, telomerase can lengthen telomeres and prevent chromosomes from being whittled down as cells repeatedly divide to replenish their numbers.
A little bit of telomerase activity may promote the health of certain types of cells. On the other hand, while the resulting longer telomeres in normal cells of the body help reduce the chances that one will get certain cancers, telomerase becomes abnormally active in well-established tumors. This superactivated telomerase helps the already aberrant tumor cells become immortal.
For their discovery of telomerase and their studies of telomeres, Blackburn and Greider shared the 2009 Nobel Prize in Physiology or Medicine with another telomere researcher and collaborator with Blackburn, Jack Szostak of Harvard Medical School.
Today, drugs that target tumor cells by blocking their abnormally high levels of telomerase already are in clinical trials. Telomeres and telomerase also remain a focus of research aimed at deepening scientific understanding of aging, stress and chronic disease.
There is even an over-the-counter telomerase activator on the market, called TA-65, licensed by T.A. Sciences from Geron. But for now, any health benefits it might provide remain unproven.
Blackburn’s University research program has broadened, and now ranges from getting at the nuts and bolts of why the status of telomeres is important at the cellular level to measuring telomere maintenance in humans and looking for new associations with disease risk.
Telomere Length, Stress and Chronic Disease
Blackburn and her colleagues are studying telomere length and telomerase activity in cells of the human immune system. New immune cells are generated throughout our entire lives. Because they are blood cells, they are the easiest to obtain for clinical telomere research. Blackburn’s research is strengthening evidence that the maintenance of telomere length – and a bit of telomerase activity – is associated with better health.
Seminal research by Blackburn and UCSF scientist Elissa Epel, PhD, first showed a link between chronic psychological stress and telomere maintenance capacity. In their initial study of caregiver mothers of chronically ill children and control mothers of healthy children in 2004, perceived psychological stress – and the number of years of caring for their chronically ill children – was associated with shorter telomere length and less telomerase activity in these mothers, providing the first indication that stress may have an impact on telomere maintenance.
Turning Back Telomere Time?
Can we take actions that will make our telomeres grow longer? Research reported by Blackburn and colleagues over the past few years indicates that we can.
First, telomeres are not always destined to shorten. They can even grow longer over time. For example, Blackburn and a UCSF research team led by cardiologist Mary Whooley, MD, found in a study of 608 elderly men and women with heart disease that nearly one-quarter of participants had telomeres that lengthened over five years of study. However, being older, being male and being obese were associated with a greater likelihood that one’s telomeres would shorten.
Will telomere lengthening itself be what may make us healthier? Blackburn says that’s less clear. It is a reasonable hypothesis and there are data to support it, she says. But Blackburn wants to understand for certain the extent to which changes in telomere length are merely consequences of the internal processes driving biological aging, as opposed to these changes in telomeres more directly driving aging and the development of chronic disease. To find out, she and her colleagues are now engaged in interventional studies.
For example, in a three-month, preliminary study of 30 men ages 49 to 80 with low-risk prostate cancer, Blackburn, along with a team led by UCSF preventive medicine researcher Dean Ornish, MD, and UCSF Department of Urology Chair Peter Carroll, MD, MPH, found that comprehensive lifestyle changes – a healthy diet, stress management and exercise – increased telomerase activity.
In another Blackburn-Epel collaboration, UCSF researchers found that vigorous exercise seems to protect people under high stress from the same degree of telomere loss that they might otherwise experience.
Blackburn, Epel and UCSF mental health researcher Owen Wolkowitz, MD, were among the researchers who conducted another recent study, which found that participants who completed a three-month meditation retreat – compared with people on a waiting list –had a greater sense of purpose and control and reduced neuroticism. The magnitudes of positive changes by these measures were proportionately associated with increased telomerase activity.
Omega-3 fatty acids found in fish oil – specifically docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) – also may influence telomere length. In the same elderly, coronary artery disease patients studied by Whooley, the researchers found that a higher level of these fatty acids in one’s cells at the beginning of the study was associated with a greater likelihood that one’s telomeres would be better maintained – and even lengthen – in the next five years.
Blackburn and her colleagues are actively following up on these intriguing observational studies. Will lengthening telomeres or boosting telomerase activity in immune cells stop chronic disease? “We have to be wary about saying that,” Blackburn cautions. Associations do not demonstrate causality, although research findings to date have been encouraging, she says.
Pace of Telomere and Disease Discoveries Quickens
Blackburn’s research on telomere length and human disease is exploding. No longer limited to smaller studies, her lab team now is collecting telomere data on close to 100,000 people. This endeavor is part of an extensive research collaboration between Kaiser Permanente of Northern California and UCSF. During the two-year project – led by Catherine Schaefer, PhD, director of the Kaiser Permanente Research Program on Genes, Environment and Health, and by Neil Risch, PhD, director of the UCSF Institute for Human Genetics – researchers are scanning the genomes of members of Kaiser Permanente Northern California.
The wealth of genomic and telomere data obtained will be coupled with a rich and continually expanding Kaiser research resource that includes long-term medical records, augmented by already-collected survey data and information on environmental exposures that may pose health risks.
With these data, Blackburn expects to be able to identify additional associations between telomere length and disease incidence and outcome. Exploring links between depression and telomere length will be an early focus for Blackburn and colleagues. In addition, it should be possible to identify human genetic variations that affect telomere length. Already, researchers have found that at least 350 of the 6,000 genes in baker’s yeast affect telomeres, Blackburn said during her seminar talk.
Previously, it would not have been possible to measure telomere length in so many human samples in any reasonable time frame. But Blackburn’s lab team has painstakingly developed automated techniques to analyze thousands of samples per day in her University lab. The researchers expect to measure average telomere length in all samples in the study over the next few months, before the rest of the key genetic data has been completely collected.
It’s now been almost a decade since Blackburn first started collaborating on telomere research focused on human health outcomes to complement her lab studies of fundamental cell biology. But now she means to ensure that her discoveries find practical application, in part by starting a new company.
Blackburn, Epel, Blackburn lab researcher Jue Lin, PhD, and leading telomere researcher Calvin Harley, PhD – former chief scientific officer of Geron – are diving deeper into the personalized medicine field with a Bay Area startup called Telome Health, Inc. The company aims to develop and bring to market diagnostics and health monitoring based on telomere and telomerase measures. The purpose is to track health and to predict disease risk and treatment response. Other startup companies focused on telomeres also have launched in the past year.
Aging Cells, Aging Selves
While some telomere research may be ripe for commercialization, there is still a great deal to be learned from studying simple cells in simple organisms, Blackburn says. Blackburn’s own early research is a testament to the fact that some of the most important biological discoveries – and their eventual applications – are unanticipated.
Biologists have long pondered and pursued the causes of aging. Telomere research helps advance the idea that cellular aging may play a strong role in pacing the aging of the whole organism.
Long after James Watson and Francis Crick, and others in their wake, began unraveling the structure of the DNA double helix, the secrets of heredity and the mysteries of how DNA replicates as cells divide, scientists still had not identified molecular equipment that was capable of replicating DNA all the way out to the tips of chromosomes.
A little bit of DNA is lost from telomeres with each cell division. DNA in telomeres consists of the same, short sequence of nucleotide building blocks – in humans, it is TTAGGG – repeated over and over. The number of repeats can vary. The DNA in telomeres doesn’t encode vital genetic information. Instead, the telomere serves as an assembly point for a suite of proteins that help form protective end caps on the chromosome – like the aglets at the tips of your shoelaces. Some of this DNA is expendable.
But eventually, one would expect that the telomere would be used up. Important genomic DNA would then be lost. Blackburn decided to study telomeres – not in humans, but in a much simpler creature, a one-celled, pond-dwelling protozoan called Tetrahymena thermophila. The protozoan is so simple, it can be used to learn about biological chains of events so basic to life that they are found in life forms ranging from humans to the simplest one-celled organisms.
Blackburn wanted to know how single-celled Tetrahymena could keep reproducing without eventually going extinct due to a loss of genes. The answer – discovered by Blackburn and Greider – turned out to be telomerase. This strange enzyme is made up not only of protein, but also RNA. The RNA acts as a template for adding telomere DNA onto the chromosome tips, and may play other important roles as well. Blackburn’s lab team and others have shown that humans with inborn defects in this RNA component of telomerase have shorter telomeres.
Telomerase Researchers Probe Yeast to Learn Cell Secrets
Blackburn and others also use another one-celled organism as a model in which to study telomeres and telomerase – the baker’s (and brewer’s) yeast Saccharomyces cerevisiae. Yeast normally can keep dividing indefinitely, with a mother cell budding off successive generations of daughter cells, in a way that’s similar to what a human stem cell does. If loss of telomeres or telomerase within cells is directly implicated in human aging, the insight into the biological mechanisms responsible might come from yeast.
In early yeast studies, researchers found that eliminating the gene for telomerase limited the number of cell divisions to about 50. But even before telomeres become too short and cells predictably stop dividing, the dividing yeast cells begin to face other challenges.
About one in 1,000 to one in 10,000 telomerase-deprived yeast cells experience a catastrophic event – such as the fusing of normally separate chromosomes during cell division. Even cells with short telomeres can be protected from these catastrophic events with a small bit of telomerase activity, Blackburn found with her then UCSF graduate student Simon Chan, now at UC Davis.
Successful cell division, involving the replication and pulling apart of DNA and chromosomes and a divvying up of genetic and other cellular material between mother and daughter cells, is an immensely complex event in the life of a cell, orchestrated by a multitude of molecular players and directors. Evidence for the importance of telomerase in cell division is growing.
Cell division without error cannot be taken for granted. Successive generations of tumor cells within many cancers become increasingly abnormal, in part, due to faulty cell division, which can sometimes allow genetic errors to accumulate. More subtle problems with cell division in a significant portion of noncancerous cells might contribute to compromised cellular functioning – and aging – long before any absolute limit on the cells’ ability to divide is reached.
Blackburn has found that something within yeast cells that have short telomeres often triggers delays in the movement of the cells through the stages of cell division. This discovery greatly interested many of the young scientists who attended Blackburn’s seminar.
“Yeast gives us very important insights to this day,” Blackburn said. “There is so much we still don’t understand.”
Tetrahymena thermophila image by Jacek Gaertig, University of Georgia, Athens.
Epel photo by Susan Merrell and Blackburn photos by Elisabeth Fall/fallfoto.com.