Prolonging our healthspan

(2012-12-29 05:45:36) 下一個
Published December 29, 2012

Studies suggest that personal choices, more than genes, are at play behind ageing and disease, says microbiologist and Nobel Laureate Elizabeth Blackburn. By Anna Teo


I don't think extending the lifespan beyond what's genetically determined, to me, that's not the point. The point is "healthspan" - it's a great term, healthspan instead of lifespan. So you want the healthspan to be as close to the lifespan as possible and so then, the question is - how do you achieve that?

ELIZABETH Blackburn has spent a lifetime peering down microscopes, deciphering the mysteries of the living cell. But listening to her wax lyrical about the potential in biomedical research today, there's nary a trace of any "been there, done that" nonchalance about it all. Nor any airs one might expect of a superstar scientist with a string of major awards to her name, including the 2009 Nobel Prize in Physiology or Medicine.

The amiable 64-year-old microbiologist is known for her pioneering work on telomeres - the protective caps at the ends of chromosomes in cells. She also created a stir in the scientific community with her discovery in late 1984, jointly with her graduate student Carol Greider, of the enzyme telomerase that regulates telomere activity. It was a breakthrough that sparked speculation that a cure for cancer, or even a means to reverse ageing, could be around the corner - and which ultimately earned both women the 2009 Nobel accolade.

Australian-born Professor Blackburn continues to explore telomeres and telomerase activity today as a professor in biology and physiology at the University of California, San Francisco, fascinated as ever about what the findings could portend in therapeutics, not least in the quest for a longer quality of life. The research is increasingly done collaboratively with psychologists and doctors these days, she tells BT during a recent trip here, describing the work as "great fun" and, at one point, invoking the Gangnam Style horse trot while discussing the effects of exercise on the length of telomeres.

Think of telomeres like the plastic tips of shoelaces that keep the laces from fraying, says Prof Blackburn, who was in town early November to deliver keynote speeches at two events at the National University of Singapore - a cancer conference and a Women in Science & Medicine symposium.

The DNA strands at the ends that prevent the chromosome from disintegrating during cell reproduction are rough and ready indicators of how long one will live. Generally, telomeres wear down as a person ages - older and diseased cells have shorter telomeres while younger and healthier cells maintain long telomeres.

"There's a gradual nature to the shortening, and it may not just be all down; sometimes, we know, telomere lengths can go back up too, in normal cells," says Prof Blackburn, who uncovered the molecular structure of telomeres during postdoctoral work on pond organisms at Yale University in 1976.

But yes, the shrinking of telomeres is "a precursor of what can become cell disorder", she says, such as when abnormal cells grow out of control, turning cancerous. "When they (telomeres) are on the way down, it's ok, but when they get too short then there are problems. But if you can catch them on their way down, that's good." Cancer, after all, "is not an event, it's a process that takes years", she points out.

"The good news is - we're seeing that there are things that will alleviate telomere shortening, things that people can actually do."

Telomerase, the mysterious regulating enzyme, restores the length of telomeres when they get worn down. But genes play "only a small part" in determining how one's telomeres shorten or lengthen over time.

"The genetic contribution to the variation, as we go more and more into adulthood and middle age, gets less and less. More and more, non-genetic effects, external factors, are in play. So that's what I'm really interested in because that's the next challenge in biomedical science - to understand those effects, in conjunction with the genetic effects."

Studies are under way, in her lab at UCSF and by other researchers elsewhere, on the link between telomere length and various behavioural and lifestyle factors such as exercise, stress, diet, smoking and alcohol consumption, even body mass index, marital status and level of education - and how these all play on ageing and disease risks.

"So we're very interested in quantifying the effects. Take exercise," says Prof Blackburn. "Several studies indicate that the more people exercise, the more you'll see quantitatively longer telomeres in these people. So the question is - does exercise alleviate the shortening and, in fact, cause them to lengthen?

"Actually, I was just in Korea, so I discovered, of course, the answer to exercise! I was in Seoul giving lectures to medical students, researchers, talking about things related to telomere-shortening that one can quantify, when it occurred to me - here I am at the home of Gangnam Style, right, which has swept the world and nobody quite understands why. People were just so happy doing it. It's exercise, right, and it's also sociable! I love zumba but it's too tiring. Gangnam's really easy, I'll show you!" And she gets off the chair and performs a little Gangnam gig.

So far, observational data abound, she says, citing studies featuring, for example, adult twins in Britain : One twin exercises, and the other who doesn't is found to have shorter telomeres.

"We have other studies where we've looked at a group of very healthy women in San Francisco area, middle-aged women, and we looked at stress-related aspects in their lives and noted that there was some relationship with telomere shortness again. And then, of these people, what about those who do or don't exercise, and you could see that the effect of stress relationship to telomere shortness was much weaker in those who also exercise. So those kinds of things are strongly suggestive. We take that as observational evidence, we're doing trials. Anyway, we all know that exercise is a good idea, people hate it, so Gangnam Style, everybody likes!" she says, laughing.

Short telomeres have also emerged as a risk factor for, apart from cancer, various chronic ailments such as cardiovascular disease, diabetes and dementia.

"So I think this telomere shortness is underlying a lot of this. I don't want to say it's the only, no, no. I'm just saying it's a feature, a thread running through amid all these other things that are going on. And as we think about these disease processes, we should keep this always in mind, and try and work out what is the relative contribution that's there. The question is how big the effect is."

She adds: "In the meantime, we should look at what we can do to start reducing these world trends, because the worldwide projection of cancers as the demographies get older and older, is huge. It's like a tsunami, it's just going to hit us as worldwide societies."

Various small pilots involving lifestyle changes such as stress reduction and nutritional supplementation have yielded encouraging results, she notes.

"Just recently, we had a placebo-controlled randomised prospective study where people were given omega-3 fatty acid supplements, which have a very good history epidemiologically in cardiovascular disease. After four months, their telomeres were longer."

But what's key, in fact, is the ratio of omega-6 (found in vegetable oils, salad dressings, fried food) to omega-3 fatty acids (in fish) in a person's blood, she adds. Not that people need rush to down omega-3 capsules; "no, you just need to eat fish a few times a week, that's sufficient", she says.

Even before her Nobel recognition, the acclaimed scientist was the subject of a 2007 biography Elizabeth Blackburn and the Story of Telomeres. "Fascinated by small living creatures, she loved to hold them and even sang to them," author Catherine Brady wrote of the shy science geek who grew up in Tasmania in a family of doctors. Her lifelong passion for nature, voracious curiosity, imaginative speculation and, not least, brilliance and perseverance in pursuing discovery in the laboratory were to fuel her career. The story also detailed the hurdles she had to traverse in a male-dominant field - including fighting turf wars while a UCSF department chair and nationally as a member of the US President's Council on Bioethics.

Prof Blackburn, who became an American citizen in late 2003, drew attention when she was abruptly dropped from the council in early 2004 after two years, as a result of her objecting to a ban on embryonic stem cell research and therapeutic cloning, and protesting the suppression of relevant scientific evidence in the council's final report. Her dismissal sparked criticism of how the Bush Administration handled science - Prof Blackburn and another council member were replaced with three appointees who, like President George W Bush and most of the 18-member panel, were opposed to using stem cells. She herself received a deluge of support from reseachers and others across America and beyond, mostly outraged that the quest for scientific truth was being manipulated for political ends. "People don't like the idea that science policy is not being based on evidence," she told a journal at that time. "Where I sort of fell afoul was that as the (bioethics council) reports were being written, I was going, 'Wait, they're not right, they're not putting the facts in!', and I just kept on nagging, kept saying no, no, no, if I'm signing my name to a report by the council, you have to get this right!" she tells BT.

"The principle that I really thought was important was - you really need to make policy based on trying to understand something (rather than outright) banning it. I thought it very important to at least lay out what was known and what wasn't known about the various stem cell types and do research on them."

In fact, "years of rigorous and careful research in animal models have documented that embryonic stem cells have great utility for scientific studies", she and a fellow council member wrote dispassionately in a March 2004 essay, Reason as Our Guide, voicing their "deep concern" about several areas in two of the council's reports, including sensational claims about the goals of "age-retardation" research.

Asked about the views on therapeutic cloning in America today, Prof Blackburn says it has become less of a public discussion. "There are regulations in place and the work is proceeding in sort of the less glamorous, research-heavy phase. Now is the long and hard work in the lab to try and understand what's going on.

"I mean, obviously I don't think you should try and clone humans because I think that would be irresponsibly dangerous." As for the spectre of designer babies, "that's so far away from reality, it's (just) a good mental exercise to go through but a lot of mental exercises tend to take extreme situations, they're not neccessarily going to relate to the realities of what we do", she says. The idea of selecting embryos for intelligence and other traits is "scientifically, simply highly unlikely and indeed may not even be feasible", she had said in the 2004 essay.

For all the research into slowing the ageing process, "eventually we're pretty much biologically programmed", she says. "We're not going to live beyond 110, 120, it seems pretty clear. So I think, ideally, you want to get to that stage as healthily as possible. I don't think extending the lifespan beyond what's genetically determined, to me, that's not the point. The point is 'healthspan' - it's a great term, healthspan instead of lifespan. So you want the healthspan to be as close to the lifespan as possible and so then, the question is - how do you achieve that?"

In any case, the hope is that biomedical research will be therapeutically useful, she says. "And the true answer is one doesn't know how and to what extent that will be the case. There's no way you can find that out unless you do basic research to find out. Just like in cancer - we know such alot about cancer, and yet there's still such difficulty in successfully treating all cancers. There's no single pathway, that's the thing; human cells are really complicated."

How has life changed post-Nobel Prize? "Well, it changed and it didn't change," she says, a little wryly.

The lab research goes on, and "you're still competing for NIH (National Institutes of Health) grants, it's very real life still", she quips. "On the other hand, more and more people do want me to talk and so on." Previously, when she received an invitation to speak, she'd go, "They want me? Oooh!", she says. Now, she knows her Nobel tag is a draw, she says, and for her part, she tries to "do something useful with that". Like show up for events on women in science, an issue close to her heart.

At the talk in Singapore, she shared her own experiences, including the key role of mentoring in her early years as a scientist. In turn, she herself has trained "many" others - notably, more than half of the top scientists in the telomere field are women, even as the upper rungs of scientific research remain a male bastion.

Not least, "I've lived my life as both a scientist and a mother", she told her audience of researchers and undergraduates at NUS. Her 26-year-old son is the third scientist in the family - not a cell biologist or biochemist like his parents but a computer scientist.

Women have "decades of very productive life ahead of them" after the children grow up, she tells BT. "I was extremely busy and I worked very hard for 18 years while he was growing up, doing family and science." Now she gets to travel with her husband, "go around the world attending conferences, go to movies, go to art galleries", she quips. "My life is different, and it was different then, so you balance things over decades. Not every week may be in balance but over decades, it all balances out."


Professor in Biology and Physiology

University of California, San Francisco

2009 Nobel Laureate (Physiology or Medicine)

1948 Born in Hobart, Australia

1970 BSc Univ of Melbourne

1972 MSc Univ of Melbourne

1975 PhD Univ of Cambridge

1975-1977 Postdoctoral work in molecular and cellular biology, Yale Univ

1978-1989 Faculty member, UC Berkeley's Dept of Molecular Biology

1990 to date Faculty member, UCSF's Dept of Microbiology and Immunology

1993-1999 Chair, UCSF's Dept of Microbiology and Immunology

Currently Faculty member, UCSF's Dept of Biochemistry and Biophysics

Non-Resident Fellow, Salk Institute


2006 Albert Lasker Medical Research Award in Basic Medical Research

2007 Named one of TIME Magazine's 100 Most Influential People

2008 North American Laureate for L'Oreal-UNESCO For Women in Science

2009 Nobel Prize for Physiology or Medicine (jointly with Carol Greider, Jack Szostak)

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