Many scientists believe that we have reached the end of the life-expectancy revolution we have witnessed over the last 150 years [1]. It is now proposed that we should now focus on managing the disease and frailty that haunt our sunset years. Others, though, think that we can start the lifespan modification revolution all over again once we have a better knowledge of the biological processes that cause cells to age.
In this short series, we look at what's new in the study of ageing. We also mark the end of the clinical phase of the MID-Frail study [2], which is looking at ways to change diseases that happen in old age, and the start of the Frailomic initiative [3], which is looking into genetic markers for the development of frailty. Niche Science & Technology Ltd. oversees both projects and gets funds from the European FP7 Framework worth many millions of euros.
You only need to look at the ends of your chromosomes to see how your cells change. At the ends of our chromosomes are special structures called telomeres. These are made up of stretches of DNA and proteins. Chromosomes are copied when a cell splits, and each daughter cell gets an exact pair. That said, our cells have trouble copying DNA. DNA polymerases are the enzymes that control the process. One strand of DNA in the chromosome can be copied quickly, but copying the other strand is much harder. Since the two strands of the double helix run in different directions, the polymerases can easily make a continuous strand of DNA going in one direction but have a harder time with it going in the other. To keep itself from getting tangled up, short pieces are made moving forward. Other enzymes then join these pieces together. Near the ends of our chromosomes, the very last part of the opposite strand, also known as the "lagging" strand, can't be copied. This is known to scientists as the "end replication problem." What this means is that the telomere DNA stretch gets shorter with each round of cell division.
One strand of DNA is a little longer than the other because telomeres are getting shorter. This is good because it lets the free DNA strand curl and tuck into the double-stranded DNA, making a loop that protects the DNA. The cell becomes senescent when the length of its telomeres hits a certain point. This means that it can no longer divide and will eventually die.
Because of the relationship of cell viability and telomere length, it has been proposed that length can be used to indicate an individual's ‘biological age’ (which can be very different from their chronological age). As part of the FP7-funded Frailomic initiative the company Life Length is looking at how telomere length relates to frailty, one of the major markers of biological age, in the elderly [4]. In our recent series on ageing we published a video describing the work done and the science behind Life Length [5]. We know that many factors – including physical exercise, sleep, depression, and certain gene mutations - are associated with reduced telomere length, and, by extension, can lead to premature biological aging. Telomeres are believed to keep a close eye on the damage that accumulates in our cells and signal when it is time for them to retire.
Whether telomere length is an indicator of biological aging or a cause of it remains to be confirmed but limiting the factors that are negatively associated with telomere length is likely to contribute to a more youthful biological age. This forms the core of the hypothesis proposed by molecular biologist Elizabeth Blackburn, who shared a Nobel Prize for her research on telomeres. Promoted in the recent book “The Telomere Effect,” is the idea that you have more control over your own aging than you may imagine. You can actually lengthen your telomeres — and perhaps your life — by following sound health advice, the authors argue, based on a review of thousands of studies.
The Centres for Disease Control and Prevention (CDC) studied the telomeres of almost 6,000 people who took part in a survey that lasted several years [6]. People were asked what kinds of physical tasks they had done in the last month and how hard they were. They also gave DNA samples that were used to test the length of telomeres. Researchers found that people who moved the most had telomeres that were much longer than people who didn't exercise at all, even when smoking, obesity, alcohol use, gender, race, and other factors were considered. People who didn't move around as much had 140 fewer base pairs of DNA at the ends of their telomeres than people who did. This is thought to be a difference of about 9 years in cellular ageing. Subjects were rated on how much exercise they said they did [7]. To be considered top-level exercisers, people had to jog for at least 30–40 minutes five days a week. A lesser amount of work was also linked to benefits for getting older, but they were not as strong. The study only found an association, not a cause-and-effect link, between the amount of exercise and telomere length. This is because the participants stated how active they were.
One problem with studying telomeres is that most of the time, researchers look at how long telomeres are in blood cells. But our bodies don't all age at the same rate [8]. Your liver may be ageing faster or slower than your blood. Also, the physically "oldest" parts of you are most likely to cause problems first. Also, measuring telomere length in the blood is thought to show the biological age and, by extension, the ability of immune stem cells to work well, rather than the age of cells in your liver, for example.
It is not clear whether the methods are quantitative enough or provide sufficient resolution to predict your biological age from the length of your telomeres. However, its value as a biomarker of health outcomes will be better qualified when the results of the Frailomic initiative are reported. In the words of Dr Stephen Matlin, CEO of Life Length, “Being able to adopt lifestyle and therapeutic interventions that slow our ageing seems very viable but for that we need to be able measure the effects. For that, telomere length is a diagnostic test that gives us insight to our rate of ageing.” While there’s no guarantee that people with longer telomeres will live longer, healthier lives, the indications are certainly in favour of adopting a healthy lifestyle if you want to live longer. It seems reasonable to assume that although you can consider yourself to have entered old age at around 60 years, without predictive tools you won't know whether you have (on average) 10 to 15 years of ‘useful contribution to’ or whether you may be a ‘burden on’ society.
References
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