Junk DNA: A Journey Through the Dark Matter of the Genome (9 page)

One obvious question is why some tissues are more susceptible to short telomeres than others. This isn’t altogether clear, but some interesting models are emerging. It’s likely that tissues where there is a lot of proliferation will be susceptible to defects that lead to shorter telomeres. The classic example is the blood stem cell population, as described earlier in this chapter. If these cells have difficulties maintaining the length of their telomeres then eventually the stem cell population will run out.

That seems like a possible explanation for aplastic anaemia but it won’t work for pulmonary fibrosis. Lung tissue replicates quite slowly, yet pulmonary fibrosis is common in people with telomere defects. It’s possible that in lung cells the effects of shortened telomeres operate in tandem with other factors that affect the genome and cell function. These take time to develop, so lung symptoms typically develop later than ones that are caused by problems with the blood stem cells.

Our lungs are exposed to potentially damaging chemicals with every breath we take, so perhaps it’s not surprising that they struggle to tolerate the burden of defective telomeres. One of the most common sources of dangerous inhaled chemicals is tobacco. The global impact of smoking tobacco on human health is huge. The World Health Organization estimates that nearly 6 million people die every year as a consequence of smoking, over half a million of them from the effects of second-hand smoke.
²⁵

Researchers examined the effects of cigarette smoke experimentally. They genetically manipulated mice so that some of them had short telomeres and then exposed various mice to cigarette smoke.
²⁶
The results are shown in Figure 5.2. Essentially, the only mice that developed pulmonary fibrosis were those that had short telomeres and were exposed to cigarette smoke.

Figure 5.2
A genetic defect and an environmental challenge are required to produce pulmonary fibrosis in mice. Mice with shortened telomeres don’t develop fibrosis, and nor do mice exposed to cigarette smoke. But mice with the double insult of shortened telomeres and exposure to cigarette smoke do develop the condition.

Cigarette smoking is not the only factor that affects human health, of course, although not smoking is probably the single smartest thing you can do for yourself. But the major factor that affects human health in wealthy countries is age itself. This wasn’t always the case. But it has been true since we made giant medical, pharmacological, social and technological progress in combating what used to kill us early: all those old-fashioned things like infectious diseases, early childhood mortality and malnutrition.

Tick-tock goes the telomere

Getting old is now the major risk factor for development of chronic conditions. That’s a big problem when we realise that by 2025 there are likely to be over 1.2 billion people above the age of 60 worldwide.
²⁷
Cancer rates rise dramatically over the age of 40. If you live to 80, there’s an even chance you will develop some type of cancer. If you are over 65 and you’re an American, there’s about the same chance you will have cardiovascular disease.
²⁸
There’s plenty more statistics that paint a similarly bleak portrait, but why depress ourselves? Oh what the heck, one last one: the Royal College of Psychiatrists in the UK has stated that about 3 per cent of over-65s have clinical depression and one in six has symptoms of milder depression that are noticed by others.
²⁹

Yet we all know that two individuals of the same chronological age may be very different in their health. Steve Jobs, the co-founder of Apple, died from cancer at the age of 56. Fauja Singh ran his first marathon at the age of 89, and his last at the age of 101 (no, it wasn’t the same one). There’s a lot we don’t know about what controls longevity – it is almost always a combination of genetics, environment and sheer luck. But what we do know is that simply counting how many years someone has been alive only gives you a very partial picture.

We are starting to realise that telomeres may be quite a sophisticated molecular clock. The rate of telomere shortening can be influenced by environmental factors. This means we may be able to use them as markers not of simple chronology, but of healthy years. The data are rather preliminary and not always consistent. This is partly because measuring telomeres in a consistent way is challenging, as described earlier, and we usually measure them in cells that we can access easily. These are typically the white blood cells, and they may not always be the most relevant cell type to examine. But despite these caveats, some intriguing data are emerging.

Let’s go back to our old enemy, tobacco. One study analysed the length of telomeres in the white blood cells of over 1,000 women. They found that the telomeres were shorter in those who smoked, with an increased rate of loss of about 18 per cent for every year of smoking. They calculated that smoking 20 cigarettes a day for 40 years was equivalent to losing almost seven and a half years of telomere life.
³⁰

A 2003 study looking at mortality rates in the over-60s claimed that the people with the shortest telomeres had the highest mortality rates.
³¹
This was mainly driven by cardiovascular mortality and the findings have been supported by a later, larger study in a different elderly population.
³²
A study in a group of centenarians from the Ashkenazi Jewish community found that longer telomeres were associated with fewer symptoms of the diseases of ageing, and with better cognitive function than that found in people of a similar advanced age but with shorter telomeres.
³³

Sometimes we forget that it’s not just physical factors that affect health and longevity. Chronic psychological stress can be very harmful for an individual, with negative impacts on multiple systems including their cardiovascular health and their immune responses.
³⁴
Individuals who suffer chronic psychological stress tend to die younger than less stressed individuals. A study of women aged between 20 and 50 showed that those in the chronically stressed group had shorter telomeres than the unstressed women. This was calculated to equate to about ten years of life.
³⁵

In the great pantheon of global human health problems that are eminently avoidable but having terrible impact, obesity seems to be on a mission to duke it out with smoking. Turning again to the World Health Organization we learn that nearly 3 million adults die each year because of being obese or overweight. Nearly a quarter of the burden of heart disease is attributable to people being overweight or obese. For type 2 diabetes, the contribution of obesity is even worse (almost half of all cases are caused by being
overweight) and it’s also true for a significant proportion of cancers (between 7 and 41 per cent).
³⁶
The economic and social costs of this global epidemic are frightening.

Recent data have shown that there is significant interaction between the systems in our cells that try to regulate and respond to energy and metabolism fluctuations, and those that maintain genomic integrity, including telomere stability.
³⁷
It’s unsurprising, therefore, that scientists have analysed the lengths of telomeres in cells from obese individuals. The same paper that examined the effects of smoking on telomere length also looked at the effects of obesity. They found that the telomere shortening associated with obesity was even more pronounced than for smoking, equating to nearly nine years of life.
³⁸

If all this inspires you to keep your weight under control, choose how you do this rather carefully. According to the United Nations, the country with the highest percentage of people who are aged 100 or over is Japan.
³⁹
The traditional Japanese diet almost certainly plays a role in this, because Japanese people who have changed to a Western diet develop Western chronic diseases. The traditional diet is based on low protein intake and relatively high carbohydrate levels. Studies in rats also showed that a low-protein diet early in life was associated with increased lifespan, which in turn was associated with long telomeres.
⁴⁰

So if you’re thinking of adopting the high-protein and low-carb Atkins or Dukan diets, have a little word with your junk DNA first. I suspect your telomeres might say no.

Footnotes

^a
The gene is called Myc.

^b
Yes, I do like Star Trek. Occasionally.

^c
The gene was called
Gcn5
. It codes for a protein with a number of functions, one of which is to add a small molecular group called acetyl to the amino acid lysine in proteins.

^d
The technical terms for this cell suicide are programmed cell death, or apoptosis.

^e
The core enzyme is encoded by the TERT gene and the RNA template is encoded by the TR gene, also known as TERC.

^f
The technical name for this population is the haematopoietic stem cell (HSC).

^g
This gene is called Dyskeratosis congenita 1 (DKC1) or dyskerin.

6. Two is the Perfect Number

One cell becomes two; two become four; four become eight and, to quote from
The King and I
, ‘et cetera, et cetera, and so forth’
¹
until there are over 50 trillion cells in a human body. Every time a human cell divides, it has to pass on exactly the same genetic material to both daughter cells as it contains itself. In order to do this, the cell makes a perfect copy of its DNA. This results in a replicate of each chromosome. The two replicates stay attached to each other initially, but then are pulled apart to opposite ends of the cell. A basic schematic for this is shown in Figure 6.1.

Figure 6.1
A normal cell contains two copies of each chromosome, one inherited from each parent. Before a cell divides, each chromosome is copied to create a perfect duplicate. The copies are pulled apart when the cell divides. This creates two daughter cells, containing exactly the same chromosomes as the original cell. For simplicity, this figure shows just one pair of chromosomes, rather than the 23 pairs in a human cell. The different colours indicate different origins of the pair, one from each parent. The diagram only shows division of the nucleus, but this is also accompanied by division of the rest of the cell.

The only exception to this is when the germ cells in the ovaries or testes create eggs or sperm. Eggs or sperm only contain half the number of chromosomes that are found in all the other cells of the body. The result of this is that when an egg and a sperm fuse, the full chromosome number is restored in the single cell (the zygote) which will then divide to become two cells et cetera, et cetera and so forth.

This halving of the chromosome number is possible because all our chromosomes come in pairs. We inherit one of each pair from our mother and one from our father. Figure 6.2 shows how the chromosome number is halved when eggs or sperm are created.

If cell division goes wrong, either when new body cells are created or when the germ cells create eggs or sperm, the effects can be really serious, as we will see later in this chapter. Cell division is an exceptionally complex process, involving hundreds of different proteins working in a highly coordinated fashion. Given how complicated it is, and how vital it is that cell division happens smoothly and successfully, it might seem surprising that quite a lot of it is critically dependent on a long stretch of junk DNA.