The Epigenetics Revolution (41 page)
Read The Epigenetics Revolution Online
Authors: Nessa Carey
Tags: #Science/Life Sciences/Genetics and Genomics
SIRT6 is targeted to specific genes by forming a complex with a particular protein. Once it’s present at those genes, SIRT6 takes part in a feedback loop that keeps driving down expression of the gene, in a classic vicious cycle. When the
SIRT6
gene is knocked out, the levels of histone acetylation at these genes stays high because the feedback loop can’t be switched on. This drives up expression of these target genes in the SIRT6 knockout mice. The target genes are ones which promote auto-destruction, or the cell’s entry into a state of permanent stasis known as senescence. This effect explains why
SIRT6
knockdown is associated with premature ageing
14
. It’s because genes that accelerate processes associated with ageing are switched on too soon, or too vigorously, at a young age.
SIRT6
gene is knocked out, the levels of histone acetylation at these genes stays high because the feedback loop can’t be switched on. This drives up expression of these target genes in the SIRT6 knockout mice. The target genes are ones which promote auto-destruction, or the cell’s entry into a state of permanent stasis known as senescence. This effect explains why
SIRT6
knockdown is associated with premature ageing
14
. It’s because genes that accelerate processes associated with ageing are switched on too soon, or too vigorously, at a young age.
It’s a little like a crafty manufacturer installing an inbuilt obsolescence mechanism into a product. Normally, the mechanism doesn’t kick in for a certain number of years, because if the obsolescence activates too early, the manufacturer will get a reputation for prematurely shoddy goods and nobody will buy them at all. Knocking out
SIRT6
in cells is a little like a software glitch that activates the inbuilt obsolescence pathway after, say, one month instead of two years.
SIRT6
in cells is a little like a software glitch that activates the inbuilt obsolescence pathway after, say, one month instead of two years.
Other
SIRT6
target genes are associated with provoking inflammatory and immune responses. This is also relevant to ageing, because some conditions that become much more common as we age are a result of increased activation of these pathways. These include certain aspects of cardiovascular disease and chronic conditions such as rheumatoid arthritis.
SIRT6
target genes are associated with provoking inflammatory and immune responses. This is also relevant to ageing, because some conditions that become much more common as we age are a result of increased activation of these pathways. These include certain aspects of cardiovascular disease and chronic conditions such as rheumatoid arthritis.
There is a rare genetic disease called Werner’s syndrome. Patients with this disorder age faster and at an earlier age than healthy individuals. The condition is caused by mutations in a gene that is involved in the three-dimensional structure of DNA, keeping it in the correct conformation and wound up to the right degree of tightness for a specific cell type
15
. The normal protein binds to telomeres. It binds most effectively when the histones at the telomeres have lost the acetyl group at amino acid 9 on histone H3. This is the precise modification removed by the SIRT6 enzyme. This further strengthens the case for a role of SIRT6 in control of ageing
16
.
15
. The normal protein binds to telomeres. It binds most effectively when the histones at the telomeres have lost the acetyl group at amino acid 9 on histone H3. This is the precise modification removed by the SIRT6 enzyme. This further strengthens the case for a role of SIRT6 in control of ageing
16
.
Given that SIRT6 is a histone deacetylase, it might be interesting to test the effect of a histone deacetylase inhibitor on ageing. We would predict that it would have the same effects as knocking down expression of the SIRT6 enzyme, i.e. it would accelerate ageing. This might give us pause for thought when we plan to treat patients with histone deacetylase inhibitors such as SAHA. After all, an anti-cancer drug that makes you age faster isn’t that attractive an idea.
Fortunately, from the point of view of treating cancer patients, SIRT6 belongs to a special class of histone deacetylase enzymes called sirtuins. Unlike the enzymes we met in
Chapter 11
, the sirtuins aren’t affected by SAHA or any of the other histone deacetylase inhibitor drugs.
Chapter 11
, the sirtuins aren’t affected by SAHA or any of the other histone deacetylase inhibitor drugs.
Eat less, live longer
All of this begs the question of whether we are any closer to finding a pill we can offer to people to increase longevity. The data so far don’t seem promising, especially if it’s true that many of the mechanisms that underlie ageing are defences against developing cancer. There’s not a lot of point creating therapies that could allow us to live for another 50 years, if they also lead to tumours that could kill us in five. But there is one way of increasing lifespan that has proven astonishingly effective, from yeast to fruit flies, from worms to mammals. This is calorie restriction.
If you only give rodents about 60 per cent of the calories they would eat if given free access to food, there is a dramatic impact on longevity and development of age-related diseases
17
. The restricted calorie intake must start early in life and be continued throughout life to see this effect. In yeast, decreasing the amount of glucose (fuel) in the culture from 2 per cent to 0.5 per cent extended the lifespan by around 30 per cent
18
.
17
. The restricted calorie intake must start early in life and be continued throughout life to see this effect. In yeast, decreasing the amount of glucose (fuel) in the culture from 2 per cent to 0.5 per cent extended the lifespan by around 30 per cent
18
.
There’s been a lot of debate on whether or not this calorie-restriction effect is mediated via sirtuins, such as Sir2 in yeast, or the versions of Sir2 in other animals. Sir2 is regulated in part by a key chemical, whose levels are affected by the amount of nutrition available to cells. That’s the reason why some authors have suggested that the two might be connected, and it’s an attractive hypothesis. There’s no debate that Sir2 is definitely important for longevity. Calorie restriction is also clearly very important. The question is whether the two work together or separately. There’s no consensus as yet on this, and the experimental findings are very influenced by the model system used. This can come down to details that at first glance might almost seem trivial, such as which strain of brewer’s yeast is used, or exactly how much glucose is in the culture liquid.
The question of how calorie restriction works might seem much less important than the fact that it does. But the mechanism matters enormously if we’re looking for an anti-ageing strategy, because calorie restriction has severe limitations for humans. Food has enormous social and cultural aspects, it’s rarely just fuel for us. In addition to these psychological and sociological issues, calorie restriction has side effects. The most obvious ones are muscle wasting and loss of libido. It’s not much of a surprise that when offered the chances of living longer, but with these side-effects, the majority of people find the prospect unattractive
19
.
19
.
That’s one of the reasons that a 2006 paper in
Nature
, led by David Sinclair at Harvard Medical School, created such a furore. The scientists studied the effects of a compound called resveratrol on health and survival in mice. Resveratrol is a complex compound synthesised by plants, including grapes. It is a constituent of red wine. At the time of the paper, resveratrol had already been shown to extend lifespan in yeast,
C. elegans
and fruit flies
20
,
21
.
Nature
, led by David Sinclair at Harvard Medical School, created such a furore. The scientists studied the effects of a compound called resveratrol on health and survival in mice. Resveratrol is a complex compound synthesised by plants, including grapes. It is a constituent of red wine. At the time of the paper, resveratrol had already been shown to extend lifespan in yeast,
C. elegans
and fruit flies
20
,
21
.
Professor Sinclair and his colleagues raised mice on very high calorie diets, and treated the mice with resveratrol for six months. At the end of this six-month period, they examined all sorts of health outcomes in the mice. All the mice which had been on the high calorie diets were fat, regardless of whether or not they had been treated with resveratrol. But the mice treated with resveratrol were healthier than the untreated fat mice. Their livers were less fatty, their motor skills were better, they had fewer diabetes symptoms. By the age of 114 weeks, the resveratrol-treated mice had a 31 per cent lower death rate than the untreated animals fed the same diet
22
.
22
.
We can see immediately why this paper garnered so much attention. If the same effects could be achieved in humans, resveratrol would be a get-out-of-obesity-free card. Eat as much as you like, get as fat as you want and yet still have a long and healthy life. No leaving behind one-third of every meal and losing your muscles and your libido.
How was resveratrol doing this? A previous paper from the same group showed that resveratrol activated a sirtuin protein, in this case Sirt1
23
. Sirt1 is believed to be important for the control of sugar and fat metabolism.
23
. Sirt1 is believed to be important for the control of sugar and fat metabolism.
Professor Sinclair set up a company called Sirtris Pharmaceuticals, which continued to make new compounds based around the structure of resveratrol. In 2008 GlaxoSmithKline paid $720 million for Sirtris Pharmaceuticals to gain access to its expertise and portfolio of compounds for treating diseases of ageing.
This deal was considered expensive by many industry observers, and it hasn’t been without its problems. In 2009, a group from rival pharmaceutical company Amgen published a paper. They claimed that resveratrol did not activate Sirt1, and that the original findings represented an artefact caused by technical problems
24
. Shortly afterwards, scientists from Pfizer, another pharmaceutical giant, published very similar findings to Amgen
25
.
24
. Shortly afterwards, scientists from Pfizer, another pharmaceutical giant, published very similar findings to Amgen
25
.
It’s actually very unusual for large pharmaceutical companies to publish work that simply contradicts another company’s findings. There’s nothing much to be gained by doing so. Pharmaceutical companies are ultimately judged by the drugs they manage to launch successfully, and criticising a competitor in the early stages of a drug discovery programme gives them no commercial advantage. The fact that both Amgen and Pfizer went public with their findings is a demonstration of how controversial the resveratrol story had become.
Does it matter how resveratrol works? Isn’t the most important feature the fact that it has such dramatic effects? If you are trying to develop new drugs to treat human conditions, it unfortunately matters quite a lot. The authorities who license new drugs are much keener on compounds when they know how they work. This is partly because this makes it much easier to monitor for side-effects, as you can develop better theories about what to look out for. But the other issue is that resveratrol itself probably isn’t the ideal compound to use as a drug.
This is often an issue with natural products such as resveratrol, which was isolated from plants. The natural compounds may need to be altered to a greater or lesser extent, so that they circulate well in the body, and don’t have unwanted side effects. For example, artemisinin is a chemical derived from wormwood which can kill malarial parasites. Artemisinin itself isn’t taken up well by the human body so researchers developed compounds that were variants of the chemical structure of the original natural product. These variants kill malarial parasites, but are also much better than artemisinin at getting taken up by our bodies
26
.
26
.
But if we don’t know exactly how a particular compound is working, it’s very hard to design and test new ones, because we don’t know how to easily check if the new compounds are still affecting the right protein.
GlaxoSmithKline is standing by its sirtuin programmes, but in a worrying development for the company they have stopped a clinical trial of a special formulation of resveratrol in a disease called multiple myeloma, because of problems with kidney toxicity
27
.
27
.
The progress of sirtuin histone deacetylase activators is of keen interest to all the big players in the pharmaceutical industry. We don’t know yet if these epigenetic modifiers will set the agenda, or sound the death knell, for development of therapies specifically aimed at increasing longevity or combatting old age. So, for now, we’re still stuck with our old routine: lots of vegetables, plenty of exercise and try to avoid harsh overhead lighting – it does nobody any favours.
All my possessions for a moment of time.
Attributed to Queen Elizabeth I
The effects of nutrition on the health and lifespan of mammals are pretty dramatic. As we saw in the previous chapter, prolonged calorie restriction can extend lifespan by as much as one-third in mice
1
. We also saw in
Chapter 6
that our own health and longevity can be affected by the ways our parents and grandparents ate. These are quite startling findings but nature has provided us with a much more dramatic example of the impact of nutrition on lifespan. Imagine, if you can, a dietary regime that means a select few in a species have a lifespan that is twenty times longer than that of most of their companions. Twenty times longer. If that happened in humans, the UK might still be in the reign of Queen Elizabeth I, and would expect to be so for about another 400 years.
1
. We also saw in
Chapter 6
that our own health and longevity can be affected by the ways our parents and grandparents ate. These are quite startling findings but nature has provided us with a much more dramatic example of the impact of nutrition on lifespan. Imagine, if you can, a dietary regime that means a select few in a species have a lifespan that is twenty times longer than that of most of their companions. Twenty times longer. If that happened in humans, the UK might still be in the reign of Queen Elizabeth I, and would expect to be so for about another 400 years.
Obviously this doesn’t happen in humans, but it does happen in one common organism. It’s a creature that we all meet every spring and summer. We use the results of its labour to make candles and furniture polish, and we have eaten its hard-earned bounty since the very beginning of human history. It’s the honeybee.
The honeybee,
Apis mellifera
, is a truly extraordinary creature. It is a prime example of a social insect. It lives in colonies that can contain tens of thousands of individuals. The vast majority of these are workers. These are sterile females, which have a range of specialised roles including gathering pollen, building living quarters and looking after the young. There are a small number of males, who do very little except mate, if they are lucky. And there is a queen.
Apis mellifera
, is a truly extraordinary creature. It is a prime example of a social insect. It lives in colonies that can contain tens of thousands of individuals. The vast majority of these are workers. These are sterile females, which have a range of specialised roles including gathering pollen, building living quarters and looking after the young. There are a small number of males, who do very little except mate, if they are lucky. And there is a queen.
In the formation of a new colony, a virgin queen leaves a hive, accompanied by a swarm of workers. She’ll mate with some males and then settle down to form a new colony. The queen will lay thousands of eggs, most of which will hatch and develop into more workers. A few eggs will hatch and develop into new queens, who can start the whole cycle all over again.
Because the queen who founded the colony mated several times, not all the bees in the colony will be genetically identical to each other, because some of them will have different fathers. But there will be groups of thousands and thousands of genetically identical bees in any colony. This genetic identity doesn’t refer only to the worker bees. The new queens are genetically identical to thousands of worker bees in the colony. We could call them sisters, but this doesn’t really describe them well enough. They are all clones.
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