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[260].
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.
Chapter 14. Long Live the Queen
All my possessions for a moment of time.
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[261]. 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.
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.
However, a new queen and her clonal worker sisters are clearly incredibly different from each other, both in physical form and in activities. The queen can be twice the size of a worker bee. After the so-called nuptial flight, when she first leaves a colony and mates, the queen almost never leaves the hive again. She stays in the darkness of the interior, laying up to 2,000 eggs a day in the summer months. She has no sting barbs, no wax glands and no pollen baskets (not much point having a shopping bag if you never leave the house). Worker bees have a lifespan that can usually be measured in weeks, whereas queens live for years[262].
Conversely, workers can do many things that the queens can’t. Chief amongst these is collecting food, and then telling the rest of the colony its location. This information is communicated using the famous ‘waggle dance’. The queen lives in darkened luxury, but she never gets to boogie.
So, a honeybee colony contains thousands of individuals who are genetically identical, but a few of them are really different physically and behaviourally. This difference in outcome is all down to how the bee larvae are fed. The pattern of early feeding completely determines whether a larva will develop into a worker or into a queen.
For honeybees the DNA script is constant but the outcome is variable. The outcome is controlled by an early event (feeding pattern) which sets a phenotype that is maintained throughout the rest of life. This is a scenario that just shrieks epigenetics at us, and in the last few years scientists have started to unravel the molecular events that underpin this process.
The critical roll of the dice for honeybees happens after the third day of life, as a fairly immobile grub or larva. Until day three, all honeybee larvae are given the same food. This is a substance called royal jelly, which is produced by a specialised group of workers. These young workers are known as nurse bees and they secrete royal jelly from glands in their heads. Royal jelly is a highly nutritious food source. It is a concentrated mix of a lot of different components, including key amino acids, unusual fats, specific proteins, vitamins and other nutrients that haven’t been well-characterised yet.
Once the larvae are three days old, the nurse bees stop feeding royal jelly to most of them. Instead, most larvae are switched onto a diet of pollen and nectar. These are the larvae which will grow up to be worker bees.
But for reasons that nobody really understands, the nurse bees continue feeding royal jelly to a select few larvae. We don’t know how these larvae are chosen or why. Genetically they are identical to the ones that are switched onto the less sophisticated diet. But this small group of larvae that continue to be nourished with royal jelly grow up to be queens, and they’re fed this same substance throughout their lives. The royal jelly is essential for the production of mature ovaries in the queens. Worker females never develop proper ovaries, which is one of the reasons they are infertile. Royal jelly also prevents the queen from developing the organs that she won’t ever need, like those pollen baskets.
We understand some of the mechanisms behind this process. Bee larvae contain an organ that has some of the same functions as our liver. When a larva receives royal jelly continuously, this organ processes the complex food source and activates the insulin pathway. This is very similar to the hormonal pathway in mammals that controls the levels of sugar in the bloodstream. In honeybees activation of this pathway increases production of another hormone, called Juvenile Hormone. Juvenile Hormone in turn activates other pathways. Some of these stimulate growth and development of tissues like the maturing ovaries. Others shut down production of the organs that the queen doesn’t need[263].
Because honeybee maturation has so many hallmarks of an epigenetic phenomenon, researchers speculated that there would also be an involvement of the epigenetic machinery. The first indications that this is indeed the case came in 2006. This was the year when researchers sequenced the genome of this species, to identify the fundamental genetic blueprint[264]. Their research showed that the honeybee genome contained genes that looked very similar to the DNA methyltransferase genes of higher organisms such as vertebrates. The honeybee genome was also shown to contain a lot of CpG motifs. This is the two-nucleotide sequence that is usually the target for DNA methyltransferases.
260
http://www.fiercebiotech.com/story/weak-efficacy-renal-risks-force-gsk-dump-resveratrol-program/2010-12-01
262
For a useful review of the differences, see Chittka and Chittka (2010),