a guest blog by Jorge I. Castillo-Quan, written for the 2015 Write About Research Competition.

If you had not heard of the term anti-ageing you have not noticed spam emails, television advertising, and articles in magazines. The term anti-ageing has definitely permeated our society. Most scientists struggle to explain to their non-scientist friends what their research is about. When I tell my friends I study ageing and anti-ageing interventions, almost everyone has an idea of what that means. Or at least they think they do. Some people think I am developing the latest generation of creams that will make wrinkles disappear, or that I am finding remedies to prevent greying hair, or the solution that will avoid balding, or even make stretch marks go away. Those with more imagination, think I am trying to defeat death and make people immortal. However, none of these ideas are in any way close to what I do. I explain to them that I do my research on ageing using the fruit fly Drosophila melanogaster. Yes, I work with those little flies that lurk around your kitchen. If you are now thinking why on Earth are you studying fly ageing, I do not blame you. I thought this once too. The first thing you should know is that I am not interested in making immortal flies (though that could be cool!), nor is my aim to understand how flies age per se. The simplest explanation is that studying ageing in an organism that is less complex than humans is more convenient and faster. After all we share 60% of our DNA with the fly. Although we look very different more than half of our genes have a counterpart in the fly. Similar things can be said about the roundworm Caenorhabditis elegans which shares 40% of our DNA. But why use these organisms that seem so unrelated to us? They have shorter lifespans and show traits of ageing. For example, as worms and flies age, they lose their ability to move properly. Is true that we do not wiggle around like worms, or fly and climb as much as flies do, but these rather specific behaviours are controlled in similar ways by locomotor programmes, some of which are similar between species. Hence, we can use these as readouts of how quickly a worm or fly is ageing. Furthermore, worms in laboratories only live about 2-3 weeks, while flies about 3 months. If you were to compare these lifespans with that of the more traditional laboratory organism, the mouse, you will find that you would be able to complete over 10 survival experiments in flies while only completing one survival experiment using mice, that live around 3 years. Each organism has its advantages. Worms are transparent so you can look and examine how every organ is changing over time. But while they do have a semi-organised neuronal system, they do not have a proper brain. Flies do, and research studying the development and organisation of the fly brain has advanced our understanding of the human brain so much so that it has been awarded several Nobel prizes in Physiology or Medicine.

Having established that flies are simpler than mammals like us and mice, and that they are relatively short-lived, the question remains, how am I developing the latest generation of anti-ageing creams using Drosophila? I have to be honest here and say that I am not working on this. Although the term anti-ageing is more commonly associated with these kind of interventions this is not the aim of my research. I study ageing to try to understand its biological principles and what drives it. I am sure that you thought that this is exactly what the multi-million anti-ageing industry is doing, but no. Although some (very little) of what is going on in the big wide world is labelled as scientifically proven, it is not. Or not at the standard that is required for prescription pills and creams you get from your GP or other health professionals. The anti-ageing industry as we know it is not regulated and is merely cosmetic. When biogerontologists (biologist studying ageing) talk about anti-ageing, we talk about physiology (function), health and disease. I try to study ageing to improve health during old age. Ageing is the major risk factor for many of the killer diseases of our time, like diabetes, cardiovascular disease and cancer. Understanding what makes aged bodies vulnerable to threat of these diseases should be a major concern of our generation. As our societies are growing older it is expected that our health systems will be overwhelmed with treatments for patients suffering from these chronic conditions. No hospital running on public funds will see you for wrinkles or stretch marks when you are 65, but they certainly have to see you for a growing lump, forgetfulness, urinary problems and other serious health issues.

Using model organisms like flies and worms we have been able to establish that specific genes have the ability to enhance longevity and health when appropriately manipulated. For example, the first genetic manipulations that showed that an organism could live healthier for longer came from research using worms. Later it was shown that the same interventions in flies and mice had similar effects and these organisms also lived healthier for longer. Nowadays, we have a more comprehensive understanding of what genes need to be manipulated to delay deterioration with age and, in some cases, even prevent the onset of diseases. Of course all of this is in worms, flies and mice. To jump to humans, interventions need to be less of the genetic kind and more on the drug side. With our current knowledge of ageing we are now trying to find ways to manipulate the function of genes with drugs. The good news is that it seems that this is possible. We do not need to manipulate the genes of an organism to delay the ageing process; this can be achieved by supplementation with specific compounds at specific doses, and in some cases at specific time of life. However, for humans to be able to take these anti-ageing interventions they need to be appropriately tested and regulated by agencies in charge of ensuring their safety for human consumption. We must continue to wait patiently…

For far too long we have considered growing older as two extremes, either as a burden to society, or as the great achievement of our generation. After all living to a 100 was quite rare 100 years ago. We should celebrate our older population and the best way is by enhancing their health and allowing them to live a fulfilling life, not one of deterioration and despair.

Next time you see an anti-ageing cream, think about this: would I rather have beauty or health? If the latter is your choice, just wait a little bit longer, we are working on it.

References

• Juengst ET, Binstock RH, Mehlman M, Post SG, Whitehouse P. Biogerontology, “anti-aging medicine,” and the challenges of human enhancement. Hastings Cent Rep. 2003 Jul-Aug;33(4):21-30
• Partridge L. The new biology of ageing. Philos Trans R Soc Lond B Biol Sci. 2010 Jan 12;365(1537):147-54
• Rose MR.Can human aging be postponed? Sci Am. 1999 Dec;281(6):106-11
• Stipp D. A new path to longevity. Sci Am. 2012 Jan;306(1):32-9

Jorge graduated with a Medical degree from the Autonomous University of Yucatan, Mexico. After this he completed an MSc in Clinical Neuroscience at the UCL Institute of Neurology, and a PhD in Genetics, Neuroscience and Biogerontology from the UCL Institute of Healthy Ageing (IHA). Currently he works as a Research Associate at the UCL IHA and Research Department of Genetics, Evolution and Environment.

Watch Jorge’s TEDx talk elaborating on the topic:

“Anti-Ageing: Beauty or Health?”

Males and females look different from each other, and these sexual dimorphisms are the result, largely, of sex differences in the expression of certain genes. Typically, scientists have studied sexual dimorphism in sexually mature adult animals, as this is the lifestage where differences are most apparent. However, many sex-specific phenotypes arise from sex-biased development, so sex-biased gene expression should be expected to begin during development. Recent research from GEE reveals complex patterns of sex- and stage-dependent gene expression, resulting from differing evolutionary pressures on difference sexes. In fact, sex-biased gene expression is actually most evident during early development.

Although there are some genetic differences between males and females, found on the sex chromosomes (Y in mammals, W in Birds), these contribute relatively little to the physical and behavioural differences between the sexes. Further, some animals (such as many reptiles) don’t possess a sex chromosome at all, instead determining sex based on environmental factors such as temperature. Scientists therefore believe that the majority of sexually dimorphic characteristics are generated from differences in the expression patterns of a shared set of genes, and there is now plenty of evidence for this in a variety of different species. In fact, sexual phenotypes appear to exist along a continuum, with some individuals in certain species exhibiting intermediate traits (e.g. subordinate male Turkeys).

In most species, sex differences are less apparent during development and appear or become more pronounced at the onset of sexual maturity. This makes sense, since that’s generally when the sex-specific traits are useful. Nevertheless, the groundwork for producing these traits in adulthood must be laid during development, so we might expect to see sex-biased gene expression in juveniles as well. A recent paper by GEE academics Professor Judith Mank and Dr Peter Harrison, and Dr Jennifer Perry (University of Oxford) investigated gene expression patterns during larval development in the fruit fly, Drosophila melanogaster.

Juveniles Show Sex-Biased Gene Expression

The authors compared gene expression patterns in pre-gonad tissue in larvae and pre-pupae with gonad tissue in adult flies. Using transcriptome sequencing, which sequences all expressed genes, they were able to detect differences in gene expression between sexes at different developmental stages. By using a single tissue, the authors hoped to gain a clearer picture of gene expression in relation to sex and development, as tissue-specific gene expression can cloud the picture. Gonad and pre-gonad tissue was the obvious candidate, since this tissue forms sperm and eggs and is therefore likely to be under strong selection for sex-biased gene expression.

Despite the long-running assumption that sex-biased gene expression should not be prevalent in juveniles, the results of this study indicated that most genes show sex-bias in at least one pre-adult stage! Over 50% of genes showed at least 2-fold differences in gene expression between the sexes during larval or pre-pupae developmental stages. Sex was still the most important factor, however, with individuals within a sex showing greater similarity in gene expression patterns than individuals within a developmental stage.

Continuity and Sex Differences

The majority of sex-biased genes showed expression patterns that remained consistent throughout development, however a significant minority (~25%) of genes showed varying sex-bias according to developmental stage. For example, a gene that showed lower expression in females during the larval stage might then show higher expression in females during adulthood.

In the majority of previous studies have found that more genes show male-bias in adults. By contrast, this study showed that in larval and pre-pupal stages of development in Drosophila melanogaster, more genes show female-biased gene expression. Females were also more likely to show stage-dependent sex-biases in gene expression. The exception to this was genes showing very extreme sex-bias, which tended to be male-biased. This is consistent with the finding that the overall magnitude of gene expression differences tended to be higher in male-biased genes.

The Rate and Form of Evolution

The authors then investigated the evolutionary dynamics that lead to these patterns of gene expression. Genes showing the most rapid recent evolution were those that showed male-biased expression continously throughout life, and those that showed female-biased expression in the larval stages. The evolutionary pressures in male- and female-biased genes were different for each sex. For female-biased genes expressed in larvae, rapid evolution was the result of a relaxation of purifying selection for stage-dependent genes (natural selection that removes harmful mutations), whereas rapid evolution in consistently male-biased genes was a result of stronger purifying selection on stage-dependent genes.

This study reveals complex and intricate relationships between sex, age, development and gene expression in the fruit fly, Drosophila melanogaster. Despite minimal visible differences between the sexes during larval and pre-pupal development, there were vast differences in terms of gene expression. Although this is contrary to previous assumptions about the nature of sex-biased gene expression, it is consistent with the fact that many sexually dimorphic traits exhibited by adults must by necessity begin to develop before adulthood. It is therefore not surprising that sex-biased gene expression is evident in juveniles, however the extent of this bias is quite a surprise. More research is needed to understand the evolutionary dynamics shaping development- and sex-specific gene expression, and how these patterns vary across different tissue types.

Original Article:

Further Reading:

This research was made possible by funding from the European Research Council (ERC), the Elizabeth Hannah Jenkinson Fund and the John Fell Oxford University Press Research Fund

By definition, males and females are physically different. In some cases, these differences are restricted to the sex organs, but in many species males and females also differ in their physical appearance and behaviour. What makes you a good male does not necessarily make you a good female, and the benefit of some genes depends upon which sex they find themselves in. These antagonistic genes have sex-dependent fitness effects, and can be a source of genetic variation in natural populations. Research in GEE shows that in small populations, chance events can alter the frequency of antagonistic mutations, and alter the balance of fitness between the sexes. Small populations tend to produce either good males and poor females, or good females and poor males, but not both. This phenomenon could have interesting implications for dispersal and fitness, especially in fragmented populations.

Differences in physical appearance between the sexes is known as sexual dimorphism, and occurs because characteristics that make you good at being male are often different from the characteristics that make you good at being female. A brightly coloured male may get more females because he is more visible or attractive, but a brightly coloured female doesn’t lay more eggs, she just gets eaten.

Sexual dimorphism allows males and females to independently adapt to different optima. The problem is dimorphism is actually quite hard to achieve. Males and females of the same species share, more or less, the same genome. Some species, such as birds and mammals, have sex-specific genes and chromosomes (e.g. the Y chromosome), but these represent a very small proportion of their genes, and many species achieve sexual dimorphism without any sex chromosomes at all. For the most part, traits that differ between males and females are generated from the same set of genes. The evolution of dimorphic traits such as body size, plumage colour and antlers proceeds not through changes to gene function, but changes in gene expression.

Gene Expression and Sexual Dimorphism

A gene that codes for a trait that is beneficial to males but detrimental to females can become sexually dimorphic if it is expressed only when it appears in males (or vice versa). This same gene, when it finds itself in a female body, simply isn’t expressed and does not exert its effect. So a female red deer carries the gene for antlers, but never grows any because the gene is silent.

Sex-specific gene expression is an elegant solution to the problem that males and females face different challenges in life. However, the road to sexual dimorphism is not that straight forward. For a new sexually dimorphic trait to evolve, it must first appear as a novel mutation in a pre-existing gene. At first, it will be expressed just like most other genes – equally in both males and females. This mutation might do great when it finds itself in a male, allowing him to produce more offspring, but when it appears in a female, it would be harmful, reducing the number of offspring produced. For this new mutation to be successful and spread through the population, it needs to avoid the negative fitness effects that come from being expressed in a female. At this stage, a second mutation altering gene regulation – so that the gene is expressed only in males – would be hugely beneficial, but this mutation may take time to arise by chance.

There are many examples in nature of sexually dimorphic traits – genetic variants expressed in one sex but not another. But scientists are increasingly finding mutations that haven’t made it to this happy equilibrium yet – their fitness effect is sex-dependent but they are still expressed in both males and females. These genes are known as ‘sexually antagonistic’ and are thought to be a major source of genetic variation within populations.

Generating Variability
Normally, a gene that has a detrimental effect (i.e. reduces how many offspring you produce) is quickly removed from the population by natural selection. Sexually antagonistic genes are different because their detrimental effect is only seen by natural selection when the mutation appears in one sex. Half the time, the mutation is beneficial, and half the time it is harmful. Overall, the effect of the gene can even out to be essentially neutral. Neutral mutations can stick around in a population for ages, although they may be lost, or spread, by chance.

Chance, also known as genetic drift, can change the frequency of mutations in a population irrespective of their fitness effects, and the effect of chance is much greater in smaller populations. Sexually antagonistic genes may be particularly susceptible to genetic drift because their effect is, on average, neutral. Most theoretical and empirical studies of sexual antagonism use very large populations with high genetic diversity, where the influence of genetic drift is very small. Researchers in GEE have been investigating the evolution of sexual antagonism in small populations to see how chance might influence their frequency.

The Role of Chance
In a recent paper in Evolution, Jack Hesketh, Kevin Fowler and Max Reuter from GEE looked at how small populations of the fruit fly Drosophila melanogaster evolved, and how sex-specific fitness changed under the influence of genetic drift, through the random spread of sexually antagonistic genes. Four populations of 100 flies were maintained for 80 generations, and the fitness of both larvae and adults was measured in terms of survival (larvae), fertilisation success (males) and egg-laying (females).

Over 80 generations of evolution in the lab, the four fruit fly populations diverged in terms of fitness. Average fitness across the sexes didn’t differ significantly between populations, but there was a strong interaction between population and sex – some populations produced very fit females and unfit males whilst others produced fit males and unfit females. This effect was not present for larval fitness however, which makes sense since larvae are primarily concerned with growth and not reproduction. In the original source populations, some individuals carried mutations beneficial to females, whilst others carried mutations beneficial to males. In this experiment, through the process of genetic drift, different populations ended up with a different selection of these mutations – some populations kept hold of the genetic variants favourable to females and consequently produce very fit females but relatively crap males (and vice versa).

This study shows that in real populations, genetic drift may lead to population-divergence in sexually antagonistic genes. This could have interesting repercussions for fragmented populations where different fragments may diverge differently in terms of sexual antagonism. Dispersal in this situation could be extremely favourable – a fit male in a population full of fit males would be faced with stiff competition, but if he wandered over into a neighbouring population full of unfit males, he would presumably have his pick of the ladies. Max Reuter and colleagues in GEE hope to continue to investigate this phenomenon and its consequences in natural populations.

Original Article:

This research was made possible by funding from the Natural Environment Research Council (NERC) and the Biotechnology and Biological Sciences Research Council (BBSRC).