Genetic manipulation of cardiac ageing

Abstract

Ageing in humans is associated with a significant increase in the prevalence of cardiovascular disease. We still do not fully understand the molecular mechanisms underpinning this correlation. However, a number of insights into which genes control cardiac ageing have come from studying hearts of the fruit fly, Drosophila melanogaster. The fly's simple heart tube has similar molecular structure and basic physiology to the human heart. Also, both fly and human hearts experience significant age‐related morphological and functional decline. Studies on the fly heart have highlighted the involvement of key nutrient sensing, ion channel and sarcomeric genes in cardiac ageing. Many of these genes have also been implicated in ageing of the mammalian heart. Genes that increase oxidative stress, or are linked to cardiac hypertrophy or neurodegenerative diseases in mammals also affect cardiac ageing in the fruit fly. Moreover, fly studies have demonstrated the potential of exercise and statins to treat age‐related cardiac disease. These results show the value of Drosophila as a model to discover the genetic causes of human cardiac ageing.

Introduction

The prevalence of cardiac disease significantly increases with age in humans and is the leading cause of death worldwide (Moran et al. 2014). Billions of dollars are spent each year treating patients with heart disease. Therefore, there is much interest in understanding the molecular mechanisms that underpin the development of cardiac disease in ageing humans. The fruit fly, Drosophila melanogaster, is a useful model of cardiac ageing because it is the most genetically tractable animal model with a heart. The fly heart, like the human heart, shows a number of functional and morphological changes with age. Also, there is significant homology between the genes that control development and adult function in human and fly hearts (Adams et al. 2000; Rubin et al. 2000). Furthermore, the molecular structure, such as contractile protein architecture and myofibrillar organization, and the basic physiology, such as ion channel function, of Drosophila myocardial cells is remarkably similar to human myocardium (Ocorr et al. 2007; Cammarato et al. 2011).

The fruit fly has inherent beneficial qualities in today's era of ever‐tightening research budgets: it has a short lifespan and a high reproductive rate, making it affordable and easy to keep large populations or multiple populations to perform complex genetic studies. The fly community has built many tools and resources to facilitate manipulation of any gene in the fly genome with temporal and spatial specificity. For example the extensive libraries at the Bloomington Stock Centre (http://flystocks.bio.indiana.edu/) and the Vienna Drosophila RNAi Center (http://stockcenter.vdrc.at/control/main) contain fly lines that express interfering RNA (RNAi) against most fly genes. With the invention of the new CRISPR gene editing technology (Sander & Joung, 2014) no doubt the list of available tools will continue to grow. Recent innovations have also made it possible to accurately measure fly heart function, morphology and gene expression in response to genetic manipulations. These advances make Drosophila a useful model to study cardiac ageing.

Methods to analyse Drosophila heart structure and function

The methods available to analyse the fruit fly heart have been extensively discussed in a recent review article (Ocorr et al. 2014). We will summarize these methods here.

Heart function can be directly visualized by surgically dissecting away surrounding tissue from fly hearts in a semi‐intact preparation (Fig. 1) (Ocorr et al. 2009). High speed movies of contracting hearts can then be analysed by Semi‐automated Optical Heart Analysis (SOHA) software to calculate heart rate and rhythm, systolic and diastolic diameters, and fractional shortening (Ocorr et al. 2009; Fink et al. 2009). SOHA also generates m modes analogous to those produced by human echocardiography. Alternatively, heart wall movement can be visualized through the cuticle without requiring dissection if hearts express a fluorescent protein such as GFP (Fig. 1), or if infrared light is used to stimulate sensors placed on the cuticle (known as optical coherence tomography or OCT) (Dulcis & Levine, 2005; Wasserthal, 2007). When fluorescent flies or OCT are used, the flies remain alive and so can be used in serial experiments. This is a major benefit over the semi‐intact technique. However, both intact fly methods require expensive specialized equipment and currently produce lower resolution images than the semi‐intact method. Another benefit of dissecting hearts is that they can be fixed, stained and histologically analysed by microscopy to assess heart morphology and protein expression.

Figure 1. Green fluorescent protein expression or semi‐intact preparation for heart function analysis .

A, fly expressing GFP in the heart tube. B, drawing showing heart tube running through thorax (labelled Ao for aorta) and abdomen (labelled H for heart) and semi‐intact fly heart preparation. Abdominal segment 3 is outlined in blue. C, measurement of heart tube diameter during diastole and systole (shown as red arrows). Figure adapted from Fink et al. (2009) and Vogler & Ocorr (2009) with permission.

It is also possible to measure the electrophysiology of the fly heart. Extracellular recordings can be done using suction electrodes or a multi‐electrode array (Papaefthmiou & Theophilidis, 2001; Ocorr et al. 2007). Intracellular recordings can be made using standard recording techniques where an electrode is inserted into a myocardial cell (Dulcis & Levine, 2005).

The mechanical properties of the Drosophila heart can be measured by atomic force microscopy (AFM) (Kaushik et al. 2012). AFM calculates myocardial stiffness in dissected hearts by nano‐indenting the hearts and measuring the deflection with a laser.

Just like in human cardiac patients, we can use stress tests in flies to uncover phenotypes. Electrical pacing or increasing the ambient temperature elevates heart rate in flies leading to increased incidence of ‘heart failure’ (fibrillation or cardiac arrest) (Wessells et al. 2004). Flies also show significant cardiac defects if exposed to acute or chronic hypoxia (R. Zarndt, S. Piloto, R. Bodmer & K. Ocorr, unpublished observations).

Next generation quantitative gene expression technologies such as Fluidigm's Biomark and Nanostring's nCounter have been adapted to measure gene expression even in single fly hearts (L. Cannon, S. Melov, F. Rus, N. Silverman & R. Bodmer, unpublished observations).

The Drosophila heart

The Drosophila heart is a tube comprising two rows of contractile cells that form an inner lumen. It is situated dorsally in the body cavities, unlike the ventral mammalian heart. However, since vertebrates have experienced an inversion of the dorsal–ventral axis, it has been postulated that the embryological origin is conserved between vertebrates and invertebrates (Bodmer, 1995). The fly heart tube is divided into thoracic and abdominal heart sections. The thoracic portion is narrower than the abdominal heart and is more like a mammalian blood vessel – thus it is termed the aorta (Fig. 1 B). The abdominal heart is divided by internal valves into four chambers (Zeitouni et al. 2007; Lehmacher et al. 2012). Inlet valves, called ostia (Rizki, 1978), are spaced along the heart tube and allow haemolymph to enter the heart after a contraction. The inter‐chamber heart valves and ostia control the flow of haemolymph and blood cells throughout the body in an open circulatory system. When the heart contracts, the ostia close and haemolymph is pumped either posteriorly into the abdominal cavity or anteriorly through the aorta towards the head. Haemolymph provides nutrients and hormones to the fly's internal organs. Unlike mammals, oxygen is not transported to tissues via the haemolymph, but instead by an interconnected web of tracheae. This allows flies to live for days with a severely damaged heart, which means that the fly can be used to study major genetic defects that would kill a mammal.

The contractile part of the Drosophila heart tube, which we refer to as myocardium, contains spirally orientated myofibrils. A ventral layer of longitudinal non‐myocardial muscle cells runs along the heart tube. The ventral layer originates from anterior primordial lymph glands, and may serve as a support structure for the heart tube, but its role is not well understood. Drosophila myocardial cells have a similar sarcomeric structure to mammalian muscle cells, expressing many of the same proteins found in mammalian cardiomyocytes, including actin, myosin heavy chain and tropomysin (Cammarato et al. 2011). Fly myocardial cells, like mammalian myocardial cells, undergo mechanotransduction via sarcomeres, the cytoskeleton, cell–cell junction and adhesion molecules, and stretch sensitive molecules in membranes (Kaushik & Engler, 2014). Ca²⁺ is required for both mechanotransduction and the cardiac action potential in the fly (Gu & Singh, 1995; Johnson et al. 1998), just as it is in mammalian cardiomyocytes. Electrophysiological studies show that the action potential in the fly heart lasts 20–30 ms and has no plateau (K. Ocorr, unpublished observations). Thus it is more similar to the action potential in mammalian atria than in mammalian ventricles. Fly hearts have a spontaneous myogenic action potential like mammalian cardiomyocytes, and so beat even when denervated (Ocorr et al. 2007). Experiments have shown that Ork1 K⁺ currents most likely set the resting membrane potential and the pacemaker rate of the spontaneous action potential (Lalevee et al. 2006), but the fly cardiac pacemaker site has not yet been located.

In flies the myocardial tube is surrounded by non‐contractile pericardial cells (Fig. 2) that act as stress sensors (Lim et al. 2014) and as nephrocytes that filter haemolymph (Zhang et al. 2013). Pericardial cells do not express muscle‐specific proteins. It is not yet known how the pericardial cells and the heart tube interact during ageing, but this provides an excellent model with which to dissect out the cell‐autonomous and non‐autonomous mechanisms of cardiac ageing. Using tissue‐specific drivers, genes can be manipulated in either pericardial cells or myocardial cells, or in both cell types, and the resulting effect on heart function and morphology can be examined in ageing animals. Such comparisons would elucidate which genes are involved in autonomous cardiac ageing versus which genes contribute to cardiac ageing in a non‐autonomous manner.

Figure 2. Fly heart tube with surrounding pericardial cells .

Blue is DAPI nuclear staining. Red is phalloidin staining of actin in the heart tube and muscles of the body wall. Green is the pericardial cells.

Age‐related cardiac dysfunction in Drosophila

The fly heart shows similar age‐related physiological decline to the human heart. Humans have an age‐related increase in incidence of cardiac arrhythmias, which is often caused by ion channel dysfunction (Strait & Lakatta, 2012). Old (5–7 weeks of age) flies also have altered ion channel expression and significantly more cardiac arrhythmias, such as asystole and fibrillation, than young (1 week) flies (Ocorr et al. 2007). Old flies also show a longer Ca²⁺ transient decay time, which causes delayed relaxation and a slower heart rate with age (Santalla et al. 2014).

The maximal heart rate in humans declines with each decade of life. This is coupled with a progressive exercise intolerance with age (Strait & Lakatta, 2012). Flies also experience an age‐related decline in heart rate and old flies are less tolerant of cardiovascular stress (Paternostro et al. 2001; Wessells et al. 2004). When hearts are electrically paced, 20–35% of young flies show ‘heart failure’, whereas that rate rises to 65–85% in old flies.

Aged human hearts show increased fibrosis. While fly hearts do not show obvious evidence of fibrosis, collagen transcripts are elevated in old fly hearts. Ventricular hypertrophy with myocardial disarray, vascular stiffening, relaxation deficits and contractile dysfunction are commonly seen in the hearts of ageing humans (Strait & Lakatta, 2012). The spiral myofibrillar structure of the Drosophila myocardium also becomes progressively disorganized with age (Taghli‐Lamallem et al. 2008). Old fly hearts are also stiffer and have decreased diastolic diameters and lower fractional shortening than young fly hearts (Cammarato et al. 2008; Fink et al. 2009; Kaushik et al. 2011, 2012). Interestingly, exercise training can delay age‐related cardiac decline in flies (Piazza et al. 2009).

The overlap between cardiac ageing phenotypes in flies and humans suggests that many of the molecular mechanisms of ageing are conserved from flies to mammals. This reason, coupled with the general benefits offered by the fly as an experimental model, make it an ideal model to study the molecular pathogenesis of cardiac ageing. The fly has been used to elucidate a number of genes and processes that contribute to ageing of the heart (Fig. 3).

Figure 3. Genes and mechanisms that contribute to cardiac ageing in Drosophila melanogaster .

TOR is target of rapamycin. FOXO is forkhead box, sub‐group O. Pygo is pygopus. CaMKII is Ca²⁺–calmodulin‐dependent protein kinase II.

Nutrient sensing controls ageing

Insulin and the insulin‐like growth factor (IGF) signalling pathways (IIS) regulate longevity in animals from worms up to humans (Kenyon, 2001). IIS interacts with two interconnected pathways involved in nutrient sensing: one mediated by the target of rapamycin (TOR) kinase and one by the FOXO transcription factor (Fig. 3).

Systemic or cardiac‐specific modulation of these pathways to inhibit insulin signalling can extend fly lifespan and improve the cardiac function of old flies. Cardiac‐specific over‐expression of FOXO or the phosphatidylinositol‐3 kinase (PI3K) inhibitor PTEN increases fly lifespan and ameliorates age‐related cardiac decline in the fly (Luong et al. 2006; Wessells et al. 2009). Likewise, flies with systemic mutations of the insulin‐like receptor (InR) or its substrate chico or with systemic inhibition of TOR have improved longevity (Tatar & Yin, 2001; Clancy et al. 2001) and less heart function decline with age (Wessells et al. 2004; Luong et al. 2006).

The converse is also true – cardiac‐specific activation of the insulin signalling pathway or over‐expression of TOR causes young fly hearts to be more susceptible to pacing‐induced ‘heart failure’, which is an old‐heart phenotype (Wessells et al. 2004, 2009). The translational repressor 4E‐BP acts downstream of both TOR and FOXO and regulates translation in cells by binding to and inhibiting the translation initiator eiF4E. Overexpression of 4E‐BP ameliorates age‐related cardiac dysfunction, whereas overexpression of eiF4E causes similar exacerbation of age‐related heart decline to up‐regulated TOR or IIS (Wessells et al. 2009).

TOR signalling also mediates the cardiac dysfunction that is caused by high caloric diets, at least in part via brummer, the fly homologue of adipocyte triglyceride lipase (ATGL), and spargel, the fly homologue of peroxisome proliferator‐activated receptor γ coactivator‐1 (PCG1) (Birse et al. 2010; Na et al. 2013; Diop et al. 2015). Systemic or cardiac‐specific inhibition of TOR or overexpression of FOXO blocks the cardiac effects of a high fat diet in flies (Birse et al. 2010). Furthermore, older flies are more susceptible than young flies to the cardiac dysfunction caused by high fat diets (R. Birse & R. Bodmer, unpublished observations).

Taken together, all these data show that modulation of IIS can control ageing by both cell‐autonomous and non‐autonomous (systemic) mechanisms.

Ion channels contribute to cardiac ageing

Potassium (K⁺) channels are integral to the ion flux that causes the cardiac action potential. Thus K⁺ channels regulate heart rate and rhythm in both Drosophila and mammals (Gu & Singh, 1995). K⁺ channel dysfunction in humans is associated with increased incidence of arrhythmias such as long QT syndrome and sudden death. Mutations in several Drosophila K⁺ channels affect heart function: Shaker, ether‐a‐go‐go and slowpoke alter heart rate in the fly (Johnson et al. 1998), and mutations in the fly KCNQ channel impair the heart's ability to repolarize, leading to cardiac abnormalities in young flies that worsen with age (Ocorr et al. 2007). KCNQ mutant flies have slower beating hearts, increased arrhythmias, including fibrillation and prolonged contractions, and are more susceptible to pacing‐induced ‘heart failure’ than control flies (Ocorr et al. 2007). Cardiac‐specific over‐expression of KCNQ ameliorates the age‐related arrhythmias seen in wild‐type flies (Nishimura et al. 2011). Likewise, the ATP‐sensitive K⁺ channel dSUR protects against pacing‐induced heart failure in Drosophila (Akasaka et al. 2006). dSUR expression decreases with age in the fly heart, indicating that lack of dSUR may contribute to age‐related increase in arrhythmias and reduced stress resistance in Drosophila myocardium. These data suggest that cardiac K⁺ channel manipulation may be a promising anti‐ageing strategy.

Sarcomeric and cytoskeletal gene mutations accelerate cardiac ageing

Similar to human hearts, fly hearts stiffen with age. Mutations in sarcomeric and cytoskeletal genes cause a number of inherited cardiac and muscular diseases in humans including hypertrophic and dilated cardiomyopathies (Fatkin & Graham, 2008) and muscular dystrophy. These diseases often lead to premature cardiac failure. Mutations in a number of sarcomeric and cytoskeletal genes also exacerbate age‐related cardiac decline in the fly (Fig. 3).

Mutations in the β‐myosin heavy chain are the most common cause of inherited hypertrophic cardiomyopathy in humans (Fatkin & Graham, 2008). Mutations in myosin heavy chain (MHC) can also cause restrictive or dilated cardiomyopathies in flies, with symptoms that worsen with age (Cammarato et al. 2008). Likewise, D45 myosin mutant flies have depressed myosin function, a slow heart rate and an accelerated increase in age‐induced cardiac arrhythmias compared with wild‐type flies (Cammarato et al. 2008). Young D45 flies have lower fractional shortening than wild‐type flies. This change is associated with age in the healthy fly heart.

Mutations in genes of the dystrophin glycoprotein complex, including dystrophin and sarcoglycan, cause muscular dystrophy in humans (Mendell et al. 2012). Dystrophin is a cytoplasmic protein that links the intracellular cytoskeleton to the extracellular matrix via the membrane spanning dystrophin‐associated protein complex. Sarcoglycan proteins sit in the cellular membrane and form part of the dystrophin‐associated protein complex. Human patients with Duchenne muscular dystrophy show progressive muscular weakening, usually accompanied by dilated cardiomyopathy (Shirokova & Niggli, 2013). The severity of symptoms directly correlates with the amount of functional dystrophin in human patients. Flies with reduced dystrophin, through mutation, knockdown or haploinsufficiency, have shortened lifespans and develop dilated cardiomyopathy which worsens with age (Taghli‐Lamallem et al. 2008). The dystrophic flies show myofibrillar disorganization by 1 week of age. This disorganization markedly worsens as the flies age. In contrast, myofibrillar disorganization is not seen until 5 weeks of age in wild‐type flies. Flies with a δ‐sarcoglycan deletion have dilated hearts (larger systolic and diastolic diameters) and shortened lifespan. Their flight muscles have shortened sarcomeres and disorganized M lines (Allikian et al. 2007).

The incidence of cardiac hypertrophy dramatically increases as humans age. Integrin‐linked kinase (ILK) expression is elevated in human hypertrophic hearts and ILK over‐expression can cause hypertrophy in mice (Lu et al. 2006). The β1‐integrin/ILK pathway also regulates whole organismal and cardiac ageing in the fly. ILK protein levels are increased in old flies and over‐expression of ilk in young flies causes an accelerated cardiac‐ageing phenotype: increased arrhythmias; decreased diastolic diameter and lower fractional shortening (Nishimura et al. 2014). Flies heterozygous for either ilk or the β1‐integrin homologue myospheroid (mys) have longer lifespans than wild‐type flies and less age‐related cardiac arrhythmias. However, stronger knockdown of ilk using RNAi technology causes increased arrhythmias in young flies which worsens with age and causes adhesion defects between cardiomyocytes. Strong knockdown of the ilk binding partner parvin or mild knockdown of ilk interacting proteins talin and pinch also ameliorates age‐related cardiac decline.

These results show the importance of sarcomeric and cytoskeletal function to normal cardiac ageing. They also highlight the fact that these genes and proteins may be appropriate targets to modulate cardiac ageing.

Non‐structural hypertrophy genes can cause premature cardiac ageing in Drosophila

A number of non‐structural genes that are involved in the pathogenesis of cardiac hypertrophy and heart failure in mammals also affect cardiac function and ageing in flies.

The Ca²⁺–calmodulin‐dependent protein kinase II (CaMKII) is activated by increased free Ca²⁺ in the cell and phosphorylates a number of proteins involved in Ca²⁺ handling, including phospholamban, the ryanodine receptor (RyR) and the voltage‐gated sodium channel Na_V1.5 (Santalla et al. 2014). Cardiac‐specific overexpression of CaMKII reduces age‐related arrhythmias in flies. Thus modulation of Ca²⁺ handling via CaMKII may ameliorate cardiac ageing in mammals as well.

Pygopus (Pygo) is a nuclear adaptor protein that mediates Wnt signalling. Cardiac‐specific knockdown of Pygo causes signs of premature ageing in young flies: slower heart rate, increased cardiac arrhythmias, decreased fractional shortening, and myofibrillar disorganization (Tang et al. 2013). These dysfunctions worsen with age in Pygo‐deficient flies and can be rescued with Pygo over‐expression. Fly hearts deficient in both Pygo and CaMKII have worse defects than hearts deficient in only Pygo, suggesting a synergistic functional interaction between Pygo and CaMKII.

The renin–angiotensin system controls blood pressure in mammals. Elevated angiotensin‐converting enzyme (ACE) can cause hypertrophy in mouse models. Conversely angiotensin‐converting enzyme related gene (ACER) inhibition in the fly causes shorter lifespans, cardiac dilatation and exacerbates age‐related cardiac dysfunction (Liao et al. 2014).

Alzheimer's and Huntington genes contribute to cardiac ageing

Similarly, two genes that cause age‐related neurodegenerative diseases in mammals also accelerate cardiac ageing in the fly.

Presenilin gene mutations cause early‐onset familial Alzheimer's disease and can cause dilated cardiomyopathy, both of which are examples of accelerated ageing. Similarly in flies, either knockdown or over‐expression of the Drosophila orthologue of mammalian presenilin (dPsn) increases age‐related cardiac arrhythmias and both myofibrillar and mitochondrial degeneration (Li et al. 2011). Altering dPsn also affects key calcium signalling genes. Knockdown of dPsn increases inositol 1,4,5‐trisphosphate receptor (dIP₃R) expression and decreases dSERCA transcripts. Therefore knockdown of dPsn may increase intracellular Ca²⁺ levels by increasing Ca²⁺ release and decreasing Ca²⁺ re‐uptake. Decreased SERCA function is known to cause heart abnormalities in flies – flies with mutant dSERCA develop severe bradycardia and dilated heart tubes (Shirokova & Niggli, 2013). By contrast, when dPsn is over‐expressed in the fly heart, RyR gene levels are reduced which may decrease intracellular Ca²⁺ levels. De‐regulation of key Ca²⁺ handling genes such as dSERCA, RyR and CaMKII is likely to contribute to the longer Ca²⁺ transient decay time seen in old fly hearts which delays relaxation in the heart leading to a slower heart rate with age (Santalla et al. 2014). dPsn may play a role in this mechanism.

Huntington's disease is caused by amyloid‐like aggregates comprising abnormal huntingtin protein that has expanded polyglutamine repeats. Aggregates occur in brain, heart and other organs causing neurodegeneration and cardiomyopathy. Over 30% of Huntington's patients die from cardiac failure. In a fly model of Huntington's, huntingtin protein fragments containing polyglutamine repeats of varying lengths (PolyQ‐46, Poly‐Q‐72, PolyQ‐102) were expressed specifically in the heart (Melkani et al. 2013). PolyQ flies have shortened lifespan and premature cardiac deficits (by 3 weeks of age), including: non‐contractile myocardial cells, bradycardia; increased arrhythmias; cardiac dilatation; decreased fractional shortening; mitochondrial degeneration; myofibrillar disorganization; and increased oxidative stress. These defects correlate with the length of the PolyQ. The cardiac defects induced by PolyQ could be significantly ameliorated by treatment with resveratrol or by co‐expressing the antioxidant enzyme superoxide dismutase (SOD). Co‐expression of the chaperone protein UNC‐45 also dramatically improved heart function in PolyQ flies. Expression of SOD and UNC‐45 together almost completely prevented cardiac defects in PolyQ flies. This shows that oxidative stress and proteostasis defects are integral pathogenic mechanisms of premature cardiac ageing due to Huntington's. These may also be appropriate treatment targets in physiologically ageing hearts.

Oxidative stress may play a role in cardiac ageing

Oxidative stress increases with both normal and accelerated ageing in mammals. However, it is unclear whether oxidative stress contributes to the pathogenesis of cardiac ageing, or is a by‐product of the molecular changes that occur with age (Edrey & Salmon, 2014). Oxidative stress is also increased in normally ageing fly hearts (Monnier et al. 2012). A recent report suggests that a certain level of endogenous reactive oxygen species (ROS) is required for normal heart function, since significant elevation or reduction of ROS causes cardiac dysfunction (Lim et al. 2014). Furthermore, ROS perform paracrine signalling in the fly heart. ROS generated by pericardial cells can regulate myocardial function in a paracrine manner. ROS activate a p38MAP kinase dependent signalling cascade in pericardial cells, which then influences myocardial function through cell–cell communication, and not by diffusion of ROS (Lim et al. 2014). Inactivation of the antioxidant enzyme catalase in the fly heart exacerbates age‐related bradycardia (Monnier et al. 2012). Conversely, catalase overexpression suppresses age‐induced bradycardia and arrhythmias (Monnier et al. 2012). However, antioxidant anti‐ageing treatment studies in mammals have very mixed results (Edrey & Salmon, 2014). Therefore, it is not yet clear whether this is a viable treatment strategy to combat cardiac ageing.

Anti‐cardiac ageing treatments

Flies experience similar anti‐ageing cardiac benefits from two treatments that are now routinely used in human patients with heart conditions: exercise and statins.

Exercise in mammals delays age‐related cardiac decline in part by increasing mitochondrial efficiency and raising levels of antioxidant enzymes which, in turn, reduces oxidative damage (Ascensao et al. 2007). Exercise is beneficial to mammalian hearts even in the case of heart failure (Owen et al. 2009). Similarly, 5‐week‐old flies that were exercised for 3 weeks were more resistant to pacing‐induced cardiac stress (Piazza et al. 2009). Exercised flies had a lower rate of cardiac arrest and a higher rate of post‐arrest recovery than unexercised flies. Interestingly, exercise had no effect on fibrillation rate. This suggests that exercise affects the contractile function of the heart but not the rhythmicity. Exercised flies had 30% higher aconitase levels, an indication of increased mitochondrial activity. Therefore, similar to mammals, exercise can improve mitochondrial function in the fly heart. Surprisingly, middle‐aged flies (3 weeks of age) did not show the same exercise‐induced benefits as older flies.

Statins work by decreasing cholesterol levels and are a mainstay of cardiovascular disease treatment in human patients. Flies treated with simvastatin show a dose‐related increase in lifespan by up to 25% and have less age‐related cardiac arrhythmias.

Since human treatments also work in flies, it may also hold true that any treatments that can impede cardiac ageing in flies could effectively treat humans. It is much quicker, easier, more affordable and ethically appropriate to do large genetic or drug screens in flies than in humans, or even mammalian models of cardiac ageing and cardiac disease. Therefore, flies could be used to screen for drug candidates to prevent the age‐related cardiac changes outlined in this review.

Summary

The fruit fly Drosophila is a genetically powerful model organism that has been used to uncover several mechanisms of cardiac ageing which may also contribute to ageing of the mammalian heart. The ease of genetic manipulation in the fly will allow future studies to dissect out more information about exactly how the heart ages, and will hopefully elucidate effective anti‐ageing treatments for both the human heart and the whole human body.

Additional information

Competing interests

The authors have no competing interests to declare.

Funding

R. Bodmer is supported by NIH grant 1 P01 AG033561. L. Cannon is supported by AHA Postdoctoral Fellowship 13POST17000049.

Biography

Leah Cannon After completing her PhD in molecular cardiology at the Victor Chang Cardiac Research Institute in Sydney, Australia, Leah is now a postdoctoral fellow in the lab of Rolf Bodmer, who is a world expert in using the fruit fly Drosophila as a model of heart development, aging and disease. Through her research, Leah aims to improve understanding of the genetic causes of cardiac disease, which is the number one cause of death worldwide. Rolf Bodmer earned his PhD in biochemistry and neurobiology from the University of Basel, Switzerland in 1983. He first trained as a postdoctoral fellow in neurobiology at the Albert Einstein College of Medicine in New York, and then studied molecular genetics with Lily and Yuh‐Nung Jan at the University of California, San Francisco. He was appointed Assistant Professor of Biology in 1990 at the University of Michigan. He joined the Sanford‐Burnham Medical Research Institute in 2003, where he is Professor, and since 2007 Program Director of the Development, Aging and Regeneration Program. Dr Bodmer discovered the first cardiac determinant, the tinman gene, and established the Drosophila heart as a research model for cardiac development, function and ageing.