An international team of scientists led by the University of Leicester has found new evidence that links faster ‘biological’ ageing to the risk of developing several age-related diseases – including heart disease, multiple sclerosis and various cancers.
The study involved scientists in 14 centres across 8 countries, working as part of the ENGAGE Consortium.
The project studied a feature of chromosomes called telomeres. Telomeres sit on the end of our chromosomes – the strands of DNA stored in the nucleus of cells. The telomeres shorten each time a cell divides to make new cells, until they reach a critical short length and the cells enter an inactive state and then die. Therefore telomeres shorten as an individual gets older. But, individuals are born with different telomere lengths and the rate at which they subsequently shorten can also vary. The speed with which telomeres wear down is a measure of ‘biological ageing’.

Professor Nilesh Samani, British Heart Foundation Professor of Cardiology at the University of Leicester and Director of the National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, who led the project said: ‘Although heart disease and cancers are more common as one gets older, not everyone gets them – and some people get them at an earlier age. It has been suspected that the occurrence of these diseases may in part be related to some people ‘biologically’ ageing more quickly than others.’

The research team measured telomere lengths in over 48,000 individuals and looked at their DNA and identified seven genetic variants that were associated with telomere length. They then asked the question whether these genetic variants also affected risk of various diseases. As DNA cannot be changed by lifestyle or environmental factors, an association of these genetic variants which affect telomere length with a disease also would suggest a causal link between telomere length and that disease.

The scientists found that the variants were indeed linked to risk of several types of cancers including colorectal cancer as well as diseases like multiple sclerosis and celiac disease. Most interestingly, the authors found that in aggregate the seven variants also associated with risk of coronary artery disease which can lead to heart attacks.

Professor Samani added: ‘These are really exciting findings. We had previous evidence that shorter telomere lengths are associated with increased risk of coronary artery disease but were not sure whether this association was causal or not. This research strongly suggests that biological ageing plays an important role in causing coronary artery disease, the commonest cause of death in the world. This provides a novel way of looking at the disease and at least partly explains why some patients develop it early and others don’t develop it at all even if they carry other risk factors.’

Dr Veryan Codd, Senior Research Associate at the University of Leicester who co-ordinated the study and carried out the majority of the telomere length measurements said: ‘The findings open of the possibility that manipulating telomere length could have health benefits. While there is a long way to go before any clinical application, there are data in experimental models where lengthening telomere length has been shown to retard and in some situations reverse age-related changes in several organs.’ University of Leicester

Two studies led by investigators at Weill Cornell Medical College shed light on the molecular biology of three blood disorders, leading to novel strategies to treat these diseases.
The two new studies propose two new treatments for beta-thalassaemia, a blood disorder which affects thousands of people globally every year. In addition, they suggest a new strategy to treat thousands of Caucasians of Northern European ancestry diagnosed with HFE-related hemochromatosis and a novel approach to the treatment of the rare blood disorder polycythaemia vera.
These research insights were only possible because two teams that included 24 investigators at six American and European institutions decoded the body’s exquisite regulation of iron, as well as its factory-like production of red blood cells.
‘When you tease apart the mechanisms leading to these serious disorders, you find elegant ways to manipulate the system,’ says Dr. Stefano Rivella, associate professor of genetic medicine in pediatrics at Weill Cornell Medical College.
For example, Dr. Rivella says, two different gene mutations lead to different outcomes. In beta-thalassemia, patients suffer from anaemia — the lack of healthy red blood cells — and, as a consequence, iron overload. In HFE-related haemochromatosis, patients suffer of iron overload. However, he adds, one treatment strategy that regulates the body’s use of iron may work for both disorders.
Additionally, investigators found another strategy, based on manipulating red blood cell production, could also potentially treat beta-thalassaemia as well as a very different disorder, polycythaemia vera.
Dr. Rivella and his colleagues tackled erythropoiesis — the process by which red blood cells (erythrocytes) are produced — as a way to decipher and decode the two blood disorders beta-thalassaemia and polycythaemia vera.
Beta-thalassaemia, a group of inherited blood disorders, is caused by a defect in the beta globin gene. This results in production of red blood cells that have too much iron, which can be toxic, resulting in the death of many of the blood cells. What are left are too few blood cells, which leads to anaemia. At the same time, the excess iron from destroyed blood cells builds up in the body, leading to organ damage. In polycythaemia vera, a patient’s bone marrow makes too many red blood cells due to a genetic mutation that doesn’t shut down erythropoiesis — the production of the cells.
The researchers studied both normal erythropoiesis, in which a person makes enough red blood cells to replace those that are old, and a mechanism called stress erythropoiesis, which flips on when a person requires extra blood cells — such as loss of blood from an accident. The hormone erythropoietin (EPO) controls red blood cell production, and can also induce stress erythropoiesis. Iron is also essential, says Dr. Rivella. ‘The two well-known elements needed to switch between normal and stress erythropoiesis are EPO and iron,’ he says.
But Dr. Rivella and his team found that a third player is essential: macrophages, the immune cells that engulf cellular garbage and pathogens. Macrophages had been known to digest the iron left when old blood cells are targeted for destruction, but Dr. Rivella discovered that they also are necessary for stress erythropoiesis. He found macrophages need to physically touch erythroblasts, the factories that make red blood cells, in order for more factories to be created so that they can churn out red blood cells.
‘No one knew macrophages were a part of emergency red blood cell production. We now know they provide fuel to push red blood cell factories to work faster,’ says the study’s lead author Dr. Pedro Ramos, a former postdoctoral researcher at Weill Cornell.
The research team then looked at diseases in which there are too many red blood cell factories. Polycythemia vera was one of the conditions examined. The researchers disabled macrophage functioning in mice with polycythemia vera and found that red blood cell production returned to normal.
In beta-thalassemia, the body increases the number of red blood cell factories to make up for the lack of viable blood cells — a strategy that doesn’t work. As a result, patients develop enlarged spleens and livers due to the overload of erythroblasts in those organs.
The researchers found in mouse models that if they suppress the function of macrophages, the number of blood cell factories revert back to normal levels. However, there was also an additional benefit discovered. One of the functions of macrophages is to put excess recycled iron into erythroblasts. Researchers report if you suppress that function, less iron goes into the red blood cells. ‘So you then make red blood cells that have less iron, and they are now closer in structure to what they should be,’ says Dr. Rivella.
In animal studies, the researchers saw that decoupling macrophages from the erythroblasts not only reduced the number of blood cell factories, but also improved anaemia.
The discovery could be translated into an experimental therapy by finding the molecule that physically binds a macrophage to an erythroblast, and then targeting and inhibiting it. ‘We need macrophages for good health, but it may be possible to decouple the macrophages that contribute to blood disorders,’ Dr. Rivella says. ‘I estimate that up 30 to 40 percent of the beta-thalassaemia population could benefit from this treatment strategy.’
Dr. Rivella also made another connection. He says polycythaemia vera ‘is sort of a tumour of the red cells, because you make too many of them.’ And he notes that previous research on macrophages found that they are very important in cancer metastasis. ‘I see a parallel between the activity of macrophages in supporting the proliferation of cells that are under stress conditions — growing tumors and red blood cells that need to grow,’ he says. ‘It seems to us that macrophages are important in supporting a switch between normal growth and increased growth.’ Weill Cornell Medical College

Genetic screening for prostate cancer is now a real possibility following results from the largest-ever study into inherited risk factors for the disease. A clinical trial is likely to start this year as a result of the ground-breaking findings from an international group led by The Institute of Cancer Research, London, and the University of Cambridge, funded by Cancer Research UK and the European Commission.
The three-year study of 50,000 men (prostate cancer patients and controls without cancer) identified 23 new genetic variations associated with an increased risk of the disease. This raises the total discovered so far to 78. Significantly, 16 of the 23 newly discovered genetic changes are associated with the disease at its most aggressive and life-threatening.
None of the 23 genetic changes on its own raises a man’s risk of prostate cancer by more than a slight amount. But when a man has a number of the genetic changes these can combine to raise his risk significantly. With the genetic changes discovered, scientists can for the first time identify men who have inherited just over a 50% lifetime risk of developing prostate cancer.
Following these discoveries scientists now think they can identify the top 1% of men with the highest risk of developing prostate cancer who have 4.7 times the risk of the population average. It is these men who, it is hoped, will be identified by screening. They would then receive close monitoring in order that, if they do develop the disease, it is caught early when it is easier to treat. The way in which that screening would be conducted – for example, through blood tests or biopsies – will be indicated by the results of future clinical studies.
Study leader Professor Ros Eeles, Professor of Oncogenetics at The Institute of Cancer Research (ICR) and Honorary Clinical Consultant at The Royal Marsden NHS Foundation Trust, said: ‘These results are the single biggest leap forward in finding the genetic causes of prostate cancer yet made. They allow us, for the first time, to identify men who have a very high risk of developing prostate cancer during their lifetime through inheritance of multiple risk genetic variants. If we can show from further studies that such men benefit from regular screening, we could have a big impact on the number of people dying from the disease, which is still far too high.’
Over 40,000 men are diagnosed with prostate cancer in the UK each year, with almost 11,000 men dying from the disease. If it is caught early treatments are more effective, which is why identifying those most at risk, particularly from aggressive forms of the disease, is so important.
The team, from the ICR and the University of Cambridge, analysed 211,000 genetic variants from blood samples from 25,000 prostate cancer patients and compared them with those of a similar number of healthy men. The gene variants were analysed as part of the COGS (Collaborative Oncological Gene-environment Study) project, which publishes a series of research papers simultaneously today about the causes of prostate, breast and ovarian cancer. The Institute of Cancer Research

Prostate cancer doesn’t kill in the prostate – it’s only once the disease travels to bone, lung, liver, etc. that it turns fatal. Previous studies have shown that loss of the protein E-Cadherin is essential for this metastasis. A University of Colorado Cancer Center study describes for the first time a switch that regulates the production of E-Cadherin: the transcription factor SPDEF turns on and off production, leading to metastasis or stopping it cold in models of prostate cancer.
‘When E-Cadherin is lost, cells become ‘rogue’ – they can detach from their surrounding tissues, move effortlessly through the circulatory system, grow and attach at new sites. In prostate tumours that had lost E-Cadherin, we put in SPDEF and the tumours once again expressed E-Cadherin. They were once again anchored in place and unable to metastasise. We can make these ‘rouge’ cells back into epithelial-like cells and these epithelial cells stay anchored and lose the ability to migrate,’ says Hari Koul, PhD, investigator at the CU Cancer Center and professor and director of Urology Research at the University of Colorado School of Medicine, the study’s senior author.

In fact, the work could have implications far beyond prostate cancer, as increasing evidence points to loss of E-Cadherin as a prerequisite for metastasis in many cancers.

Koul and colleagues first showed that E-Cadherin levels varied directly with the addition or subtraction of SPDEF. Then the group artificially knocked down E-Cadherin despite the presence of SPDEF and showed that cells remained able to migrate and invade new tissues (SPDEF didn’t by itself affect metastasis and was instead dependent on modulating E-Cadherin, which is the driver). The group also showed a one-way switch – SPDEF regulates E-Cadherin, but E-Cadherin expression does nothing to affect levels of SPDEF.

‘Taken together, these studies paint a pretty compelling picture of SPDEF working in part through the modulation of E-Cadherin to inhibit prostate cancer metastasis,’ Koul says. ‘To the best of our knowledge these are the first studies demonstrating the requirement of SPDEF for expression of E-Cadherin.’

Koul says that his group is getting very close to turning off the loss of E-Cadherin in cancer cells by re-arming tumours with the gene that makes SPDEF and by testing small molecules that increase SPDEF in cancer cells.

‘This could be a real landmark,’ Koul says. ‘We see a prerequisite for metastasis and now we have a very clear picture of how to remove this necessary condition for the most dangerous behaviour of prostate cancer.’ University of Colorado Cancer Center