Lorna Rothery spoke to cardiovascular regenerative medicine expert, Professor Paolo Madeddu, who co-led a groundbreaking study that identified a mutant anti-ageing gene that could broaden curative options for cardiovascular disease.
We all want to live a long life, free from chronic disease. But unfortunately, while increases in life expectancy are a positive reflection of modifications to lifestyle and our environment, many older people still spend their later years in poor health. According to the World Health Organization, by 2050, the world’s population of people aged 60 and over will double. In addition, the number of people aged 80 years or older is expected to triple between 2020 and 2050 to reach 426 million. With old age often characterised by the emergence of multiple health issues due to biological changes and variations in physical and social environments, research into longevity and the impact of lifestyle and genetics is becoming increasingly important.
Insights into how genetics affect ageing have also given rise to the potential of gene therapy to reverse age-associated diseases. For example, earlier this year, scientists at the University of Bristol and the MultiMedica Group in Italy discovered an anti-ageing gene, often seen in healthy centenarians, which could rewind the heart’s biological age and halt further decay of heart function. Hopefully, this new study could inform future therapeutic approaches for those suffering from, or at risk of, cardiovascular conditions like heart failure. In addition, carriers of these mutant anti-ageing genes, such as those living in Blue Zones where people typically live longer in good health, can pass them to their offspring; this study demonstrates the possibility of transferring this beneficial gene/protein to unrelated organisms.
To learn more about the study and how research into longevity and gene therapy is evolving, Lorna Rothery spoke to Paolo Madeddu, a professor of experimental cardiovascular medicine at the University of Bristol’s Bristol Heart Institute who is one of the study’s authors, together with Annibale Puca, a medical geneticist at MultiMedica in Milan.
How has research into ageing and longevity evolved in recent years?
Over the last decade, life expectancy has increased and will still increase in developing countries but it is likely to plateau in developed countries. This is mainly due to improvements in environmental conditions, though equally, it is unclear how the effects of climate change will impact life expectancy in the future. Similarly, while the average life expectancy in Europe is around 80, there are disparities due to the prevalence of chronic diseases among people with low socioeconomic status.
Longevity, living longer than the average population, is determined by environmental conditions and inherited genes, and research in this area considers how these factors affect our lives. A long-lasting health span does not simply equate to a long life but a healthier life free from the burden of chronic disease. Research is helping to broaden understanding of the positive and negative impact of environmental factors and genes on longevity and health.
Genes are sequences of letters that encode proteins. Mutations of the code often occur during life, affecting the genetic sequence irreversibly; most of these mutations are harmless, but some can cause disease. For example, if a parent carries a gene mutation in their egg or sperm, it can pass to their child. Hereditary mutations include cystic fibrosis, haemophilia, and sickle cell disease. Some harmful mutations may have ‘advantageous side effects,’ like some forms of blood cell disease that confer resistance to malaria. Those carrying the gene defect survive better in areas where malaria is endemic. Equally, some mutations can, by chance, have a positive impact and can affect life early on and be propagated.
Scientists, in many cases, can decipher the mutation responsible for the disease and try using gene therapy to supply the proper gene or, more recently, employ modern gene editing technologies to try cutting out the faulty gene and introducing a functional one.
There is also another means by which genes can affect the development of disease. Genes comprise DNA, the code of our makeup, and supporting histones that act as spools around which DNA winds. Some genes can be reversibly ‘shut off’ or ‘switched on’ by environmental factors through chemical changes of the DNA/histone complex, called epigenetic modifications, which can have both positive and negative effects depending on the function of the affected gene. For instance, smoking could activate negative gene signalling and shut off genes that protect us from cancer. On the other hand, exercise could do the opposite. These changes are reversible. Therefore, it is possible to correct the modification before it causes harm to our organs.
Some researchers believe we can use drugs to affect the epigenetic landscape (the reversible trait of the DNA/histone unit) similarly to how the environment affects gene expression. For example, researchers in the US are currently looking into epigenetic rejuvenation strategies involving the so-called Yamanaka factors (four transcription factors (Oct3/4, Sox2, Klf,4 and c-Myc)). This follows ground-breaking research carried out by Nobel Prize winner Shinya Yamanaka who showed it was possible to reprogramme cells using the four master genes. Yamanaka reprogrammed adult mouse fibroblasts back to an embryonic state defined as pluripotency; the cell behaves like an embryonic stem cell and can become any other cell type in the body. From the concept, scientists questioned whether they could directly translate these transcription factors to live animals, and they were able to reprogramme the phenotype and demonstrate cell rejuvenation. However, dedifferentiation is also observed in cancer development, so there could be a risk. It also needs to be determined how long the beneficial effects of this type of gene therapy would last.
Regarding our research, we want to exploit those mutations seen in healthy centenarians, passing them to the general population, either using gene therapy or, even better, giving the encoded protein. My colleague Professor Puca at MultiMedica discovered that a mutation affecting the BPIFB4 gene is associated with healthy longevity. Based on this discovery, my team in Bristol collaborated with Puca delivering the longevity gene in mice, elderly mice, or mice with a form of cardiomyopathy caused by diabetes. We found that the longevity gene offered significant benefits in the recovery of the heart’s contractility and the homeostatic processes in the heart’s ageing. However, we do not know how long such benefits would last in humans.
Our focus is to determine if giving the longevity protein instead of the gene would also work; a treatment based on a protein is safer and more viable than gene therapy. Initially, there will be a research study using a recombinant protein in volunteers to ensure safety and subsequent studies in patients with severe diseases. We hope our research is the first in a series of studies on beneficial gene mutations and essential proteins in healthy centenarians. Our goal is not for people to live longer but healthier lives.
Can you explain the effects of gene-environment interaction on the expression of ageing and cardiovascular decline?
Generally, this interaction does exist, and the combination of good genes and the environment is an essential consideration in the context of ageing. For example, people living in Blue Zone areas such as Sardinia have good genes but are also wise enough to care for their environment and diet. Diets rich in nutrients, for instance, contribute to good cardiovascular health and a healthy bacterial environment in the gut.
What are some of the challenges associated with gene therapy, and how do you hope to develop your research to potentially improve the safety and viability of these therapeutics?
Gene therapy is an excellent approach for the definitive correction of monogenic diseases. Research is evolving rapidly with the possibility of cutting the wrong gene and inserting the correct gene into the genome.
Somatic gene therapy for cardiovascular diseases has also been trialled preclinically and in patients, but it comes with its challenges. There are immunological issues associated with this as the body can recognise the sequences of the (inactivated) viral vectors that carry the gene, thereby triggering an immune response, which limits the durability of gene expression with repeated administrations. Given the complexity of this approach, it is why, after experimental demonstrations show our strategy is effective, we are looking to move away from gene therapy into protein therapy. We could place the longevity protein in a capsule and administer it like a standard drug. The challenge is understanding the quantities that would be beneficial (we cannot exclude large amounts that might have a negative effect). Moreover, to perform a clinical trial, we need large quantities of recombinant clinical-grade protein, which is very expensive to be prepared by an academic team.
How will cardiac regenerative medicine develop over the next few years?
Different approaches are evolving alongside pharmaceutical companies developing new drugs. Still, there is a dichotomy between academic research and the companies that can develop ideas and move the product toward clinical application. For example, when we collected evidence that our study could inform a new therapeutic approach, we contacted companies. Still, we were told that while it sounded promising, such products were outside their pipeline. We would need an estimated £3-10 million to produce many proteins and conduct a safety trial. Because of the complexities of these processes, and the need for investment, it can often delay patient access to novel therapies. Communicating these challenges to the broader public is essential to have realistic expectations.
The NHS is struggling because we have too many people who are affected by disease, and so if we can find ways to treat those people – even though the initial cost to generate new drugs will be high – the overall costs to the health system will be reduced in the long term.
Now, there is a focus to develop technologies that allow us to better target the specificity of diseases in different people, also known as personalised individual therapy. It is also essential to understand the diversity of cells within the human body and single organs to guide them through therapeutic restoration rather than adverse remodeling and scarring. Epigenetic medicine – drugs that affect the configuration of the DNA – histones could be another future approach.
What key lessons can we take from centenarians to safeguard our cardiovascular health?
Centenarians are generally very optimistic people, with lots of social connections, traditions, and a relaxed outlook on life. We can learn a lot from them because our lives can be very stressful, and often, we are bombarded with messaging about what constitutes a happy life, which can leave us feeling quite negative and eager to make changes quickly. Equally, we can find ourselves investing a lot of money and time to try and find joy which is having the opposite effect. In conclusion, healthy centenarians are the fruit of natural evolutionary success. They could be our most precious resource for the future thanks to their generosity in sharing genes and the way they interpret life.
The study entitled ‘The longevity-associated BPIFB4 gene supports cardiac function and vascularization in aging cardiomyopathy’ was funded by the Bristol Heart Foundation, Diabetes UK, and the Medical Research Council, and the Italian Ministry of Health.
Professor Paolo Madeddu
Professor of Experimental Cardiovascular Medicine
University of Bristol
mdprm@bristol.ac.uk
https://www.bristol.ac.uk/people/person/Paolo-Madeddu-c6fb7687-13a9-41d9-bdb5-a2cfad1db973/
This article is from issue 25 of Health Europa Quarterly. Click here to get your free subscription today.
