Università Cattolica del Sacro Cuore

Ageing is a pleasant problem! - issue#1

Technologies which allow to sequence microbial systems and metagenomics are able to shed a light on how to improve ageing and increase life expectancy


By Bruno Pot
Research Director at the Institut Pasteur Lille, Lille, France
Director of Business Development at Applied Maths NV, Sint-Martens-Latem, Belgium
Guest Professor at the Vrije Unversiteit Brussel, Brussels, Belgium

 
When asked for an opinion, I thought about this title almost immediately. When I googled “Ageing is a pleasant problem!”, nothing identical came up; a good start. The closest match was “Ageing is not a medical problem“.  Both are right, I believe.
We all age, some faster, some slower; some hopeful for the future, others looking back at the past. While most of us enjoy the increased life expectancy, few of us really seek to understand why and how that is. Of course we realize that we have antibiotics, and of course we have many drugs to take care of age-related hypertension, bad cholesterol and diabetes, maybe even our overweight or depression. The use of modern medicine has clearly helped to increase life expectancy: by reducing child mortality mainly, and by conquering infectious and other diseases. But, is that really so?

  • Healthy people have always been growing old. You may know the beautiful painting ‘La Mort de Socrate’ (The death of Socrates) by the French painter Jacques-Louis David (1787). It represents the execution through poisoning of the great Greek philosopher Socrates, … at the age of seventy! Already 2400 years ago.
  • Quality of life has not only been improving due to modern medicine. You may have heard about the ‘hygiene hypothesis’, the famous 2002 article of Jean-Francois Bach in the prestigious ‘New England Journal of Medicine’ on ‘The effect of infections on susceptibility to autoimmune and allergic diseases’, in which the author shows an almost perfect relation between the decrease of infectious diseases and the increase of ‘modern’ diseases as allergy, multiple sclerosis, diabetes, Crohn disease and other autoimmune diseases, since the 50-ties, the time we started to use antibiotics on a larger scale.
    Of course this was an intriguing observation that needed clarification. This shift could not be genetically explained! Not in two generations only. And the clarification came: it is the bacteria again! They are responsible for it! Only, this time the message was: We need the bacteria!  
     

What’s been going on?
Metagenomic research, the technology that allows to sequence the full complexity of a microbial ecosystem in one single experiment, has allowed the profound investigation of our bacteria, of our microbiota, the collection of live micro-organisms that can be found in and on each of us. Hundreds of species, thousands of bacterial strains, hundred-thousand-billion individual bacteria. The European MetaHit project  has contributed significantly to explain why JF Bach was right, in many ways. By comparing the microbiome of an obese with a lean host, or a patient with inflammatory bowel disease to a healthy person, it became clear that there are considerable differences in the microbiota. Differences in diversity for instance: less diversity often means less flexibility and an increased risk to develop disease.  Differences in composition too: patients with inflammatory bowel problems seemed to have less of the formerly unknown bacterium Faecalibacterium prausnitzii in their intestine and obese people had less of Akkermansia muciniphila than healthy volunteers. Differences according to the diet also, as diet is the ‘food’ that is offered to our intestinal bacteria. Finally, differences according to age too, as discussed here. Age was found to cause remarkable differences in the microbiota composition. But it is not really clear, even now, if the immune system of the host is first changing with age, influencing the microbiota composition, or if the changing microbiota will influence the immune system, causing immunosenescence.
The most striking observation for me, however, was the importance of the microbiota during the first two years of life. It is impossible to summarize here all the fascinating research results obtained. How the microbiota development of the newborn is initiated, maintained and fortified by the mother and e.g. the many factors in her breast milk. How some specific bacteria are necessary to epigenetically change the genome of the baby in a way that it has a lifetime long effect. How this needs to happen within a very limited time frame, or will never happen. How diversity is necessary and being established (how does the baby know which bacteria are good and which are not?) and how the establishment of this adult microbiota can be disturbed with a single antibiotics course at a bad moment early in life, making the microbiota in deficit for the rest of the babies entire life and determining its risk for the development of allergy, obesity, inflammatory- or auto-immune diseases.
Or how ‘simple’ observations, supported by powerful technology, have launched one of the most multidisciplinary revolutions in biology since the discovery of DNA. Bioinformaticians and algorithm engineers liked the challenge of sorting out millions of these short sequence reads.  Immunologist want to understand how the microbiota is shaping the immune system and when it goes wrong; infectiologists want to know how to fortify the microbiota content to increase it resilience and resistance to pathogens; medical people link microbiota quality to a whole new set of possible disease targets, from obesity to IBD, IBS to autism. Microbiologist want to understand the stability of the ecosystem and how to intervene with pro- or prebiotics; nutritionists want to understand the link between the microbiota and the efficiency for energy recuperation, vitamin production, etc… Neonatologists want to protect preterm babies by giving them the bacteria they need to improve their chances to survive. And for elderly too, there are many benefits. An improved quality of the microbiota will increase their quality of life at old age. It starts as a baby, it lasts until the end. Microbiota transplants save elderly from Clostridium difficile infections, and interventions may sooner or later prevent or delay the development of immunosenescence. Mental illnesses may be substantially reduced because of less intestinal toxins and better gut-brain signaling.
The beauty of that all: It turns out that one of the best alternatives to antibiotics, which we used to kill our bacteria, are … our bacteria. We can use them in all safety, as probiotics or as lactic acid bacteria that are part of so many delicious food preparations, without any side effect, no risk to develop resistance, and less expensive than many drugs...
They make ageing more pleasant and less problematic!
They can bring together scientists and politicians.