The microbiology of ageing
Posted on January 16, 2025 by John Tregoning
Staring down the barrel of my 45th birthday and following fresh on the heels of discovering that my hair was no longer blond, but actually grey, I turned to worrying about what I might die of and if there was anything I can do about it. This journey led me to write Live Forever? A curious scientist’s guide to ageing, wellness and death. One of the things that clearly emerged from this was the central role that microbes play in our ageing, especially their interplay with the immune system.
First and foremost is that we are become increasingly susceptible to infections as we age. This was very clearly seen during the COVID-19 pandemic, when the virus became the leading cause of death in over 80’s in the UK in 2020 and 2021. But even in non-pandemic years, pneumonia floats around the top 10 causes of mortality, in a large part driven by influenza virus, but with a helping hand for bacterial pathogens. We are not only more prone to infection with new pathogens, but old ones can recur – shingles, reactivation of chicken pox increases fivefold from the under 50s to the over 80s. Other viral infections increase with age – RSV causes a large, and often uncounted burden of mortality in the elderly. The great news is that there are now vaccines against most of the agents that cause severe disease later in life – with the rollout of an RSV vaccine nearly 50 years after it was discovered.
And remarkably it doesn’t just improve lifespan from preventing direct disease, but subsequent ‘non-communicable’ conditions. Influenza virus for example increases the risk of heart attacks for up to a year after infection. It is not the only virus that can cause other disease later in life. Human papilloma virus (HPV) has a clear link to cervical cancer – though again, vaccination campaigns can have a huge impact – a recent survey revealed no cases of cervical cancer have been detected in Scotland in anyone who received the HPV vaccine. Other conditions may also have an infectious cause, diabetes has been associated with human enterovirus infection. And recent studies have revealed a link between Epstein Barr Virus (EBV) infection and MS, raising the possibility that a vaccine could prevent an autoimmune condition. This may be complex though – identifying antigens that prevent infection without triggering the body to attack itself. A similar problem has slowed the development of vaccines for group A streptococcus (GAS). In some people, GAS infection can lead to a secondary condition called rheumatic heart disease, where the immune system attacks the heart muscle. This has been associated with antibody immunity to the M-protein, though it may be more nuanced than that. Whatever the causes, a trial in the 1960s raised safety concerns with regulators leading to a long hiatus in vaccine development. This has been since revoked and research on GAS vaccines has accelerated. Identifying alternative antigens for pathogens with the risk of cross-reactivity can be achieved using more modern methods – so-called reverse vaccinology, which lead to the development of the MenB vaccine.
As well as direct infection caused disease there are slightly harder to pin down effects in terms of cause and effect. Infections can accelerate the onset of frailty and loss of independence. Sometimes this can be driven by a loss of appetite and muscle wastage. It can also be because it accelerates immunosenescence. One chronic virus in particular is associated with exhausting the immune system – cytomegalovirus (CMV). It has been suggested that nearly 40% of CD8 T cells in elderly individuals are CMV specific [12165524]. This potentially limits responses to new infection, but may contribute to other conditions. The interplay of immune stimulation and chronic disease is complex, but has a major driver – inflammation. But age-related inflammation shouldn’t be imagined as a balance correctable by pushing it in the opposite direction. Prof Sian Henson (QMUL) described it as a snapped seesaw – as you grow older you can have both too much of the autoimmunity kind of inflammation AND too little of the anti-infection kind. Inflammation puts stress on a whole range of bodily systems and is a contributor to all the main killers: heart disease, cancer, strokes and dementia.
One contributor to the inflammation is gut leakiness. As we age the integrity of our intestines slowly fails. This then allows in increasing amounts of bacteria; for example an excess of bacteria in the mouth and the gum disease they cause is linked to heart attacks. Which leads us to the final consideration of microbes and ageing – the role of the microbiome. It is a simplification to describe this as complex! There are clear correlations between microbiome and health outcomes, but the functional mechanisms are still a long way from being defined. In attempt to understand these, I undertook a woefully underpowered n=1 study looking at longitudinal sampling of my gut microbiome following dietary perturbations – the results were surprising (but you’ll need to read Live Forever to find out!).
Altering my microbiome was one of several (ultimately unsuccessful) attempts to improve my healthspan. In the end, it mostly comes down to eat well, do exercise, don’t smoke and don’t drink. If you don’t follow those strictures, then all of the antioxidant containing blueberries in the world are going to have little impact. However, one of the other things I realised after crossing the final t of my manuscript was that the answer had been staring me in the face all along – getting vaccinated will dramatically extend your life!