From bench to care home: improving immune resilience in older people

We know that older people have been disproportionately affected by the coronavirus pandemic – but how many of us know why?

A keynote lecture given by scientists Professor Lynne Cox, Professor Janet Lord and Dr Joan Mannick at the 2020 UK SPINE annual conference helps provide an insight. The answer – at least part of it – lies in the immune system. Like most of our physical characteristics, from the firmness of our skin to the robustness of our joints, our immune systems deteriorate with age. A weaker immune system means greater susceptibility to infectious diseases like COVID-19 and a more severe disease when we become infected.

This vulnerability has had tragic consequences around the world. At the time of writing, in late January 2021, the UK alone has seen more than 100,000 deaths recorded with COVID-19 on the death certificate – around three-quarters involving people over 75. Perhaps if we could reduce or delay this decline in immune response, we could help avoid similar tolls in the future.

Ageing in human cells

Professor Lynne Cox is a group leader and fundamental scientist in Oxford University’s Department of Biochemistry, working on the ageing of human cells. Speaking at the 2020 UK SPINE conference as part of a panel session exploring how ageing science can boost immune resilience in older people, Professor Cox said: ‘By the age of 85, almost everybody has at least one long-term condition – some as many as eight or more. Older people are more susceptible to infections, and we’ve seen this very clearly than in COVID-19’.

‘There are major implications for people who suffer from multimorbidity – that is, the presence of two or more chronic conditions at the same time. There are also implications for their families, and for health and social care systems. This is a problem we need to tackle with urgency.’

One way of tackling the problem, says Professor Cox, is to stop thinking about multimorbidities as independent diseases, and to recognise that they all associate strongly with ageing. We should look, therefore, at the underlying biological processes of ageing to help us find solutions to multimorbidity.

Professor Cox’s lab is interested in a process called cell senescence, or cell ageing. ‘We all start off with young cells – healthy cells – which have specialised functions and healthy DNA. But as those cells undergo multiple rounds of cell division, they get damaged – whether that’s through the wrong genes being switched on or through processes such as glycation, which can result from high sugar consumption.’

This cell ageing process isn’t necessarily benign: senescent cells can gain the ability to secrete molecules that damage tissue. Consequences range from causing ageing of the skin to providing a hospitable environment for the growth of cancer cells. At this point, still hanging around but no longer fulfilling their original function, senescent cells are known colloquially as ‘zombie cells’. This process has been shown experimentally in mice to contribute to the multimorbidities of ageing.

‘There’s a lot of evidence,’ says Professor Cox, ‘to suggest that senescent cells are bad for us, and getting rid of them is a good idea.’ One study that removed senescent cells from mice found that they had a much lower incidence of developing kyphosis (a rounding of the spine). Another found that it also markedly increased their lifespan.

Even the immune system can’t fight off senescence. ‘The problem with ageing is that the pillars of the immune system can start to lose function, and barriers to disease become weakened. For example, our innate immune cells may become poor at recognising pathogens, or our adaptive immune cells may fail to tell the difference between harmful agents and the body’s own cells, leading the immune system to attack itself and develop autoimmune diseases such as Rheumatoid Arthritis.’

Investigating the ageing immune system

Professor Janet Lord, director of the University of Birmingham’s Institute of Inflammation and Ageing, is delving deep into our immune system in an effort to understand exactly why it performs more poorly as we age. Professor Lord, who chaired the immunity session at the UK SPINE conference, said: ‘One type of cell we’re looking at is the neutrophil, which has a number of functions in response to infection, including the ingestion and destruction of foreign bacteria. Our analysis shows that neutrophils are much less effective at migrating from the bloodstream to the site of infection in older people than they are in younger people – I always say it’s like they’ve lost their sat nav. This can be a major problem if you’ve got a pathogen that’s reproducing very quickly. It’s the same whether you look at neutrophils or other immune cells like macrophages or lymphocytes – they don’t move as accurately as you get older.’

This matters for more than one reason, says Professor Lord. As cells like neutrophils move from blood to tissue, they release enzymes called proteases that cause tissue damage along the way. ‘So we hypothesise that older neutrophils actually cause more tissue damage and inflammation, and that could be why older adults are sicker when they get any sort of infection.’

A weakened immune system doesn’t just increase susceptibility to (or severity of) infection among older people – it can reduce the impact of vaccines. This is because there are fewer, new T-cells around to produce the required response that protects against future infection. It’s another apparent injustice of the COVID-19 pandemic that those who most need the vaccine are likely to have the weakest response to it.

Tackling cell senescence to protect us as we age

For many years, Professor Cox's lab in Oxford has been growing human cell cultures, allowing young cells to become old before playing a game of molecular ‘spot the difference’ to identify the changes of ageing. One of the most interesting changes happens in a powerful and versatile protein called mTOR, which has an important role in areas including cell growth and proliferation. In senescent cells, mTOR appears to be permanently switched on.

Studies by Professor Cox and colleagues on cell cultures show that mTOR inhibitors – for example, a first-generation drug called rapamycin – can achieve results including the rejuvenation of skin fibroblasts and the delayed onset of senescence in those cells. In fact, mTOR’s full name is the ‘mechanistic target of rapamycin’, in reference to the ability of rapamycin – a natural compound first discovered on Easter Island – to suppress its activities. Studies of rapamycin in animals have produced similarly promising results, including one in mice with Alzheimer’s that improved cognitive function and reduced deposits of the harmful protein tau that is associated with the disease.

Dr Joan Mannick is Head of Research and Development at Life Biosciences, a US-based company targeting the biology of ageing. Presenting at the UK SPINE conference, Dr Mannick described studies looking at whether therapies that inhibit the activity of the mTOR protein can improve immune function and decrease the incidence of respiratory tract infection in older adults.

In phase 2 trials of an mTOR inhibitor called RTB101, participants responded better to flu vaccination after six weeks of taking the drug, and had fewer respiratory tract infections. Antiviral gene expression was also increased, suggesting this could be the mechanism behind the results. A phase 3 trial, however, failed to confirm these results – possibly because the ‘endpoint’ requested by the trial regulators involved self-reported respiratory symptoms, rather than lab-confirmed diagnoses. What the trial did confirm is that low doses of RTB101 are well-tolerated in older adults, and that the drug appears to boost activity of virus-fighting proteins called interferons, which can be deficient in older people and may be another reason why COVID-19 disproportionately affects the elderly. Two clinical trials are now under way into whether RTB101 can reduce the severity of COVID-19 symptoms in older adults including care home residents in the US.

Dr Mannick told conference attendees: ‘I think dysfunction of the ageing immune system is an area of medicine that has been mostly ignored by drug developers, but whose importance is highlighted by the COVID-19 pandemic. RTB101 provides a feasible way of safely targeting ageing biology to improve at least some aspects of immune dysfunction in older adults – in this case, a deficiency in type 1 interferon-induced antiviral response. We have to work with payers and regulatory authorities to determine the right clinical trial endpoints and the right patient populations for drugs that improve immune function’.

‘What’s interesting to me is that all these different mechanisms of the ageing immune system – such as senescence, or mTOR, or DNA damage – are just biology that can be targeted by medicines and improve the way we age.’

Keynote conclusion

This keynote session at the UK SPINE conference led to two important overall conclusions: first and foremost, that the immune system is a significant focus for ageing disease and multimorbidity. Understanding immunosenescence in particular may help us develop new drugs to boost the body’s natural defences and help fight off devastating infections such as COVID-19. Second, developing such drugs is a complex endeavour, and large-scale collaboration between academic and industrial partners may prove pivotal in tackling the diseases of ageing – no single institution has the capacity to develop and test such drugs alone.