Targeting senescence via the immune system

Longevity Week: Professor Janet Lord to speak on inflammation, senescence and the immune system’s role in aging.

One of the speakers at this week’s Investing in the Age of Longevity event at Longevity Week, is University of Birmingham Professor Janet Lord. In her role at the Institute of Inflammation and Aging, she explores the key changes that occur to the immune system with advancing age and how this impacts upon many aspects of health in old age.

Longevity.Technology: Professor Lord is highly regarded for her outstanding research in human aging, and is a recipient of the Lord Cohen of Birkenhead medal from the British Society for Research in to Aging. We caught up with her ahead of her presentation at Master Investor’s event at Longevity Week to learn more about her work in this field.

Overall, Lord’s work is focused on aging processes, and particularly on the role played by inflammation.

Janet Lord
Professor Janet Lord, University of Birmingham.

“We know that, with old age, the inflammation in the body increases and that this is associated with the increased risk of a whole range of age-related diseases, but also with things like physical frailty,” she explains. “For example, the loss of muscle mass, strength and function seen in sarcopenia, which is one of the underlying factors in frailty.”

Inflammation and intrinsic aging

Lord’s lab has particularly focused on the sources of that inflammation – trying to determine why it happens in the first place, and what can be done about it.

“We look at which aspects of human aging are to do with modern lifestyles, and which are intrinsic processes that are ‘normal’ and you really can’t do much about them,” she says.

“One of the ways we’ve tried to address this question is to look at adults who’ve maintained a positive lifestyle most of their lives.”

Lord is referring to the study behind her key 2018 paper, which focused on a group of 125 older adults (men and women, aged 55 to 79) who were members of a cycling club. Most were cycling at least 100 kilometres a week and had been doing that most of their adult lives.

“The reason we chose them is that our hypothesis was that humans haven’t had time to adapt to modern society,” says Lord. “We have not evolved to be sedentary and eating three meals a day – we are still essentially hunter gatherers. Whereas these cyclists were doing lots of physical activity, so they were much closer to what we would consider a hunter gatherer.”

Stay active to beat sarcopenia

The comprehensive cross-sectional study looked at things like muscle mass and function, bone density, hormonal changes, immune system, cognitive function and more.

“Across the age group, we found no decline in muscle mass and function – so they did not have sarcopenia at all,” says Lord. “So we can say that sarcopenia is not a ‘normal’ part of getting older, it’s because we’re not physically active enough.”

Similarly, while the participants in the study did show some bone density loss, it was not as much as you would expect to see in a typical older adult. However, some factors, like maximum heart rate and lung function, still declined across the age group.

“They were at a higher setpoint than non-exercising adults, but they still declined,” says Lord. “So it looks like those factors are down to intrinsic aging processes.”

Immune system and healthy aging

But the finding that really made Lord, an immunologist by training, sit up and take notice, was the data that emerged when analysing the immune systems of the study group. In particular, when looking at the thymus, the organ that produces the T cells that are critical to the immune system function.

“The thymus starts to shrink from about the age of 20, and you lose two to three percent of it a year, which is why as you get older, you’re not really good at responding to vaccines or new pathogens like COVID,” explains Lord. “But what we found in these older cyclists was that the number of T cells coming out of the thymus was like that of a 20 year old – they didn’t have age-related thymic atrophy.”

So it seems that, like frailty, the decline of our immune system is not necessarily an intrinsic part of getting older. The original study work was conducted nine years ago, and Lord’s lab is now conducting another study on the same group to generate longitudinal data.

“We know that some of them are still cycling, but some of them have tapered off and are either doing less or not cycling at all,” says Lord. “But that’s going to be interesting in itself, to look what’s happened to the ones who’ve stopped cycling. Do they look just like their counterparts who never cycled? Or have they got some of that benefit of being active for so long?”

Helping immune cells target senescence

But, even though her work has found that some aspects of aging may be “intrinsic”, Lord is also exploring ways to target those areas, particularly the increase in old or “senescent” cells that accumulate with age. This is the work that she will be speaking about during her Master Investor session this Wednesday at Longevity Week.

“One of the big drivers of aging is this build-up of senescent cells in the body, which are highly pro-inflammatory,” says Lord. “We know that there are mouse studies which have induced senescence only in T cells, and that was enough for the mice to develop multimorbid conditions and frailty. So we actually think that targeting the immune system may be enough – you may not even have to completely get rid of senescent cells elsewhere.”

Rather than explore the approach of using a senolytic compound to kill senescent cells, Lord and her team are looking how to get the immune system to do the job instead.

“There are two types of immune cell – CD8 T cells and natural killer cells – whose job is to actually kill senescent cells,” she says. “As you get older, those cells don’t work as well and can’t kill as well, so what we’re trying to do is to get them to kill senescent cells better. This may have other benefits, because their other jobs are to kill virus-infected cells and tumour cells. So it would have all-round benefits if we could improve their function.”

While Lord’s work in this area is still in its early stages, her lab has been using drug screening approaches to try to correct the function of these important immune cells.

“How they kill is that they recognise the target, be it a senescent cell or a virus cell, and they then release a molecule called perforin, which, as the name suggests, perforates a hole in the target cell,” she says. “Then they pump in another compound which kills the cell. What we’ve learned is that as we age these cells don’t release the perforin very well. So we’re now trying to find compounds that will increase that.”

 Image credit: Munbaik Cycling Clothing / Unsplash

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