Immune systems and internal clocks in aging

We are an aging population – but what is happening internally as the years pass us by?

We continue our overview of the Longevity Forum’s Science Summit at Oxford’s Oriel College, part of Longevity Week and hosted by Professor Lynne Cox and Jim Mellon.

Longevity.Technology: Severe community-acquired infections (such as community-acquired pneumonia and COVID-19) are more common in older adults, and overall outcomes are worse. But why as we get older are we more susceptible and can we harness the immune system to improve clinical trajectories in older adults?

Professor Liz Sapey is the Chair of Acute Medicine and an academic acute and respiratory medicine physician at the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust. Sapey presented on what is known about susceptibility to infection as we age.

Sapey used neutrophils as an example of how our immune systems may be implicated with age. Neutrophils need to be able to move to the site of infection or injury to accomplish their function. As we age, neutrophils undergo an age-related loss of ability to migrate up chemotactic gradients.

“If these cells are not able to migrate accurately, not only are they not able to clear the pathogen, but they also create more damage to the surrounding tissues through the release of proteinases,” explained Sapey.

Further evidence of the increased harm to tissue from dysregulated neutrophils is in the lungs of severe COVID-19 patients. These patients’ lungs are filled with neutrophils and have higher levels of myeloperoxidase (granule derived proteins released by activated neutrophils) in comparison with pneumonia patients. Interestingly, there is also an association with less accurate neutrophil migration and adjusted hand grip and the stroop test (functional indicators of frailty).

So, can we target neutrophils to help improve clinical trajectories for the elderly?
“Statins traditionally lower cholesterol, but if you come into hospital with pneumonia, already on a statin, it reduces the chances of death,” said Sapey.

In vitro and proof-of-concept clinical trials have shown that simvastatin can improve the migratory accuracy of neutrophils from older people. For example, a randomised, double-blinded, crossover trial on healthy elderly subjects taking 80 mg simvastatin or placebo daily for two weeks showed a significant improvement in neutrophil migration with no effect on other neutrophil functions such as phagocytosis or the release of neutrophil extracellular traps to destroy pathogens [1].

Data like this is important as it is the first time a reversal of age-related neutrophil defects in an elderly population has been reported and, in the words of Professor Sapey, it shows that: “we don’t just have to target the pathogen. We might be able to target the host as well – this is a new paradigm in treatment”.

From Professor Sapey’s data, it is clear our immune systems change as we get older. But what else is happening to the body as we age?

Professor Aarti Jagannath is Associate Professor and BBRSC Davis Phillips Fellow at the Sleep and Circadian Neuroscience Institute within the Nuffield Department of Clinical Neuroscience.

Most aspects of physiology and behaviour, including the sleep-wake cycle display 24-hour rhythms and these rhythms are being increasingly recognised for their role in maintaining health and wellbeing throughout the life course.

“The circadian clock is synchronized to the dawn-dusk cycle, and we are interested in the mechanisms by which light entrains the clock,” began Jagannath. “My talk covers our work on the transcriptional pathways activated by light and the pharmacological targeting of these pathways to treat sleep and circadian rhythm disruption.”

Humans’ circadian rhythm relies on the light from the sun. This light is picked up by photoreceptors in the retina and sent through to the brain to the suprachiasmatic nucleus (SCN) within the hypothalamus. Within the SCN there is a “master body clock” which in turn regulates clocks within the cells and organ systems of the body.

So how does the clock respond to light? Jagannath’s research group examined the light-regulated transcriptome of the SCN and identified a key role for salt inducible kinase 1 (SIK1) in clock re-setting. SIK1 provides negative feedback, acting to suppress the effects of light on the clock [2].

“Identification of regulators of the clock like this will help us develop chronotherapeutics, which will allow us to move the hands of the clock artificially,” Jagannath explained.

And why would we need to manipulate our internal clocks? Disruption of sleep and circadian rhythms can precipitate many chronic diseases including Type II diabetes, neuropsychiatric and neurodegenerative disorders, so figuratively moving the hands could contribute to our overall wellness and healthspan.

Circadian rhythm is hugely disrupted by even a single night of sleep deprivation and the impact of this on health was observed during the pandemic.

“Shift workers were more susceptible to severe positive COVID-19 status,” explained Jagannath. “When we sleep deprived mice and did RNA-seq in the lungs, sleep deprivation had a massive impact on the lung transcriptome. Inflammatory genes were up-regulated and those that regulate inflammation were down-regulated”.

Circadian rhythms shift throughout our lifespan, peaking in lateness during adolescence and then gradually shifting back as we age. Changes to the circadian rhythm are a common cause of sleep problems in older adults, with 15-20% treated with benzodiazepines for sleep disruption. Clearly light through the retina is a critical input to the SCN and it could be that is becomes dysfunctional with age, catalysing changes to the circadian rhythm.

Jagannath spoke of mouse studies where the same light intensity in an old mouse did not activate the SCN in the brain like it did in a younger model. Research into

chronotherapeutics could help reset clocks in the elderly and mitigate the impact of the disrupted circadian rhythms on chronic disease.

More from the Science Summit:

The environment and the exposome in longevity – Professors Sarah Harper and Paul Shiels

Care needs of an aging population – Professor Adam Gordon