Frailty and immunesenescence: as a clinician do I really care?

24 January 2019

Daisy Wilson is a Clinical Lecturer and Specialist Trainee in geriatric medicine at the University of Birmingham. She will be speaking at the upcoming BGS Trainees’ Weekend 2019, 2-3 February in Birmingham.

Until four years ago my answer would have been a resounding no.  As a relatively junior geriatrics trainee I was concentrating on the things I thought I needed to know to be a good doctor.  I had long operated an ‘only learn the essentials’ policy which had until that point stood me in relatively good stead (a few failed attempts at MRCP aside).  A title that contained immunesenescence would have been immediately banished to the esoteric and unnecessary pile.  However, four years, a bit of serendipity and a lot of hard work led me to completing a PhD investigating just that.  This has somehow turned me in to a fervent advocate of all things research and in particular translational gerontology.  It has also afforded me the opportunity of 600 words or so to try and convince you that immunesenescence in frailty is important and worth being on your radar.

Immunesenescence, or the deterioration in immune function with age, is clinically obvious.  You just have to think about how many patients you admit with pneumonia under 40 on a take compared to those over 80.  An important component of immunesenescence is ‘inflammageing’, a term that describes increased inflammation, in the absence of infection, with ageing.  Again another clinically apparent phenomenon – how many CRPs of 15 have you ignored in a well 90 year old.  These phenomenon are both relatively well investigated in ageing research but less well defined in frailty and sarcopenia. 

Immunesenescence and inflammageing have long been considered important contributors to the development of frailty and sarcopenia but good quality research into frailty and immunesenescence is limited.  However, from appraising the available literature we can still draw some solid conclusions.  

Population based research has demonstrated that frailty is associated with immunesenescence; the risk of dying from pneumonia if you live in a nursing home is eleven times higher than if you live in your own home.  We also know from mouse models of frailty and sarcopenia that loss of muscle strength and muscle size is associated with an increase in the pro-inflammatory marker, IL-6.  Cross-sectional studies in humans have demonstrated that inflammation (raised IL-6 and TNF╬▒ (pro-inflammatory markers)) is associated with reduced muscle size and strength.  Conversely low levels of CRP are associated with increased muscle strength.  Perhaps more importantly when we consider causality we also know that one, raised inflammatory markers can predict later muscle loss and reduction in muscle strength and two, a raised white cell count in late middle age can predict the development of frailty ten years later suggesting immunesenescence predates the syndrome. 

Although this is fascinating (at least to me) the most important question is how is this clinically relevant?  The main points to consider are one, can we consider a dysregulated immune system a contributor to the development of frailty and sarcopenia and two, can we modulate a dysregulated immune system to improve outcomes in frail older adults? 

There is enough evidence to suggest an association between frailty and immunesenescence but causative effect has yet to be established, although with the evidence available it seems likely. 

Improving outcomes following the modulation of a dysregulated immune system in frail older adults can be considered in both the shorter and long-term. 

In the short-term we may be able to improve immune function during an acute episode such as illness or preceding a procedure that benefits from immune-competence, for example, vaccination.  A recent study has demonstrated both in vitro and in vivo that administration of high dose statins alongside antibiotics in older adults with LRTI or CAP admitted to hospital improved neutrophil function and was associated with improved clinical outcomes. 

In the longer term are we able to modulate the immune system to both improve immune function and reduce chronic inflammation and consequently halt or slow the development of frailty?  Possible options could include intra-cellular targets as described above with high dose statin administration or even exercise.  Tailored exercise programmes have been used to reverse frailty in studies and increased activity levels in older adults have been associated with improved immune function.  Although, often difficult to implement in practice is it possible that tailored exercise programmes could both improve immune function and reverse, halt or slow the onset of frailty?     

              

Comments

Thank you. You succeeded in persuading me that I should be interested in the relationship between immunesenescence and frailty. An interesting summary and I will keep a closer eye on this developing area of knowledge.

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