The Ageing Immune System and Health (II)
Here’s the first post about the book. I finished it a while ago but I recently realized I had not completed my intended coverage of the book here on the blog back then, and as some of the book’s material sort-of-kind-of relates to material encountered in a book I’m currently reading (Biodemography of Aging) I decided I might as well finish my coverage of the book now in order to review some things I might have forgot in the meantime, by providing coverage here of some of the material covered in the second half of the book. It’s a nice book with some interesting observations, but as I also pointed out in my first post it is definitely not an easy read. Below I have included some observations from the book’s second half.
“The aged lung is characterised by airspace enlargement similar to, but not identical with acquired emphysema . Such tissue damage is detected even in non-smokers above 50 years of age as the septa of the lung alveoli are destroyed and the enlarged alveolar structures result in a decreased surface for gas exchange […] Additional problems are that surfactant production decreases with age  increasing the effort needed to expand the lungs during inhalation in the already reduced thoracic cavity volume where the weakened muscles are unable to thoroughly ventilate. […] As ageing is associated with respiratory muscle strength reduction, coughing becomes difficult making it progressively challenging to eliminate inhaled particles, pollens, microbes, etc. Additionally, ciliary beat frequency (CBF) slows down with age impairing the lungs’ first line of defence: mucociliary clearance  as the cilia can no longer repel invading microorganisms and particles. Consequently e.g. bacteria can more easily colonise the airways leading to infections that are frequent in the pulmonary tract of the older adult.”
“With age there are dramatic changes in neutrophil function, including reduced chemotaxis, phagocytosis and bactericidal mechanisms […] reduced bactericidal function will predispose to infection but the reduced chemotaxis also has consequences for lung tissue as this results in increased tissue bystander damage from neutrophil elastases released during migration […] It is currently accepted that alterations in pulmonary PPAR profile, more precisely loss of PPARγ activity, can lead to inflammation, allergy, asthma, COPD, emphysema, fibrosis, and cancer […]. Since it has been reported that PPARγ activity decreases with age, this provides a possible explanation for the increasing incidence of these lung diseases and conditions in older individuals .”
“Age is an important risk factor for cancer and subjects aged over 60 also have a higher risk of comorbidities. Approximately 50 % of neoplasms occur in patients older than 70 years […] a major concern for poor prognosis is with cancer patients over 70–75 years. These patients have a lower functional reserve, a higher risk of toxicity after chemotherapy, and an increased risk of infection and renal complications that lead to a poor quality of life. […] [Whereas] there is a difference in organs with higher cancer incidence in developed versus developing countries [,] incidence increases with ageing almost irrespective of country […] The findings from Surveillance, Epidemiology and End Results Program [SEER – incidentally I likely shall at some point discuss this one in much more detail, as the aforementioned biodemography textbook covers this data in a lot of detail.. – US]  show that almost a third of all cancer are diagnosed after the age of 75 years and 70 % of cancer-related deaths occur after the age of 65 years. […] The traditional clinical trial focus is on younger and healthier patient, i.e. with few or no co-morbidities. These restrictions have resulted in a lack of data about the optimal treatment for older patients  and a poor evidence base for therapeutic decisions. […] In the older patient, neutropenia, anemia, mucositis, cardiomyopathy and neuropathy — the toxic effects of chemotherapy — are more pronounced […] The correction of comorbidities and malnutrition can lead to greater safety in the prescription of chemotherapy […] Immunosenescence is a general classification for changes occurring in the immune system during the ageing process, as the distribution and function of cells involved in innate and adaptive immunity are impaired or remodelled […] Immunosenescence is considered a major contributor to cancer development in aged individuals“.
“Dementia and age-related vision loss are major causes of disability in our ageing population and it is estimated that a third of people aged over 75 are affected. […] age is the largest risk factor for the development of neurodegenerative diseases […] older patients with comorbidities such as atherosclerosis, type II diabetes or those suffering from repeated or chronic systemic bacterial and viral infections show earlier onset and progression of clinical symptoms […] analysis of post-mortem brain tissue from healthy older individuals has provided evidence that the presence of misfolded proteins alone does not correlate with cognitive decline and dementia, implying that additional factors are critical for neural dysfunction. We now know that innate immune genes and life-style contribute to the onset and progression of age-related neuronal dysfunction, suggesting that chronic activation of the immune system plays a key role in the underlying mechanisms that lead to irreversible tissue damage in the CNS. […] Collectively these studies provide evidence for a critical role of inflammation in the pathogenesis of a range of neurodegenerative diseases, but the factors that drive or initiate inflammation remain largely elusive.”
“The effect of infection, mimicked experimentally by administration of bacterial lipopolysaccharide (LPS) has revealed that immune to brain communication is a critical component of a host organism’s response to infection and a collection of behavioural and metabolic adaptations are initiated over the course of the infection with the purpose of restricting the spread of a pathogen, optimising conditions for a successful immune response and preventing the spread of infection to other organisms . These behaviours are mediated by an innate immune response and have been termed ‘sickness behaviours’ and include depression, reduced appetite, anhedonia, social withdrawal, reduced locomotor activity, hyperalgesia, reduced motivation, cognitive impairment and reduced memory encoding and recall […]. Metabolic adaptation to infection include fever, altered dietary intake and reduction in the bioavailability of nutrients that may facilitate the growth of a pathogen such as iron and zinc . These behavioural and metabolic adaptions are evolutionary highly conserved and also occur in humans”.
“Sickness behaviour and transient microglial activation are beneficial for individuals with a normal, healthy CNS, but in the ageing or diseased brain the response to peripheral infection can be detrimental and increases the rate of cognitive decline. Aged rodents exhibit exaggerated sickness and prolonged neuroinflammation in response to systemic infection […] Older people who contract a bacterial or viral infection or experience trauma postoperatively, also show exaggerated neuroinflammatory responses and are prone to develop delirium, a condition which results in a severe short term cognitive decline and a long term decline in brain function […] Collectively these studies demonstrate that peripheral inflammation can increase the accumulation of two neuropathological hallmarks of AD, further strengthening the hypothesis that inflammation i[s] involved in the underlying pathology. […] Studies from our own laboratory have shown that AD patients with mild cognitive impairment show a fivefold increased rate of cognitive decline when contracting a systemic urinary tract or respiratory tract infection […] Apart from bacterial infection, chronic viral infections have also been linked to increased incidence of neurodegeneration, including cytomegalovirus (CMV). This virus is ubiquitously distributed in the human population, and along with other age-related diseases such as cardiovascular disease and cancer, has been associated with increased risk of developing vascular dementia and AD [66, 67].”
“Frailty is associated with changes to the immune system, importantly the presence of a pro-inflammatory environment and changes to both the innate and adaptive immune system. Some of these changes have been demonstrated to be present before the clinical features of frailty are apparent suggesting the presence of potentially modifiable mechanistic pathways. To date, exercise programme interventions have shown promise in the reversal of frailty and related physical characteristics, but there is no current evidence for successful pharmacological intervention in frailty. […] In practice, acute illness in a frail person results in a disproportionate change in a frail person’s functional ability when faced with a relatively minor physiological stressor, associated with a prolonged recovery time […] Specialist hospital services such as surgery , hip fractures  and oncology  have now begun to recognise frailty as an important predictor of mortality and morbidity.”
I should probably mention here that this is another area where there’s an overlap between this book and the biodemography text I’m currently reading; chapter 7 of the latter text is about ‘Indices of Cumulative Deficits’ and covers this kind of stuff in a lot more detail than does this one, including e.g. detailed coverage of relevant statistical properties of one such index. Anyway, back to the coverage:
“Population based studies have demonstrated that the incidence of infection and subsequent mortality is higher in populations of frail people. […] The prevalence of pneumonia in a nursing home population is 30 times higher than the general population [39, 40]. […] The limited data available demonstrates that frailty is associated with a state of chronic inflammation. There is also evidence that inflammageing predates a diagnosis of frailty suggesting a causative role. […] A small number of studies have demonstrated a dysregulation of the innate immune system in frailty. Frail adults have raised white cell and neutrophil count. […] High white cell count can predict frailty at a ten year follow up . […] A recent meta-analysis and four individual systematic reviews have found beneficial evidence of exercise programmes on selected physical and functional ability […] exercise interventions may have no positive effect in operationally defined frail individuals. […] To date there is no clear evidence that pharmacological interventions improve or ameliorate frailty.”
“[A]s we get older the time and intensity at which we exercise is severely reduced. Physical inactivity now accounts for a considerable proportion of age-related disease and mortality. […] Regular exercise has been shown to improve neutrophil microbicidal functions which reduce the risk of infectious disease. Exercise participation is also associated with increased immune cell telomere length, and may be related to improved vaccine responses. The anti-inflammatory effect of regular exercise and negative energy balance is evident by reduced inflammatory immune cell signatures and lower inflammatory cytokine concentrations. […] Reduced physical activity is associated with a positive energy balance leading to increased adiposity and subsequently systemic inflammation . […] Elevated neutrophil counts accompany increased inflammation with age and the increased ratio of neutrophils to lymphocytes is associated with many age-related diseases including cancer . Compared to more active individuals, less active and overweight individuals have higher circulating neutrophil counts . […] little is known about the intensity, duration and type of exercise which can provide benefits to neutrophil function. […] it remains unclear whether exercise and physical activity can override the effects of NK cell dysfunction in the old. […] A considerable number of studies have assessed the effects of acute and chronic exercise on measures of T-cell immunesenescence including T cell subsets, phenotype, proliferation, cytokine production, chemotaxis, and co-stimulatory capacity. […] Taken together exercise appears to promote an anti-inflammatory response which is mediated by altered adipocyte function and improved energy metabolism leading to suppression of pro-inflammatory cytokine production in immune cells.”
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