Exploring the potential of salivary and blood immune biomarkers to elucidate physical frailty in institutionalized older women
Introduction
Biomarkers reflecting organ system functioning are intrinsically inter-related and are well suited for the study of the development of frailty (Gale et al., 2013; Walston, 2002). Especially in advanced age, the clinical health status is characterised by long-term musculoskeletal, immune and neurocognitive morbidities, that impact on people's physical functioning. Clinical health outcomes are more than just the absence of disease, and include all physiological structures related to the aging process. Recently, studies have revealed that poor clinical health is associated with an imbalance in several biomarkers involved in the immune system, especially in frail individuals (Gale et al., 2013; Kumar et al., 2014; Leng et al., 2007, Leng et al., 2011; Lu et al., 2016).
In the last decade, frailty was conceptualized as a state in which reserve function across multiple physiologic systems declines, compromising the individual's capacity to withstand biological stress, thereby predisposing them to poor health, functional decline, institutionalization and death (Mitnitski et al., 2015; Rockwood and Bergman, 2012). Recent approaches to the frailty syndrome include factors connected with multiple negative psychosocial and emotional facets that manifest during the aging process and where frailty has a negative effect on psychological aspects (Freitag and Schmidt, 2016). Using a classical approach, Linda Fried and colleagues established the Physical Frailty (PF) concept and identified five components, Weakness, Slowness, Exhaustion, Weight loss and Low levels of Physical Activity (PA) to characterize it (Fried et al., 2001). With this protocol, it is possible to categorise the older population in frail, pre-frail and non-frail subgroups, according to the presence or absence of each of the five individual components (see for a detailed description, the methodology section). Accumulating evidence from observational studies also supports a progressive relationship between the frail syndrome and the malfunctioning of the immune and neuroendocrine systems (Clegg et al., 2013).
A study showed that a decrease in the immune response is closely associated with several aspects of frailty, including sarcopenia and osteopenia (Aw et al., 2007). The molecular mechanisms involved in this relationship are quite complex, which hinders firm conclusions about which biomarkers could have a greater power in explaining the early development of the frail phenotype (Yao et al., 2011). Some experts suggest that the main reason for the difficulty in understanding the phenomenon is the diversity of mechanisms and players involved in the immune system, such as catecholamines, sex steroid hormones, anti and pro-inflammatory cytokines, and several cellular subsets that impact on immune function (Calvani et al., 2015; Darvin et al., 2014; Mitnitski et al., 2015). Systematic reviews and meta-analyses showed that frailty (and pre-frailty) were associated with higher levels of interleukins (IL). Several studies reported that frailty in older community dwelling or institutionalized dwelling persons was strongly associated with high levels of pro-inflammatory markers (Baylis et al., 2013; Lu et al., 2016; Soysal et al., 2016). A recent paper (Rossi et al., 2019) also highlighted the importance of using the ratio between anti and pro-inflammatory markers when seeking associations with several health conditions associated with aging, such as the TNF-α/Il-10 ratio, which has been used as an inflammatory index (Chupel et al., 2017).
Numerous researchers have sought to assess the most prominent clinical or physiologically relevant biomarkers and their relationship with PF and poor clinical status, or assessed how putative predictors of PF could serve as additional screening tools (Schoufour et al., 2016). The Newcastle 85+ Study assessed whether a set of 40 biochemical markers predicted the frailty index, and examined their collective effect in predicting mortality as compared with individual biomarkers (Mitnitski et al., 2015). The results showed that the combined biomarkers Frailty-index was more powerful for mortality prediction than any individual biomarker. In another study, serum sirtuins (NAD dependent deacetylases with anti-aging properties) were described as promising non-invasive biomarkers for the PF status (Kumar et al., 2014). Associations between PF in older institutionalized men and levels of inflammatory makers, in particular IL-6, Tumour Necrosis Factor-Alpha (TNF-α) and high sensitivity CRP have also been reported (Hubbard et al., 2009; Soysal et al., 2016).
Analysing multisystem risk factors of frailty in cross-sectional data of 1685 older adults aged ≥55 in the Singapore Longitudinal Aging Studies, the researchers found that white blood cell counts, haemoglobin, albumin, lymphocytes and total cholesterol were also highly associated with pre-frail and frail subgroups (Ng et al., 2014). A recent study that focused on the female population found that high concentrations of C-Reactive Protein (CRP) were more strongly predictive of frailty incidence in women than in men (Gale et al., 2013). Many studies in the scientific literature are based on community-dwelling elderly people, and the extrapolation of these results to a sample of institutionalized older people can be imprecise.
Since institutionalization increases demands on public health systems, especially on medical and long-term social services, the research interest for this subpopulation has grown in the last years (Conroy et al., 2011). In studies conducted with samples of elderly who require social support and health care, the incidence of the frailty (15% to 40%) trait seems to reach higher percentages in women, but with men dying earlier (Abizanda et al., 2014; Furtado et al., 2018; González-Vaca et al., 2014). In Portugal, the results of the first study recently published indicated that the prevalence of PF in elderly communities was 34.9% (n = 339 participants) and the incidence among older women (40.9%), higher than that in older men (32.5%) (Duarte and Paúl, 2015). To our knowledge, this is the first study looking at the association between PF (physical frailty) and biochemical parameters in sample of Portuguese institutionalized elderly.
Although cognitive, psychosocial and/or functional impairment (including physical frailty) are the main predictors of frailty that lead to elderly institutionalized long-term living (Luppa et al., 2009), the study of blood and salivary biomarkers could give important clues to the nature of the underlying causal deficits leading to age-related frailty, thereby helping to expose targets for early preventative interventions (Mitnitski et al., 2015). In addition, to understand how some biochemical markers independently associate with different PF components could help tailor the interventions that aim to prevent, mitigate and even reverse the incidence of PF.
Older adults living in institutionalized care are a dissimilar population with regards to many geriatric clinical health outcomes. Many questions remain unresolved for this population, including how some of the biomarkers are related with PF and their components. To our knowledge, the use of salivary immune and hormonal markers and their association with PF has not been reported in the literature. In this study, we propose to assess several biomarkers (cytokines, sex steroid hormones, anti-microbial proteins and blood counts) reflecting different organ systems' functioning may explain PF and test the strength of their relationship with Fried's five components of PF in institutionalized older women. It was hypothesized that the frail sub-group would have a lower immune profile than the prefrail and non-frail groups, and that both salivary and blood biomarkers could also reveal significant associations with frailty in this population which would be useful for screening.
Section snippets
Design
This is a cross-sectional exploratory study of institutionalized-dwelling individuals based on a survey aimed to assess the PF incidence in people living (long-term) in centres for social and health care support (CHS). The sample consisted of a subset of the participants who took part in the previous published study protocol (Teixeira et al., 2016). Cross-sectional data from the baseline assessments were used for the current paper.
Eligibility criteria
Participants were women, aged 75 years and over, who were
Declaration of competing interest
The authors declare that they have no competing interests.
Acknowledgments
We would like to thank the all residents and workers from SHSC that accepted to participate in this study. Thanks to the students Filipa Pedrosa, Nelba Souza, Fábio Direito, Rafael Carvalho and Taís Rieping for helping with data collection.
Contributors
Guilherme Furtado drafted the paper. Chupel and Minuzzi helped with data acquisition and biochemical data analysis. Patrício and Loureiro statistically analysed the data. Hogervorst and Bandelow helped with the proposal, revised the manuscript critically and suggested additional statistical analyses. Teixeira and Ferreira coordinated the research study and revised the manuscript critically. All the authors approved the final version of the manuscript.
Financial support
This study was financed by the Portuguese National Funding Agency for Science, Research and Technology (FCT), Project: Hormonal mediation of exercise on cognition, stress and immunity” [FCT PTDC/DTP-DES/0154/2012]. Guilherme Furtado and Matheus Uba Chupel (PhD students) were financed by a grant from CAPES/CNPQ – Ministry of Education – Brazil, reference BEX: 11929/13-8 and BEX: 13642/13-8, respectively.
Data Statement.
The directors and managers of all SHSC required confidentiality by the nature
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