With advancing age, the composition of leukocyte subpopulations in peripheral blood is known to change, but how this change differs between men and women and how it relates to frailty is poorly ...understood. Our aim in this exploratory study was to investigate whether frailty is associated with changes in immune cell subpopulations and whether this differs between men and women. Therefore, we performed in-depth immune cellular profiling by enumerating a total of 37 subpopulations of T cells, B cells, NK cells, monocytes, and neutrophils in peripheral blood of 289 elderly people between 60-87 years of age. Associations between frailty and each immune cell subpopulation were tested separately in men and women and were adjusted for age and CMV serostatus. In addition, a random forest algorithm was used to predict a participant's frailty score based on enumeration of immune cell subpopulations.
In the association study, frailty was found to be associated with increased numbers of neutrophils in both men and in women. Frailer women, but not men, showed higher numbers of total and CD16
monocytes, and lower numbers of both CD56
T cells and late differentiated CD4
TemRA cells. The random forest algorithm confirmed all the findings of the association studies in men and women. In men, the predictive accuracy of the algorithm was too low (5.5%) to warrant additional conclusions on top of the ones derived from the association study. In women however, the predictive accuracy was higher (23.1%), additionally revealing that total T cell numbers and total lymphocyte numbers also contribute in predicting frailty.
In-depth immune cellular profiling revealed consistent associations of frailty with elevated numbers of myeloid cell subpopulations in both men and women. Furthermore, additional associations were found between frailty and lower numbers of some T cell subpopulations, in women only. Thus, our study indicates sex-specific associations of immune subpopulations with frailty. We hope that our study will prompt further investigation into the sex-specific immune mechanisms associated with the development of frailty.
With aging, the human immune system undergoes several changes. The clinical relevance of these changes, however, is relatively unknown. We investigated immunological aspects of human aging in ...relation to frailty in the Doetinchem Cohort Study (DCS).
We calculated a frailty index score based on 36 health parameters for each individual in the DCS with data obtained in the period 2008–2016. The frailty index was used to define three health groups (‘healthy’, ‘intermediate’, and ‘frail’), stratified by age and sex. In a subcohort (n = 289, 60–85 years, selected by balanced random sampling per frailty group), we collected blood samples between October 2016 and March 2017 to determine absolute numbers of leukocyte subsets. In addition, cytomegalovirus serostatus was assessed. C-reactive protein (CRP) levels were longitudinally assessed in four consecutive plasma samples per individual. These samples had been previously collected (1993–2013) as part of the DCS at regular time intervals and spanning a period of >15 years.
We observed higher numbers of myeloid derived neutrophils and monocytes in the frail group compared to the healthy group in both men and women, and, retrospectively, consistently higher CRP concentrations over a period of >15 years. An increase in CRP concentration with age was found in women, but not in men. Frailty was not associated with cytomegalovirus serostatus or with changes in lymphoid derived T-, B-, or NK-cell numbers.
Frail elderly, compared to their age- and sex-matched peers, endure a chronic and stable low-grade inflammation, which is associated with a myeloid cell lineage expansion. These findings could help to monitor clinically significant immunological decline in the elderly.
•Frail elderly show continuous low-grade inflammation during at least 15 years.•This inflammation is associated with an expansion of circulating myeloid cells.•The results were observed in both sexes but were more pronounced in women.
The Healthy Aging Index (HAI), an index of physiological aging, has been demonstrated to predicts mortality, morbidity and disability. We studied the longitudinal development of the HAI to identify ...aging trajectories and evaluated the role of baseline sociodemographic characteristics and lifestyle factors of the trajectories. Four measurements with intervals of 5 years were included from the Doetinchem Cohort Study. The HAI reflects levels of systolic blood pressure, non-fasting plasma glucose levels, global cognitive functioning, plasma creatinine levels and lung functioning. The HAI score ranges from 0 to 10: higher scores indicate a better health profile. Latent class mixture modelling was used to model within-person change and to identify aging trajectories. Area under the curve was calculated per trajectory to estimate total healthy years. In total, 2324 women and 2013 men were included. One HAI trajectory was identified for women, and two trajectories for men, labelled ‘gradual’ aging (76%) and ‘early’ aging (24%). Men who were medium/high educated, below 36 years at baseline, complied with guidelines on physical activity and were not obese in any round were associated with increased odds to ‘gradual’ aging of 1.46 (CI: 1.18–1.81), 1.93 (CI: 1.42–2.62), 1.26 (1.02–1.57) and 1.76 (1.32–2.35), respectively. Between 30 and 70 years of age, men in the ‘early’ aging trajectory had the least healthy years (29.6 years), followed by women (30.1 years), and ‘gradual’ aging men (34.7 years). This study emphasizes that ‘physiological aging’ is not only an issue of older ages. Between 30 and 70 years of age, ‘early’ aging men and women had approximately five healthy years less compared to ‘gradual’ aging men. Lifestyle factors (e.g. nutrition and physical activity) seem to play an important role in optimal aging.
Objective
The aim of this exploratory study was to investigate the development of low‐grade inflammation during ageing and its relationship with frailty.
Methods
The trajectories of 18 inflammatory ...markers measured in blood samples, collected at 5‐year intervals over a period of 20 years from 144 individuals aged 65–75 years at the study endpoint, were related to the degree of frailty later in life.
Results
IFN‐γ‐related markers and platelet activation markers were found to change in synchrony. Chronically elevated levels of IL‐6 pathway markers, such as CRP and sIL‐6R, were associated with more frailty, poorer lung function and reduced physical strength. Being overweight was a possible driver of these associations. More and stronger associations were detected in women, such as a relation between increasing sCD14 levels and frailty, indicating a possible role for monocyte overactivation. Multivariate prediction of frailty confirmed the main results, but predictive accuracy was low.
Conclusion
In summary, we documented temporal changes in and between inflammatory markers in an ageing population over a period of 20 years, and related these to clinically relevant health outcomes.
This exploratory study gives unique insight into longitudinal changes in the immune profile of ageing men and women over a period of about 20 years, and revealed multiple associations of immune markers with clinically relevant outcomes at study endpoint, such as frailty, handgrip strength and lung function. More specifically, the findings implicate an important role for the IL‐6 pathway due to elevated markers such as CRP and, only in women, monocyte activation due to the involvement of sCD14.
Elderly often show reduced immune functioning and can develop chronic low-grade inflammation. Why some elderly are more prone to become frail is unknown. We investigated whether frailty is associated ...with altered cytokine signaling through the JAK-STAT pathway in leukocytes of 34 individuals aged 65-74 years. In addition, we investigated how this relation is affected by chronic low-grade inflammation during the previous 20 years. Cytokine signaling was quantified by measuring intracellular STAT1, STAT3, and STAT5 phosphorylation in monocytes, B cells, CD4
T cells and CD8
T cells upon stimulation with IL-2, IL-6, IL-10, IFNα and IFNγ, using phospho-flow cytometry. Presence of chronic low-grade inflammation was investigated by evaluating 18 different plasma inflammatory markers that had been measured repeatedly in the same individuals over the previous 20 years. Frailty was assessed as a score on a frailty index.
We found that lower cytokine-induced pSTAT responsiveness in the various cell subsets was seen with higher frailty scores in both men and women, indicative of dysfunctional pSTAT responses in frailer individuals. Associations differed between men and women, with frailer women showing lower pSTAT1 responses in monocytes and frailer men showing lower pSTAT5 responses in CD4
and CD8
T cells. Notably, lower IL-10-induced pSTAT3 responses in men were related to both higher frailty scores and higher CRP levels over the past 20 years. This might indicate poor resolution of low-grade inflammation due to defective regulatory pSTAT signaling in older men.
Our results emphasize the importance of preserved JAK-STAT pathway signaling in healthy aging and reveal cellular pSTAT levels as a candidate biomarker of frailty.
Cognitive decline is part of the normal aging process. However, some people experience a more rapid decline than others due to environmental and genetic factors. Numerous single nucleotide ...polymorphisms (SNPs) have been linked to cognitive function, but only a few to cognitive decline. To understand whether cognitive function and cognitive decline are driven by the same mechanisms, we investigated whether 433 SNPs previously linked to cognitive function and 2 SNPs previously linked to cognitive decline are associated with both general cognitive functioning at baseline and general cognitive decline up to 20-years follow-up in the Doetinchem Cohort Study (DCS). The DCS is a longitudinal population-based study that enrolled men and women aged 20-59 years between 1987-1991, with follow-up examinations every 5 years. We used data of rounds 2-6 (1993-2017, n = 2559). General cognitive function was assessed using four cognition tests measuring memory, speed, fluency and flexibility. With these test scores, standardized residuals (adjusted for sex, age and examination round) were calculated for each cognition test at each round and subsequently combined into one general cognitive function measure using principal component analyses. None of the 435 previously identified variants were associated with baseline general cognitive function in the DCS. But rs429358-C, a coding apolipoprotein E (APOE) SNP and one of the variants previously associated with cognitive decline, was associated with general cognitive decline in our study as well (p-value = 1 × 10
, Beta = -0.013). These findings suggest that decline of general cognitive function is influenced by other mechanisms than those that are involved in the regulation of general cognitive function.
Objectives: To determine whether a functional‐task exercise program and a resistance exercise program have different effects on the ability of community‐living older people to perform daily tasks.
...Design: A randomized, controlled, single‐blind trial.
Setting: Community leisure center in Utrecht, the Netherlands.
Participants: Ninety‐eight healthy women aged 70 and older were randomly assigned to the functional‐task exercise program (function group, n=33), a resistance exercise program (resistance group, n=34), or a control group (n=31). Participants attended exercise classes three times a week for 12 weeks.
Measurements: Functional task performance (Assessment of Daily Activity Performance (ADAP)), isometric knee extensor strength (IKES), handgrip strength, isometric elbow flexor strength (IEFS), and leg extension power were measured at baseline, at the end of training (at 3 months), and 6 months after the end of training (at 9 months).
Results: The ADAP total score of the function group (mean change 6.8, 95% confidence interval (CI)=5.2–8.4) increased significantly more than that of the resistance group (3.2, 95% CI=1.3–5.0; P=.007) or the control group (0.3, 95% CI=−1.3–1.9; P<.001). Moreover, the ADAP total score of the resistance group did not change significantly compared with that of the control group. In contrast, IKES and IEFS increased significantly in the resistance group (12.5%, 95% CI=3.8–21.3 and 8.6%, 95% CI=3.1–14.1, respectively) compared with the function group (−2.1%, 95% CI=−5.4–1.3; P=.003 and 0.3%, 95% CI=−3.6–4.2; P=.03, respectively) and the control group (−2.7%, 95% CI=−8.6–3.2, P=.003 and 0.6%, 95% CI=−3.4–4.6; P=.04, respectively). Six months after the end of training, the increase in ADAP scores was sustained in the function group (P=.002).
Conclusion: Functional‐task exercises are more effective than resistance exercises at improving functional task performance in healthy elderly women and may have an important role in helping them maintain an independent lifestyle.
Background and aims
: Insufficient vitamin D status, commonly found in older people, has been associated with muscle weakness which, in old age, impairs mobility and is a risk factor for falling. In ...a randomized, double-blind placebo-controlled trial, we tested the hypothesis that vitamin D + calcium supplementation improves muscle strength and mobility, compared with calcium mono-therapy in vitamin D-insufficient female geriatric patients.
Methods
: Seventy female geriatric patients >65 years of age with serum 25-hydroxyvitamin D
3
(25OHD) concentrations between 20 and 50 nmol/L, visiting an outpatient geriatric department, were included. Participants received either cholecalciferol 400 IU/day + calcium 500 mg/day (D/Cal group) or a placebo + calcium 500 mg/day (Plac/Cal group) for 6 months. At baseline and 6 months, muscle strength, power and functional mobility were tested.
Results
: At baseline, 25OHD was significantly (p<0.05) associated with knee extension strength (r=0.42), handgrip strength (r=0.28), leg extension power (r=0.34), Timed Get Up and Go (r=−0.31) and Modified Cooper test (r=0.44). At 6 months, a significant difference in 25OHD (77.2 vs 41.6 nmol/L, p<0.001) and 1,25OHD was found between the two groups. Significantly improving vitamin D status in the D/Cal group compared with the Plac/Cal group did not result in a significant difference in strength or functional mobility between the two groups.
Conclusions
: Daily 400IU vitamin D + 500 mg calcium supplementation is not enough to significantly improve strength or mobility in vitamin D-insufficient female geriatric patients.
Objectives
Cytomegalovirus infection is thought to affect the immune system and to impact general health during ageing. Higher CMV‐specific antibody levels in the elderly are generally assumed to ...reflect experienced viral reactivation during life. Furthermore, high levels of terminally differentiated and CMV‐specific T cells are hallmarks of CMV infection, which are thought to expand over time, a process also referred to as memory inflation.
Methods
We studied CMV‐specific antibody levels over ~ 27 years in 268 individuals (aged 60–89 years at study endpoint), and to link duration of CMV infection to T‐cell numbers, CMV‐specific T‐cell functions, frailty and cardiovascular disease at study endpoint.
Results
In our study, 136/268 individuals were long‐term CMV seropositive and 19 seroconverted during follow‐up (seroconversion rate: 0.56%/year). CMV‐specific antibody levels increased slightly over time. However, we did not find an association between duration of CMV infection and CMV‐specific antibody levels at study endpoint. No clear association between duration of CMV infection and the size and function of the memory T‐cell pool was observed. Elevated CMV‐specific antibody levels were associated with the prevalence of cardiovascular disease but not with frailty. Age at CMV seroconversion was positively associated with CMV‐specific antibody levels, memory CD4+ T‐cell numbers and frailty.
Conclusion
Cytomegalovirus‐specific memory T cells develop shortly after CMV seroconversion but do not seem to further increase over time. Age‐related effects other than duration of CMV infection seem to contribute to CMV‐induced changes in the immune system. Although CMV‐specific immunity is not evidently linked to frailty, it tends to associate with higher prevalence of cardiovascular disease.
We conducted a retrospective longitudinal study spanning ~27 years, which enabled us to identify cytomegalovirus (CMV) seroconverters in an ageing population and to quantify duration of CMV infection. We found that age‐related effects other than duration of CMV infection are important to CMV‐induced changes in the immune system, such as T‐cell responses and the expansion of the T‐cell memory pool. Although CMV‐specific immunity is not evidently linked to frailty, it tends to associate with higher prevalence of cardiovascular disease.
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