Selenium Concentrations and Mortality Among Community-Dwelling Older Adults: Results from ilSIRENTE Study

Abstract

Background

Selenium has a wide range of pleiotropic effects, influencing redox homeostasis, thyroid hormone metabolism, and protecting from oxidative stress and inflammation. Serum selenium levels are reduced in the older population.

Objectives

to investigate the association of serum selenium levels with all-cause mortality in a sample of community-dwelling older adults.

Design and Setting

Data are from the ‘Invecchiamento e Longevità nel Sirente' (Aging and Longevity in the Sirente geographic area, ilSIRENTE) study, a prospective cohort study that collected information on individuals aged 80 years and older living in an Italian mountain community (n=347). The main outcome was risk of death after ten years of follow-up.

Participants and measurements

Participants were classified according to the median value of selenium (105.3 μg/L) in two groups: high selenium and low selenium.

Results

A total of 248 deaths occurred during a 10-year follow-up. In the unadjusted model, low levels of selenium was associated with increased mortality (HR, 0.66; 95% CI 0.51-0.85). After adjusting for potential confounders the relationship remained significant (HR, 0.71; 95% CI 0.54-0.92).

Conclusions

Low serum levels of selenium are associated with reduced survival in elderly, independently of age and other clinical and functional variables.

Introduction

Selenium is a trace element that has a wide range of pleiotropic effects, influencing redox homeostasis, thyroid hormone metabolism, and protecting from oxidative stress and inflammation (1). Selenium has a direct role in antioxidant protection because it is present within the active centre of Glutatione peroxidises, a family of selenoproteins, which protect the cells from oxidative damage by catalyzing the reduction of the hydrogen peroxide by glutathione (2). It is well known that oxidative stress increases with age (3) and that aging is characterized by selenium deficit due to low intake, reduced physical functioning or severe pathologies (4).

Interestingly, a recent study (5) documented that weight change might be detrimental in older adults thus suggesting clinical interventions should focus on a correct nutritional status rather than weight loss or gain.

Moreover, it has been reported that the appropriate selenium blood levels at old age are associated with better self-perception of health (6, 7), chewing ability (6), reduce cognitive decline (8) and protect from diabetes (9). In this context, epidemiological findings link a low selenium levels to neurodegenerative (10) and cardiovascular (11) diseases as well as to increased cancer risk (12, 13).

In particular, there are reports from observational studies of an increased risk for myocardial infarction in patients with the lowest selenium status (14) while there were no conclusive evidence supporting an inverse association (15) between selenium levels and hypertension rate considering the presence of studies reporting non-significant16or even a positive (17) association.

In previous studies, low selenium level has been found to predict cancer-related mortality18 and all-cause mortality (19, 20) among community-dwelling adults aged from 50 to 80 years. However, so far, limited evidence is available on the association of selenium with mortality in older adults aged 80 or more. In healthy older adults selenium concentrations are slightly reduced compared to younger adults, but a relevant reduction in the concentration of this element is described in institutionalised (21) or frail elderly (22). In this perspective, the present study focuses on the prognostic role of selenium in a sample of frail octogenarians and nonagenarians living in community and it is aimed at investigating whether selenium serum levels predict all-cause mortality over a 10 years period in participants of the “Invecchiamento e Longevità nel Sirente” (Aging and longevity in the Sirente geographic area, ilSIRENTE Study) study.

Materials and methods

The ilSIRENTE study is a prospective cohort study conducted in the Sirente geographic area (L'Aquila, Abruzzo) in Central Italy. The protocol ilSIRENTE study is described in details elsewhere (23). The overall sample population enrolled in the ilSIRENTE study consisted of 364 individuals. Seventeen patients were excluded because the blood sample for the haematological assessment was insufficient. Finally, the study sample included 347 individuals.

Data collection

Baseline participants' assessment began in December 2003 and was completed in September 2004. The Minimum Data Set for Home Care (MDS-HC) form was administered to all study participants following the guidelines published in the MDSHC manual (24, 25). The MDS-HC contains over 350 data elements including socio-demographics, physical and cognitive status variables, as well as major clinical diagnoses (26) and an extensive array of signs, symptoms, syndromes, and treatments (24, 25). The MDS items have shown an excellent inter-rater and test-retest reliability when completed by nurses performing usual assessment duties (average weighted Kappa = 0.8) (27). Additional information about family history, lifestyle, physical activity and behavioral factors were collected using specific questionnaires shared with the “Invecchiare in Chianti Study” (28).

Blood measurements

Venus blood samples were drawn in the morning after an overnight fast using EDTA commercial collection tubes. Samples were immediately centrifuged at 1000 × g for 10 min at 4°C. The supernatant, corresponding to the plasma fraction, was collected, aliquoted and stored at −80°C until analysis. Standard determinations of serum albumin, cholesterol (total and HDL), and triglycerides were performed by commercially available kits (Olympus, Italy) suitable on Olympus 2700 instrumentation. Plasma interleukin-6 levels and Tumor Necrosis Factor -α were measures by enzyme-linked immunosorbent assay (ELISA; High Sensitivity Quantikine KitR&D Systems, Minneapolis, MN). Values were measured in duplicate and the average value was reported for all the assays. C-reactive protein was performed by commercially available kits (Olympus, Italy) suitable on Olympus 2700 instrumentation. Serum selenium levels were measured by graphite furnace atomic absorption spectrometry using a Perkin Elmer Analyst 600 with Zeeman background correction (Perkin Elmer Corporation, Norwalk, Connecticut). Within-run and between-run coefficients of variation were 5.8 percent and 4.8 percent. The distribution of serum selenium is normal. Given a lack of a standardized clinical cutoff for low-serum selenium, we considered participants with serum selenium up to the median (≤105.3 μg/L) to have low-serum selenium. Furthermore, our median value is closed to the assumed selenium/L of plasma or serum requirement for full plasma glutatione peroxidises expression (29).

Covariates

Disability status was assessed through the basic activities of daily living (ADL) (30) and instrumental ADL (IADL) (31) scales. The ADL scale explores the following tasks: eating, dressing, personal hygiene, mobility in bed, locomotion, use of the toilet and transfer. The scale ranges between 0 and 7, with higher scores indicating more severe impairment. The IADL scale explores meal preparation, shopping, telephone use, housekeeping, medication intake, handling finance and use of transportation. Similar to the ADL scale, the IADL scale ranges between 0 and 7, with higher scores indicating more severe impairment. Cognitive performance was assessed using a 6-items, 7-category scale (Cognitive Performance Scale - CPS) (25) with higher values corresponding to worse cognitive performance. Medical diagnoses and drugs were directly collected by general practitioners. Medical diagnoses were defined as conditions that have a relationship to the patient's functional, cognitive, and behavioral status, medical treatment, and risk of death. The diagnoses were listed on the MDS-HC form in a check-box section containing (27) specific diagnostic categories. General practitioner collected information on up to 18 different drugs received by each patient in the 7 days preceding the assessment. The body mass index (BMI) was calculated as the weight in kg divided by the square of height in metres. Current smoking was defined as the regular use of tobacco (at least once a week) in the last year.

Survival status

Survival status was obtained from general practitioners and confirmed by the National Death Registry. Time to death was calculated from the date of baseline assessment to that of death. All events that occurred over 10 years from enrolment were considered for the analyses.

Statistical analysis

To test the hypothesis that joint elevation of selenium plasma levels would confer the greatest risk of death, participants were classified in two groups by its median value (selenium: 105.3 μg/L). Cox proportional hazards models were used to estimate crude and adjusted hazard ratios and 95% confidence intervals of death by selenium levels. Time to death was calculated from the date of baseline assessment to the date of death. We examined all events which occurred during the 10 year follow up. Analyses were adjusted for age, gender, functional impairment (IADL scale score), BMI, Cancer, HDL-cholesterol levels, IL-6, CRP. The impact of selenium on survival was also tested comparing the survival curves obtained with the Kaplan- Meier method.

Results

Characteristics of the study population according to the serum selenium levels are summarized in Table 1. Participants in the low selenium group were older, more likely to be women and to report a history of cancer. Concerning biological parameters, total cholesterol and tryglicerides concentrations were higher in individuals with high selenium blood levels (p<0.001 and p=0.033, respectively) such as protective HDLcholesterol (p=0.001). Participants with higher selenium levels had lower blood levels of IL-6 (p=0.002) and CRP (p=0.001), but no association was observed between selenium and TNF-α.

Table 1.

Characteristics of Study Population according to selenium serum levels

Characteristic	Total sample (n=347)
	High selenium (n=172)	Low selenium (n=175)	p
Age, years	85.1 ± 4.1	86.5 ± 5.3	0.009
Female	123 (49)	108 (67)	0.034
Marital status
Married	44 (25.6)	55 (31.4)	0.411
Widowed	111 (64.5)	101 (57.7)	0.410
Never married	17 (9.9)	19 (10.9)	0.284
Living alone	54 (31.8)	41 (24.8)	0.100
Education, years	5.1 ± 1.5	5.1 ± 1.6	0.799
Activity of Daily Living Scale score ^	1.2 ± 2.3	1.6 ± 2.5	0.149
Instrumental Activity of Daily Living Scale score ∞	2.8 ± 2.5	3.34 ± 2.6	0.053
Cognitive Performance Scale score +	0.7 ± 1.3	1.0 ± 1.7	0.075
Number of diseases	2.2 ± 1.2	2.0 ± 1.3	0.210
Specific Disease
Hypertension	127 (73.8)	122(69.7)	0.232
Congestive Heart Failure	9 (5.2)	13 (7.4)	0.269
Chronic Heart Disease	22 (12.8)	18 (10.3)	0.287
Cancer	5 (2.9)	12 (6.9)	0.072
Chronic Obstructive Pulmonary Disease	22 (12.8)	24 (13.7)	0.462
Diabetes	53 (30.8)	50 (28.6)	0.367
Cerebrovascular Diseases	7 (4.1)	9 (5.1)	0.413
Number of medications	3.1 ± 2.1	3.4 ± 2.2	0.163
Body Mass Index, kg/m2	26.0 ± 4.5	25.1 ± 4.5	0.071
Smoking habit	170 (98.8)	169 (96.6)	0.147
Hematological parameters
Albumin, g/dl	4.2 ± 0.2	4.1 ± 0.3	0.061
Total Protein g/dl	7.0 ± 0.4	6.9 ± 0.6	0.14
Hemoglobin	13.3 ± 1.5	13.0 ± 1.9	0.08
Total cholesterol, mg/dl	206 ± 43.3	185.2 ± 42.7	<0.001
HDL-cholesterol, mg/dl	48.1 ± 15.7	43.2 ± 10.3	0.001
Triglycerides, mg/dl	151.5 ± 61	137.7 ± 58.3	0.033
IL-6, pg/mL	2.5 ± 2.2	3.4 ± 2.8	0.002
CRP, mg/L	3.5 ± 3.1	4.8 ± 3.7	0.001
TNF-α, pg/mL	1.8 ± 2.1	2.05 ± 2.3	0.335

*Data are given as number (percent) for the following variables: gender, marital status, living alone, specific disease, smoking habit; for all the other variables means ± SD are reported; ^Activity of Daily Living Scale ranges from 0 (no functional impairment) to 7 (severe functional impairment); ∞Instrumental Activity of Daily Living Scale ranges from 0 (no functional impairment) to 8 (severe functional impairment); +Cognitive Performance Scale ranges from 0 (no cognitive impairment) to 6 (severe cognitive impairment)

After ten years of follow-up, 248 participants (72%) had died. Of these, 135 (78.5%) had serum selenium levels up to the median and 113 (65.7%) above the median (p<0.001). Table 2 shows Cox proportional hazards models. In the unadjusted model, low levels of selenium were associated with increased mortality (HR, 0.66; 95% CI 0.51–0.85). After adjusting for potential confounders, low levels of selenium were still associated with a significantly increased risk of death (HR, 0.71; 95% CI 0.54–0.92). The impact of serum selenium levels on 10-year survival was also tested comparing the survival curves obtained with the Kaplan-Meier method as shown in Figure 1. Survival curves illustrate that the relationship between serum selenium and mortality remained pertinent during the entire 10-year period, with a log rank<0.001.

Table 2.

Association between Selenium Levels and All-Cause Mortality, after Adjustment for Various Confounders

SELENIUM	Mortality	Unadjusted	Model 1*	Model 2^
during
10-years
follow-up
	Number	Hazard Ratio (95% Confidence Interval)
	(%)
All subjects (n=347)
Low selenium	135 (78.5)	-	-	-
(n=172)
High selenium (n=175)	113 (65.7)	0.66 (0.51-0.85)	0.69 (0.53-0.89)	0.71 (0.54-0.92)

* In Model 1 we adjusted for age, gender, IADL scale score, BMI, Cancer; ^ In Model 2 we adjusted for age, gender, IADL scale score, BMI, Cancer, HDL-cholesterol, IL-6, CRP.

Figure 1.

Survival curves for patients according to the serum selenium levels at baseline

Discussion

In the present study, we investigated the role of serum selenium levels as predictor of 10-year mortality in a sample of community-dwelling individuals aged 80 years and older. This study shows that, in a representative sample of the Italian elderly population, participants with low serum selenium levels are at higher risk of death. These results are consistent with observations from three other cohort studies, the Etude du Vieillissement Arteriel (EVA) study (18), the Women's Health and Aging Studies I and II (WHAS) (19) and the InCHIANTI Study (20) showing a relationship between plasma/serum selenium levels and mortality in unselected elderly of three distinct geographic areas. These findings are in agreement with the low percentages of selenium deficiencies reported as a possible explanation for longevity in the nonagenariancentenarian study (32). To further corroborate these results , in an elderly Swedish population has been reported a higher cardiovascular mortality among those with low serum selenium concentration with substantial reductions after the dietary supplementation over four years with selenium and coenzyme Q10 (33).

We showed in our study an inverse correlation between serum selenium and IL-6 and CRP. Old subjects with the lowest selenium levels display high IL-6 and CRP levels coupled with an higher risk of mortality over a period of 10 years, with thus a close relationship between selenium state and inflammation mediated by IL-6 and CRP in elderly (34). Consistently, serum selenium was inversely associated with inflammatory cytokine interleukin-6 among elderly living in long-term care facilities in Taiwan (35).

It has been proven that all selenoproteins are able to protect cellular membranes from hydroxyl radicals and peroxynitrite or at least to maintain the redox state within the cells (36). However, a well-known activity of selenium is protecting the immune cells from reactive oxygen species produced during inflammation (37) .Higher selenium levels may potentially reduce redox-related upregulation of IL-6 and CRP thus positively influence the age-related pro-inflammatory state.

Selenium deficiency is associated with many inflammatory tissue reactions and with disease progression, including myocarditis, human immunodeficiency virus, thyroid dysfunction, arthritis, cancer, depression, and cardiovascular disease (38). This selenium deficiency-related hastening of a host of disease processes may partly clarify the association between mortality and lower selenium levels.

A limitation of the present study is that the specific causes of death have not yet been ascertained, and that this study reports only all-cause mortality. Although specific causes of death were known in the IlSIRENTE study, the power to detect a relationship between serum selenium levels and specific causes of mortality may currently be limited because of small sample size. In the EVA study, when the underlying causes of death were considered, an association with low selenium and cancerrelated mortality was found (18).

Conclusion

In conclusion, in our study low serum selenium concentrations were associated with an increased risk of dying among older adults living in the community. Our findings support the hypothesis of a strong implication of selenium status in the process of living an extremely long life.

Funding

The “Invecchiamento e Longevità nel Sirente” (ilSIRENTE) study was supported by the “Comunità Montana Sirentina” (Secinaro, L'Aquila, Italy).

Conflict of interest

None.

Statement of authorship

All authors have made substantial contributions to all of the following: (1) the conception and design of the study, or acquisition of data, or analysis and interpretation of data, (2) drafting the article or revising it critically for important intellectual content, (3) final approval of the version to be submitted.