How to grow older and still maintain good health
As we grow older, our health tends to deteriorate. Our blood vessels clog up, our circulation slows down, our hearts lose strength, we have problems with our joints, and we tend to tire more easily. It’s only natural – but so are the things we can do to prevent this from happening.
How Swedish scientists managed to cut heart deaths by over 50%
Leading Swedish cardiologists have published a sensational study showing how easily they were able to reduce cardiovascular mortality by over 50% among a large group of town villagers.
Medical history is being written these days in a hamlet called Kisa just outside of Linköping in the southeastern region of Sweden. Some of Sweden’s leading cardiologists have conducted a study on 443 of the elderly town villagers and discovered, much to their own surprise, that a novel treatment which has never been tested before reduces the risk of dying from heart disease by over 50 per cent. Considering that cardiovascular disease is the number one killer in Western countries, this discovery is quite a sensation.
The KiSel-10 Study
The KiSel-10 clinical trial was a prospective randomized, double-blind, placebo-controlled study designed and carried out by Professor Urban Alehagen and a team of researchers at Linköping University in Sweden.
The study was an investigation of the effect of a combination of Coenzyme Q10 capsules and high-selenium yeast tablets, as compared with placebo capsules and tablets, on the rate of death from heart disease, the age-related change in heart function as measured by echocardiograms, and the changes in blood concentrations of cardiac natriuretic peptides.
The researchers enrolled, initially, 443 healthy elderly citizens of the Kinda municipality, both men and women, aged 70 – 87 years. The study participants received either the active treatment — a combination of 200 milligrams per day of Coenzyme Q10 and 200 micrograms per day of organic selenium yeast — or matching placebos daily for four years. The study began in 2003 and was completed in 2010.
At the start of the study, the mean serum selenium concentration was 67.1 μg/L (SD 16.8). After 48 months, the concentration of selenium in the active treatment group was 210.3 μg/L (SD 59.4).
Regarding the concentration of coenzyme Q10, the pre-intervention concentration in the population was 0.82 mg/L (SD 0.31), and the concentration in the active treatment group after 48 months was 2.17 mg/L (SD 1.33).
To date, autumn 2021, the researchers have published 19 papers detailing the results of the analysis of the data from the KiSel-10 study.
Following are the citations and summaries of these 19 published journal articles.
1. Alehagen U, Johansson P, Björnstedt M, Rosén A. Relatively high mortality risk in elderly Swedish subjects with low selenium status. Eur J Clin Nutr. 2016;70:91-6.
The Linköping University researchers knew that the daily dietary intake of selenium is generally quite low in Sweden. They measured and evaluated the serum selenium levels of 668 elderly citizens of the rural municipality of Kisa. They established that the serum selenium concentrations of the study participants in this sample was, on average, 67.1 micrograms per liter. This is a level considerably below the physiological saturation level required for the activation of several important selenoproteins.
The researchers made appropriate adjustments to rule out the effect of such confounding variables as male gender, smoking, diabetes, chronic obstructive pulmonary disease, and impaired heart function and found that individuals in the lowest quartile of serum selenium concentrations were at a 43% greater risk of death from all causes and at a 56% greater risk of death from heart disease. The researchers concluded that moderate daily supplementation with selenium might improve the overall health of the Swedish population.
2. Alehagen U, Johansson P, Björnstedt M, Rosén A. Cardiovascular mortality and N-terminal-proBNP reduced after combined selenium and coenzyme Q10 supplementation: A 5-year prospective randomized double-blind placebo-controlled trial. Int J Cardiol. 2013;167:1860-1866.
This 2013 journal article was the first and primary report based on data from the KiSel-10 study. Professor Alehagen and his colleagues reported that four years of daily supplementation with a combination of Coenzyme Q10 and high-selenium yeast had resulted in a 54% reduction in the risk of dying from heart disease.
Moreover, the data showed significantly lower levels of the N-terminal proBNP peptide – a known biomarker for heart disease – in the blood of the study participants who had received the combination of Coenzyme Q10 and selenium, and the echocardiograms of the study participants receiving the active treatment showed significantly better heart function.
3. Johansson P, Dahlstrom O, Dahlstrom U, Alehagen U. Effect of selenium and Q10 on the cardiac biomarker NT-proBNP. Scand Cardiovasc J. 2013;47:281-8.
The purpose of the KiSel-10 study was to investigate whether four years of supplementation with a combination of Coenzyme Q10 and high-selenium yeast would slow the age-related decline of heart function in elderly Swedish citizens. The researchers’ analysis of the data from measurements of the biomarker N-terminal natriuretic peptide at baseline and again after four years of supplementation showed that individuals in the middle three quintiles – quintiles two through four, representing individuals with mild to moderate heart function impairment – benefitted most from the supplementation.
4. Alehagen U, Lindahl TL, Aaseth J, Svensson E. Levels of sP-selectin and hs-CRP decrease with dietary intervention with selenium and coenzyme Q10 combined: a secondary analysis of a randomized clinical trial. PLoS One. 2015;10:e0137680.
The KiSel-10 researchers also evaluated the effect of the combination supplementation on the blood concentrations of the C-reactive protein – a known biomarker for inflammation – and of the sP-selectin cell adhesion molecules – known biomarkers for oxidative stress. Elevated levels of each of these biomarkers may be related to higher risk of atherosclerosis and heart disease.
The study results showed that C-reactive protein levels increased in the placebo group over time but decreased significantly in the active treatment group. Levels of the sP-selectin molecules increased in both groups but increased very significantly in the placebo group and only slightly in the active treatment group.
5. Alehagen U, Aaseth J, Johansson P. Less increase of copeptin and MR-proADM due to intervention with selenium and coenzyme Q10 combined: Results from a 4-year prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens. Biofactors. 2015;41:443-52.
Both Coenzyme Q10 (in its reduced form) and selenium as a component of certain selenoproteins function as antioxidants in the body. The KiSel-10 researchers evaluated the effect of the combination supplementation on two biomarkers of oxidative stress: copeptin and adrenomedullin.
Over the four-year period of the study, the data showed a significant increase in copeptin levels in the placebo group, as compared to the active treatment group. Similarly, the data showed a lesser increase of adrenomedullin in the active treatment group compared to the placebo group.
And, of course, the KiSel-10 data showed significantly less death from heart disease in the active treatment group. The same cardioprotective effect of the supplementation was seen again in a follow-up study after 10 years of observation.
6. Johansson P, Dahlstrom O, Dahlstrom U, Alehagen U. Improved health-related quality of life, and more days out of hospital with supplementation with selenium and coenzyme Q10 combined. J Nutr Health Aging. 2015;19:870-7.
In a sub-analysis of the data from KiSel-10 study participants who were matched for age, gender and baseline cardiac wall tension as measured by NT-proBNP, the researchers found that the average number of days hospitalized was significantly lower in the active treatment group as compared to the placebo group.
Furthermore, the study participants who received the combination supplementation showed significantly lesser declines in various aspects of health-related quality of life: physical role performance, vitality, cognitive function, nervous system function, and overall quality of life.
The supplementation with Coenzyme Q10 and selenium increased the number of days study participants stayed out of the hospital and slowed the age-related decline in health-related quality of life.
7. Alehagen U, Aaseth J, Johansson P. Reduced cardiovascular mortality 10 years after supplementation with selenium and coenzyme Q10 for four years: follow-up results of a prospective randomized double- blind placebo-controlled trial. PLoS One. 2015; 10(12):e0141641.
Using the information in death certificates and autopsy reports available from the Swedish National Registry of Mortality, the KiSel-10 researchers were able to follow study participants for up to ten years following the initiation of the four-year intervention period. They reported that no participant was lost to follow-up.
The significantly reduced risk of death from heart disease, first reported in 2013, was seen to persist for the entire ten-year follow-up period in the study participants who had received the Coenzyme Q10 and selenium combination. Sub-group analysis of the data showed that the effect persisted in both males and females.
8. Alehagen U, Aaseth J. Selenium and coenzyme Q10 interrelationship in cardiovascular diseases – A clinician s point of view. J Trace Elem Med Biol. 2015;31:157-62.
Professor Alehagen (Sweden) and Professor Aaseth (Norway) explained the clinical significance of the combination supplementation with Coenzyme Q10 and high-selenium yeast by pointing to the potential role of selenium deficiency in heart disease, with emphasis on the antioxidant role of various selenoproteins, including the glutathione peroxidases and selenoprotein P.
In their explanation, they stressed the special interrelationship between selenium and Coenzyme Q10, itself a fat-soluble anti-oxidant in its reduced form.
Insufficient intakes of selenium can prevent the cells from getting adequate concentrations of Coenzyme Q10. Moreover, the cells need adequate Coenzyme Q10 levels in order to achieve optimal selenium function.
9. Alehagen U, Alexander J, Aaseth J. Supplementation with selenium and coenzyme Q10 reduces cardiovascular mortality in elderly with low selenium status: a secondary analysis of a randomised clinical trial. PLoS One. 2016;11:e0157541.
The KiSel-10 researchers did a secondary analysis of the available data to determine whether the positive effects of daily supplementation with Coenzyme Q10 and high-selenium yeast for four years are directly associated with the baseline serum selenium levels of study participants.
They reported two important findings from their secondary analysis: 1) the risk of death from heart disease was higher among study participants with baseline serum selenium concentrations lower than 65 micrograms per liter as compared with study participants whose baseline serum selenium concentrations were above 85 micrograms per liter, and 2) the daily supplementation with a combination of Coenzyme Q10 and high-selenium yeast was shown to provide protection against death from heart disease in the study participants with baseline serum selenium levels below 85 micrograms per liter.
10. Alehagen U, Johansson P, Aaseth J, Alexander J. Significant changes in circulating microRNA by dietary supplementation of selenium and coenzyme Q10 in healthy elderly males: A subgroup analysis. PLoS One. 2017;12:e0174880.
The KiSel-10 researchers focused in on the data from 50 study participants, all males, 25 of whom had been in the active treatment group and 25 of whom had been in the placebo group. They isolated RNA from the plasma of these 50 study participants.
Then they analyzed the pre-treatment and post-treatment levels of expression of numerous microRNAs. At baseline, there were no significant differences between the two groups in terms of microRNA expression levels. After four years of treatment with either Coenzyme Q10 and high-selenium yeast or placebo, however, the data showed significant differences between the two groups in as many as 70 different microRNAs. (MicroRNAs are non-coding RNA molecules involved in the regulation of genes that code for proteins. These microRNAs can inhibit the expression of genes and thus influence the formation of proteins. MicroRNAs can play a significant role in the development of heart disease and diabetes.)
The researchers concluded that the significant differences between the Coenzyme Q10/high-selenium yeast treatment group and the placebo group in the expression of microRNAs might be one of the biological mechanisms by which the supplementation with Coenzyme Q10 and high-selenium yeast reduced significantly the risk of death from heart disease and reduced the extent of inflammation in the elderly Swedish citizens.
11. Alehagen U, Johansson P, Aaseth J, Alexander J. Increase in insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 1 after supplementation with selenium and coenzyme Q10. PLoS One. 2017;12:e0178614.
The KiSel-10 study data show conclusively that daily Coenzyme Q10 and high-selenium yeast supplements provide protection against death from heart disease and from age-related declines in heart function. The researchers trace these beneficial effects in part to the antioxidant and anti-inflammatory functions of the two substances.
Insulin-like growth factor-1 (abbreviated IGF-1) has many functions in the body such as cell growth and metabolism and also anti-inflammatory and antioxidative effects. IGF-1 concentrations decrease with age and during periods of inflammation.
The KiSel-10 researchers examined the effects of four years of daily supplementation with Coenzyme Q10 and high-selenium yeast on concentrations of IGF-1 and its binding protein IGFBP-1 in the elderly Swedish study participants. They found that the individuals in the group taking Coenzyme Q10 and high-selenium yeast supplements had significantly increased IGF-1 and IGF-1 SD scores at the end of the study period while individuals in the placebo group had reduced concentrations.
The researchers suggested that the positive effect of Coenzyme Q10 and high-selenium yeast supplementation on IGF-1 concentrations might be one of the biological mechanisms explaining the positive clinical effects the risk of death from heart disease and on heart function.
12. Alehagen U, Aaseth J, Alexander J, Svensson E. Less fibrosis in elderly subjects supplemented with selenium and coenzyme Q10: A mechanism behind reduced cardiovascular mortality? Biofactors. 2018;44:137-147.
Professor Alehagen and his research colleagues investigated the effect of supplementation with Coenzyme Q10 and high-selenium yeast on eight bio-markers of fibrogenic activity in healthy elderly Swedish citizens, aged 70 – 88 years. They analyzed the blood concentrations of the various bio-markers at the six-month mark and the 42-month mark in the study. The data showed that there were significantly reduced blood concentrations of seven of the eight bio-markers in the active Coenzyme Q10 and selenium group after 42 weeks of supplementation as compared with the placebo group. The reduced fibrogenic activity seems to be a consequence of the daily intervention with Coenzyme Q10 and high-selenium supplements. There appears to be an association between the supplementation and the reduction in the bio-markers of fibrosis and the statistically significant reduction in the risk of death from cardiovascular disease among the elderly study participants.
Note: Cardiac fibrosis – the development of excess fibrous tissue depositions in the heart muscle or heart valves – can increase the risk of heart failure.
13. Alehagen U, Aaseth J, Alexander J, Johansson P. Still reduced cardiovascular mortality 12 years after supplementation with selenium and coenzyme Q10 for four years: A validation of previous 10-year follow-up results of a prospective randomized controlled trial. PLoS One. 2018;13:e0193120 .
Even as long as 12 years after the supplementation with Coenzyme Q10 and high selenium yeast, elderly Swedish citizens who got the active treatment rather than the placebo treatment showed significantly lower risk of death from heart disease. Moreover, the reduced risk in the active treatment group was seen in such subgroups of patients as those with diabetes, hypertension, ischemic heart disease, and impaired functional capacity. Professor Alehagen and his team of researchers have not determined all of the mechanisms of the protective action of the Coenzyme Q10 and selenium supplements, but they point to the documented effects of the supplement combination on heart function, oxidative stress, fibrosis, and inflammation.
14. Alehagen U, Alexander J, Aaseth J, Larsson A. Decrease in inflammatory biomarker concentration by intervention with selenium and coenzyme Q10: a subanalysis of osteopontin, osteoprotergerin, TNFr1, TNFr2 and TWEAK. J Inflamm (Lond). 2019;16:5.
In a secondary analysis of a sub-group of 219 individuals from the larger KiSel-10 study of 443 senior citizens aged 70 to 88 years at baseline, Professor Alehagen and his colleagues examined the effect of daily supplementation with 200 micrograms of high-selenium yeast and 200 milligrams of ubiquinone CoQ10 on plasma bio-markers of inflammation after 6 months and after 42 months. The results showed significantly lower concentrations of the following bio-markers for inflammation: osteopontin, osteoprotegerin, sTNF receptor 1, and sTNF receptor 2. Only the tumor necrosis factor-like weak inducer of apoptosis called TWEAK did not show a significant reduction associated with the selenium yeast and Coenzyme Q10 supplementation.
These results follow the earlier report that daily supplementation with selenium yeast and Coenzyme Q10 in the KiSel-10 study was associated with significant positive changes in the inflammatory bio-markers C-reactive protein and sP-selectin, reflecting important effects on inflammation and atherosclerosis in the individuals who took the combined selenium yeast and Coenzyme Q10 treatment as compared to the individuals who took the matching placebos.
These results indicating a significant decrease in inflammation could be one of the mechanisms by which the combined selenium yeast and Coenzyme Q10 supplementation reduced cardiovascular mortality and improved heart function in senior citizens. In an earlier publication, Professor Alehagen and his colleagues presented evidence that the four-year combined supplementation was associated with significantly reduced levels of oxidative stress.
One possible conclusion is that the combined supplementation improved the senior citizens’ anti-oxidative and anti-inflammatory defenses to an extent that resulted in reduced cardiovascular mortality, improved heart function, and improved health-related quality of life.
15. Alehagen U, Johansson P, Aaseth J, Alexander J. Significant changes in metabolic profiles after intervention with selenium and coenzyme Q10 in an elderly population. Biomolecules. 2019;10:E553.
In this sub-analysis, Professor Alehagen reported clear differences in the metabolic profiles in plasma from elderly men who took 200 micrograms of selenium and 2 x 100 milligrams of Coenzyme Q10 daily for at least 18 months as compared to the metabolic profiles of elderly men who took matching placebos. The researchers found major differences in such biological pathways as the pentose phosphate pathway, the mevalonate pathway, and the beta-oxidation pathway. They concluded that these effects of the combined selenium and Coenzyme Q10 supplementation, together with the reduced levels of oxidative stress, inflammation, and fibrosis associated with the combined supplementation, help to explain that four years of supplementation with selenium and Coenzyme Q10 is associated with significantly reduced cardiovascular mortality, improved heart function, and improved health-related quality of life in senior citizens.
16. Alehagen U, Alexander J, Aaseth J, Larsson A. Significant decrease of von Willebrand factor and plasminogen activator inhibitor-1 by providing supplementation with selenium and Coenzyme Q10 to an elderly population. European Journal of Nutrition. 2020;59:3581-3590.
The elderly KiSel-10 Study participants (age range: 70 – 88 years) were given 200 milligrams of Coenzyme Q10 (2 times 100 milligrams at different times) and 200 micrograms of organic selenium yeast or matching placebos daily for four years. One of the main results from the study was a significant reduction in cardiovascular mortality. In this sub-analysis, Professor Alehagen and his team of researchers found significantly lower levels of von Willebrand factor and plasminogen activator inhibitor-1 in the active treatment group as compared to the placebo group. They interpreted these outcomes as an indication that the intervention had improved endothelial function. The better endothelial function may be one of the mechanisms by which the combination of selenium and Coenzyme supplements results in significantly reduced cardiovascular mortality.
Increased concentrations of the von Willebrand factor have been linked to increased risk of cardiovascular disease and heart attack. The von Willebrand factor is a plasma glycoprotein that is important for hemostasis and coagulation (the first stage of wound healing). The von Willebrand factor is produced and stored in the endothelial cells and platelets. However, increased concentrations of the von Willebrand factor are regarded as a sign of vascular dysfunction.
Plasminogen activator inhibitor-1 is secreted from endothelial cells and liver cells. It is also synthesized and stored in platelets. Higher levels of plasminogen activator inhibitor-1 have been associated with increased risk of ischemia and coronary artery disease and with the development of diabetes and insulin resistance.
In this sub-study of the KiSel-10 Study, the concentration of both von Willebrand factor and plasminogen activator inhibitor-1 were significantly lower after 36 months of supplementation with selenium and Coenzyme Q10.
17. Alehagen U, Aaseth J, Alexander J, Johansson P. Supplemental selenium and coenzyme Q10 reduce glycation along with cardiovascular mortality in an elderly population with low selenium status. Journal of Trace Elements in Medicine and Biology. 2020;61:126541.
In this sub-study of the KiSel-10 Study of heart disease mortality, Professor Alehagen determined the fructosamine plasma concentrations after six and 42 months of intervention in 219 study participants supplemented with selenium yeast (200 μg/day) and Coenzyme Q10 (200 mg/ day) (n = 118 of whom 20 had diabetes at inclusion) or matching placebos (n = 101 of whom 18 had diabetes at inclusion).
Fructosamine is a marker for long-term glycemic control in diabetic patients. It is positively associated with risk of cardiovascular diseases both in diabetics and non-diabetics.
The data show that the intervention with selenium and Q10 was associated with a significant decrease in plasma fructosamine concentration. The decrease was observed in both males and females, in both the middle-aged and in the elderly, and in the non-diabetic group. Study participants with a lower pre-intervention level of selenium had a more pronounced decrease in plasma fructosamine concentrations.
Professor Alehagen suggested that the decrease in plasma fructosamine levels may have contributed to the reduced cardiac mortality associated with the selenium and Coenzyme Q10 intervention and might reflect the lower levels of bio-markers of inflammation and oxidative stress that have been associated with the combination supplementation.
18. Alehagen U, Brismar K, Alexander J, Aaseth J. Selenium and Coenzyme Q10 supplementation improves renal function in elderly deficient in selenium: observational results and results from a subgroup analysis of a randomised placebo controlled trial. Nutrients. 2020;12(12):3780.
In a sub-analysis of the KiSel-10 data, Professor Alehagen searched for a possible association between selenium and renal function in an elderly population low in selenium and coenzyme Q10 and investigated the impact of intervention with selenium and coenzyme Q10 on the renal function. In individuals with a deficiency of selenium and coenzyme Q10, low selenium status was found to be related to impaired renal function, and supplementation with selenium and coenzyme Q10 resulted in significantly improved renal function as seen from creatinine levels and cystatin-C levels and through the use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) algorithm.
19. Alehagen U, Aaseth J, Lindahl TL, Alexander J. Dietary supplementation with selenium and Coenzyme Q10 prevents increase in plasma D-dimer while lowering cardiovascular mortality in an elderly Swedish population. Nutrients. 2021;13:1344.
Elevated levels of fragments of the fibrinolysis process, called D-dimers, in the blood are a bio-marker for possible thromboembolic processes. In addition, elevated D-dimer levels may reflect age-related inflammatory activity and endothelial dysfunction.
In a sub-analysis of data from elderly community-living Swedish citizens with a relative selenium deficiency at the start of the KiSel-10 Study, Professor Urban Alehagen and a team of researcher found that the level of plasma D-dimer in the placebo group had increased during the study period but had remained unchanged or was slightly reduced in the active treatment group receiving 200 milligrams of Coenzyme Q10 and 200 micrograms of selenium daily. After 48 months, the plasma D-dimer levels were significantly lower in the active treatment group compared with the placebo group.
The researchers observed a significantly reduced heart disease mortality among study participants with a high baseline D-dimer level when given selenium and Coenzyme Q10 as compared to study participants given placebo. The researchers also found lower concentrations of D-dimer as a result of the supplementation in patients with hypertension or ischemic heart disease.
As more studies based on the KiSel-10 data are published, we will summarize them here for you.
In addition to publishing journal articles based on the data from the KiSel-10 clinical trial, Professor Alehagen has co-authored papers on the following topics together with Professor Jan Aaseth and Professor Jan Alexander.
Alehagen U, Opstad TB, Alexander J, Larsson A, Aaseth J. Impact of selenium on biomarkers and clinical aspects related to ageing. A review. Biomolecules 2021;11:1478.
Aaseth J, Alexander J, Alehagen U, Tinkov A, Skalny A, Larsson A, Crisponi G, Nurchi VM. The Aging Kidney-as influenced by heavy metal exposure and selenium supplementation. Biomolecules. 2021 Jul 22;11(8):1078.
Aaseth J, Alexander J, Alehagen U. Coenzyme Q10 supplementation – In ageing and disease. Mech Ageing Dev. 2021 Jul;197:111521.
Aaseth J, Ellefsen S, Alehagen U, Sundfør TM, Alexander J. Diets and drugs for weight loss and health in obesity – An update. Biomed Pharmacother. 2021 Aug;140:111789.
Alexander J, Alehagen U, Aaseth JO. Selenium – a trace element of clinical significance. Tidsskr Nor Laegeforen. 2020 Nov 23;140(17).
Alexander J, Tinkov A, Strand TA, Alehagen U, Skalny A, Aaseth J. Early nutritional interventions with zinc, selenium and vitamin d for raising anti-viral resistance against progressive COVID-19. Nutrients. 2020 Aug 7;12(8):2358.
Aaseth J, Alexander J, Bjørklund G, Hestad K, Dusek P, Roos PM, Alehagen U. Treatment strategies in Alzheimer’s disease: a review with focus on selenium supplementation. Biometals. 2016 Oct;29(5):827-39.