Total Cholesterol and All-cause Mortality by Sex and Age: A Prospective Cohort Study Among 12.8 Million Adults
It is unclear whether associations between total cholesterol (TC) levels and all-cause mortality and the optimal TC ranges for lowest mortality vary by sex and age. 12,815,006 Korean adults underwent routine health examinations during 2001–2004, and were followed until 2013. During follow-up, 694,423 individuals died. U-curve associations were found. In the TC ranges of 50–199 and 200–449 mg/dL, each 39 mg/dL (1 mmol/L) increase in TC was associated with 23% lower (95% CI:23%,24%) and 7% higher (6%,7%) mortality, respectively. In the age groups of 18–34, 35–44, 45–54, 55–64, 65–74, and 75–99 years, each 1 mmol/L higher TC increased mortality by 14%, 13%, 8%, 7%, 6%, and 3%, respectively (P < 0.001 for each age group), for TC ≥ 200 mg/dL, while the corresponding TC changes decreased mortality by 13%, 27%, 34%, 31%, 20%, and 13%, respectively, in the range < 200 mg/dL (P < 0.001 for each age group). TC had U-curve associations with mortality in each age-sex group. TC levels associated with lowest mortality were 210–249 mg/dL, except for men aged 18–34 years (180–219 mg/dL) and women aged 18–34 years (160–199 mg/dL) and 35–44 years (180–219 mg/dL). The inverse associations for TC < 200 mg/dL were stronger than the positive associations in the upper range.
Reduction of total cholesterol (TC) has been an integral part of public health campaigns, such as Healthy People 2020 in the US and Under 5 in Norway1,2,3, as well as cardiovascular disease (CVD) risk prediction models. This goal has primarily been supported by the success of statin trials showing that statin therapy reduced mortality from ischemic heart disease (IHD)4,5. “The lower, the better” cholesterol hypothesis has been accepted by many health professionals. However, the statin trials were mainly performed in persons at a high risk of heart disease, especially in men with manifest CVD, in whom heart disease mortality constituted approximately 50% of all deaths6.
Although disease-specific morbidity and mortality, such as IHD mortality, have their analytical merits, all-cause mortality is arguably the most important endpoint for patients or the general population when assessing risk factors and the effectiveness of a treatment or a public health intervention for life-threatening diseases7. The target TC levels for public health interventions in the general population should be determined after careful consideration of the levels associated with the lowest mortality in the general population. The associations of TC and all-cause mortality, however, have been relatively infrequently examined, and the associations have been inconsistent: positive linear8, inverse9, U-curve10,11,12, and reverse-L-curve13,14 associations have all been found. Moreover, cholesterol levels differ by sex and age15,16,17,18. It is unclear whether and to what extent the associations of cholesterol with mortality differ by sex and age3,17.
Through a large prospective cohort study among over 12 million participants, we examined whether the association between TC levels and all-cause mortality varied by sex and age, and estimated the sex- and age-specific levels of TC associated with the lowest mortality. Additionally, detailed estimates of the mean (and median) concentrations of TC according to sex and age are presented.
Study population and follow-up
Ninety-seven percent of the Korean population receives compulsory health insurance through the National Health Insurance Service (NHIS). The Korean Metabolic Risk Factor (KOMERIT) study included 12,845,017 NHIS beneficiaries 18–99 years of age who underwent routine health examinations from 2001 to 200419. Persons (n = 26,136) with missing information on serum total cholesterol, fasting glucose, blood pressure, and body mass index (BMI) were excluded, as were 3,665 individuals with extreme anthropometric measures and another 210 with a missing date of the health examination. The final study population included 12,815,006 participants, who were followed until December 31, 2013 through the Resident Register of Korea. The authors were granted access to the anonymized data by the NHIS, without specific informed consent from the participants according to Korean law. This study was approved by the Institutional Review Board of Catholic Kwandong University with a waiver of informed consent. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist for cohort studies was used to guide the reporting of our study.
Serum TC and fasting glucose were assayed using enzymatic methods. Blood pressure was measured once in a seated position using a standard mercury sphygmomanometer, and the systolic blood pressure was measured as the first Korotkoff sound. Weight and height were measured to the nearest kilogram and centimeter, respectively19. BMI was calculated by weight in kilograms divided by the square of height in meters (kg/m2). Information on smoking history, alcohol use, and known heart disease or cancers was collected via a self-administered questionnaire. A standard protocol officially registered by the Korean government was applied for health examinations and data collection. External quality assessments of clinical chemistry were regularly performed20.
Baseline TC concentrations were mainly categorized into 18 groups (mg/dL; <120, 120–129 to 270–279 in increments of 10, ≥280). The cholesterol category with the lowest mortality (220–229 mg/dL) in all participants was used as the reference. Three groups (<200 [reference, desirable], 200–239 [borderline high], and ≥240 [high]), defined according to the cut-points proposed by the National Cholesterol Education Program (NCEP) of US, were used in an additional analysis21. In the spline analysis, a restricted cubic spline transformation of TC with 5 knots (138, 170, 191, 213, and 260 mg/dL; 5th, 27.5th, 50th, 72.5th, and 95th percentiles in all participants) was used to evaluate non-linear associations.
The hazard ratios (HRs) for death were calculated using Cox proportional hazards models stratified by age (years) at baseline (18–24, 25–34, 35–44, 45–54, 55–64, 65–74, or 75–99). In the multivariable model, the following variables were adjusted for: age at baseline (continuous variable; within each age group), sex, smoking status (current smoker, former smoker, never smoker, or missing information), alcohol use frequency (none, 2 days/month-2 days/week, 3–7 days/week, or missing information), physical activity (at least once a week; yes or no), systolic blood pressure (<120, 120–139, or ≥140 mm Hg), fasting glucose (<100, 100–125, or ≥126 mg/dL), and BMI (<18.5, 18.5–24.9, 25–29.9, or ≥30 kg/m2).
The apparent optimal ranges of TC for survival were determined by a general inspection of the curvilinear association. Generally, the interval of 40 mg/dL (roughly 1 mmol/L) with the lowest risk (the lowest unweighted geometric mean of HRs in 4 consecutive TC categories in the categorical analysis, and in 5 consecutive 10-mg/dL TC levels in the spline analysis [for example, the points of 200, 210, 220, 230, 240 mg/dL]), were considered the optimal ranges.
Subgroup analyses by sex and age, as well as various categorical, spline, and linear analyses, served as sensitivity analyses. All p-values were 2-sided. All analyses used SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).
This study was approved by the Institutional Review Board of Kwandong University (Gangneung, Republic of Korea).
During a mean 10.5 years of follow-up, 454,546 men and 239,877 women died. At baseline, the participants’ mean ± SD age was 44.4 ± 14.2 years, their mean TC level was 194.2 ± 49.0 mg/dL (Table 1), and 11.2% of participants had high TC levels (≥240 mg/dL). Individuals with higher TC levels were older and had higher levels of fasting glucose, systolic blood pressure, and BMI (Table 1). People with TC ≥240 mg/dL tended to be non-drinkers and were more likely to have comorbid heart disease, stroke, or cancer. The number of individuals was highest in the TC range of 180–189 mg/dL (Table 1, Supplementary Fig. 1).
TC concentrations according to sex and age
Men had on average higher TC levels than women between 24–25 to 48–49 years old, while women had higher levels than men in the age ranges of 18–23 years and ≥50 years (Fig. 1, Supplementary Table S1). Among men, the mean TC levels increased from 159.0 mg/dL at 18–19 years to a maximum of 201.4 mg/dL at 50–51 years, and among women, the mean levels increased from 170.5 mg/dL at 20–21 years to a maximum of 212.4 mg/dL at 56–57 years. The decrease in TC levels after the peak values were reached was greater in men than in women. The gradient of increase in TC levels with age was steepest from 18–19 to 28–29 years in men, while it was steepest from 44–45 to 52–53 years in women (Fig. 1).
Associations between total cholesterol and mortality
U-curve associations between TC levels and mortality were found in both men and women (Fig. 2). The TC range associated with the lowest mortality was 210–249 mg/dL (Supplementary Table S2). When age was further considered, U-curve associations were observed regardless of sex or age (Fig. 3), and the optimal TC range for survival was 210–249 mg/dL for each age-sex group, except for men at 18–34 years (180–219 mg/dL) and for women at 18–34 years (160–199 mg/dL) and at 35–44 years (180–219 mg/dL) (Supplementary Table S3).
In the spline analysis (Fig. 4, Supplementary Fig. 2), the TC ranges associated with the lowest mortality were approximately 200–240 mg/dL, except for men at 18–34 years (approximately 180–220 mg/dL) and for women at 18–34 years (approximately 160–200 mg/dL) and at 35–44 years (approximately 180–220 mg/dL).
When assuming linear associations for TC levels of 50–449, 50–199, and 200–449 mg/dL, each 39 mg/dL (1 mmol/L) increase in TC was associated with 8% lower (HR = 0.92, 95% CI = 0.917–0.922), 23% lower (HR = 0.77, 95% CI = 0.76–0.77), and 7% higher (HR = 1.07, 95% CI = 1.06–1.07) mortality, respectively (Fig. 5).
At cholesterol levels <200 mg/dL (Table 2), inverse associations were the strongest in men aged 45–54 years and women aged 55–64 years, the age group with the highest mean TC level in both sexes (Pinteraction [age] <0.001). At cholesterol levels ≥200 mg/dL, the HRs per 39 mg/dL (1 mmol/L) higher levels were highest in the youngest groups (aged 18–44 years), and lowest in the oldest group (aged 75–99) years in both sexes (Pinteraction [age] <0.001).
The associations were modestly stronger in men than in women at TC levels of 50–449, 50–199, and 200–449 mg/dL (Pinteraction [sex] <0.001 in each TC range), when all ages were combined. At cholesterol levels <200 mg/dL, men had stronger inverse associations than women in age groups <65 years.
Associations across standard classifications of TC
Compared to the desirable levels of <200 mg/dL (Supplementary Table S3), borderline high levels of 200–239 mg/dL were associated with a lower risk of mortality in each age-sex group except for women aged 18–34 years, while high levels of ≥240 mg/dL were associated with a decreased risk in both sexes and each age group except for women aged 18–44 years and men aged 18–34 years, in whom high levels were associated with increased mortality.
A U-shaped relationship between TC and mortality was observed in each age-sex group. TC levels associated with the lowest mortality were 210–249 mg/dL in both sexes in all age groups, except for the youngest groups of men, aged 18–34 years (180–219 mg/dL), and women aged 18–34 years (160–199 mg/dL) and 35–44 years (180–219 mg/dL). At TC levels of 50–199 and 200–449 mg/dL, each 39 mg/dL (1 mmol/L) increase in TC was associated with 23% lower (95% CI = 23–24%) and 7% higher (6–7%) mortality, respectively. Inverse associations in the lower TC range were strongest at the ages for which the mean TC levels were highest (men aged 45–54 years and women aged 55–64 years), while positive associations in the upper TC range were strongest in the youngest ages (<45 years) in both sexes. Both the inverse associations in the lower TC range and the positive associations in the upper TC range weakened with advancing age beyond the ages with the strongest associations.
Previous cohort studies have reported inconsistent results on the shape of associations between TC and all-cause mortality, including positive linear, inverse, U-curve, and reverse-L-curve (or reverse-J-curve) associations3,8,9,10,11,13,14,17,22. Some previous studies suggested different shapes of associations by sex and age3,17. The associationbetween TC and mortality was substantially modified by age and, to a lesser degree, by sex, in our study. Our study clearly demonstrated that the shape of association is a U-curve in each sex and each age group, including those aged 75–99 years (mean age: 79.0 years), which constituted 154,321, 80,776, and 18,080 elderly people aged 75–79, 80–84, and ≥85 years, respectively. Considering the weaker effect size associated with high TC with advancing age in the elderly, it is no surprise that previous studies conducted mainly in elderly populations found generally inverse or reverse-L-curve associations13,14. Additionally, the previously reported positive associations in younger adults8, may be explained by the stronger positive associations and lower optimal range in younger ages observed in our study, combined with the higher TC concentrations and larger proportions of morbidity and mortality from heart diseases in Western populations.
The NCEP experts classified TC levels into 3 categories: <200, 200–239, and ≥240 mg/dL, as desirable, borderline high, and high levels, respectively, mainly based on the association between TC and IHD21. In the current study, however, TC levels of 210–249 mg/dL and approximately 200–240 mg/dL were associated with the lowest mortality in the categorical and spline analyses, respectively. Our study suggested that the optimal ranges for overall survival are higher than that those for IHD. Similarly, a higher optimal range for overall survival than for IHD mortality has also been reported for BMI23. In contrast, the optimal ranges for all-cause mortality and IHD mortality were similar for fasting glucose and blood pressure24,25,26,27. Cholesterol levels might be a marker of general health, rather than a marker specific for CVD28. Even within CVD subtypes, TC ranges associated with lowest risk have not been consistent. For example, for stroke, TC levels <200 mg/dL were not associated with the lowest mortality in prospective cohort studies29,30, and randomized trials have not provided clear evidence of whether lipid-lowering therapies, including statins, reduce stroke mortality6,31. Hemorrhagic stroke, respiratory diseases (especially chronic obstructive pulmonary disease), digestive diseases (especially liver disease), and several cancers have been suggested to be associated with lower TC levels10,30,32,33,34; thus, the ranges associated with lowest risk might be even higher for these diseases than those for all-cause mortality. However, we could not examine whether the associations differed by cause of death, due to data unavailability.
Reverse causality has been suggested as an explanation of higher mortality associated with low cholesterol levels. However, a long term follow-up study in a Japanese-American population showed that individuals with low cholesterol levels maintained over a 20-year period had the worst all-cause mortality, and concluded that reverse causality was unlikely to account for the higher mortality associated with low cholesterol entirely14.
Lower optimal ranges for survival at younger ages than at older ages have also been observed for BMI19, whereas consistent ranges have been found regardless of sex and age for blood pressure and fasting glucose26,27,29. Whether different proportions of cause-specific mortality by age lead to the lower optimal range at younger ages needs to be investigated.
The sex- and age- specific levels of TC in the current study of Koreans were lower than those reported in other high-income countries, including Japan, England, and the US15,16,17,35,36. The distribution of TC levels by sex and age, however, were generally similar to those of other regional and ethnic populations, although detailed information is not always available. TC levels peaked at 50–51 years in men and at 56–57 years in women, and after the peak age, the levels decreased more rapidly in men than in women. The crossover point of the mean TC levels between sexes occurred at the age of 50–51 years, exactly at the median age of menopause37. The steep decline in estrogen corresponds well to the sharp increase in TC in women that was observed around the time of menopause in the current study.
Randomized trials have provided evidence that statin therapy may lower the overall mortality risk in persons with increased cardiovascular risk, mostly due to the reduction of mortality from heart disease5,6. The evidence, however, may not be definitive enough to claim that “the lower the cholesterol, the better” for all-cause mortality reduction in the general population with relatively low heart disease risk38.
The current cholesterol guidelines are heavily based on heart disease risk and recommend a TC range of <200 mg/dL as desirable. TC range <200 mg/dL, however, may not be necessarily a sign of good health when other diseases are considered. The diseases associated with lower TC levels and potential mechanisms have not been conclusively identified. Since the inverse associations in lower TC range were stronger than the positive associations in upper TC range, identification of diseases associated with lower TC levels and further understanding of the mechanisms of such associations may help improve health outcomes in the general population. Pending more research for clarification, careful evaluation and management might increase the chance of preventing and diagnosing potentially life-threatening diseases at an earlier stage in adults with low TC levels.
A very large number of participants, the prospective nature of the study, and complete follow-up for death are clear strengths of this study. Another major strength is that the study participants were ethnically homogeneous and lived in a similar environment covered by the same health care system. Another strength is that this study estimated mortality risk associated with TC levels down to below 120 mg/dL. However, there are limitations. First, the use of lipid-lowering medication was unaccounted for. The risk associated with high cholesterol might have been underestimated. However, in Korea, IHD mortality accounted for only approximately 5% of all-cause mortality, and only 10% of people with hypercholesterolemia received lipid-lowering therapy39. Therefore, the impact of not considering medication use is likely to be modest, and the TC levels in this study generally reflect levels without lipid-lowering medications. Additionally, this study could not determine whether statin-induced low cholesterol increases mortality. Second, other lipid measures, such as low-density lipoprotein and high-density lipoprotein cholesterol levels, were unavailable. Recent dyslipidemia management guidelines are more closely focused on these sub-fractions of cholesterol, so the direct application of our findings to individual patient care might be somewhat limited. Further study is needed to determine the sex- and age-specific associations of cholesterol fractions. Third, information on cause-specific mortality was not available. Fourth, the generalizability of our findings may be affected by the fact that the study participants were homogeneously Korean. The U-curve associations may be generalized to other ethnic populations, since the shape of the associations was generally the same for each sex and each age group, despite their varying cardiometabolic risk profiles. However, some results, such as the magnitude of relative risk associated with TC and the TC range associated with the lowest mortality, may vary by ethnic groups with different distributions of cause-specific mortality and dyslipidemia-related healthcare utilization.
In conclusion, U-curve relationships between TC and mortality were found, regardless of sex and age. TC ranges associated with the lowest mortality were 210–249 mg/dL in each sex-age subgroup, except for the youngest groups of men, aged 18–34 years (180–219 mg/dL), and women aged 18–34 years (160–199 mg/dL) and 35–44 years (180–219 mg/dL). Inverse associations in the range <200 mg/dL were more than 3-fold stronger than positive associations for cholesterol levels ≥200 mg/dL, except for the youngest adults. Positive associations in the upper TC range were strongest for youngest adults and weakened with advancing age. TC levels <200 mg/dL may not necessarily be a sign of good health. Identification and proper management of diseases associated with lower TC levels might improve survival.
The data supporting the findings of this study are available from the NHIS, but restrictions apply to the availability of these data, which were used under license for the current study; therefore, the data are not publicly accessible.
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The authors thank the staff at the Big Data Steering Department at the NHIS of Korea for providing the data and support.
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The hyperbaric oxygen market is growing rapidly as scientists discover more uses in preventing cognitive decline.
An innovative form of hyperbaric oxygen therapy (HBOT) may be able to improve cognitive ability in aging adults. Researchers at the Shamir Medical Center, and Tel Aviv University found for the first time in a peer-reviewed study, that HBOT improvements in cerebral blood flow could boost the cognitive performance of healthy adults.
Longevity.Technology: As the population ages, cognitive decline within otherwise healthy adults is becoming a growing problem. As solutions such as HBOT prove their effectiveness in increasing oxygen saturation, demand is likely to grow.
The main areas of improvement came in the speed with which information was processed, executive function and cognitive function, all of which decline with age. There was also a correlation between positive cognitive gains and cerebral blood flow in specific regions.
The study was designed by Professor Shai Efrati and Dr Amir Hadanny on the HBOT protocol developed over the past decade at Sagol Center. It involved a randomised controlled clinical trial of 63 healthy adults over the age of 64 who were either in a control group or received HBOT treatment.
“In our study, for the first time in humans, we have found an effective and safe medical intervention that can address this unwanted consequence of our age-related deterioration.”
There is a growing interest in the value of HBOT treatments. During the process, a patient breathes normal air which increases the oxygen solubility and stimulates the release of stem cells and other factors which can promote healing. It is being used in a growing number of environments around the world to treat issues such as non-healing wounds.
However, as this study shows, there is also increasing interest in the regenerative potential of HBOT. Delivering high levels of oxygenation at high pressure increases oxygen levels within tissue while targeting genes which are sensitive to both oxygen and pressure. The result is an improved metabolism in which the target genes proliferate stem cells, reduce inflammation, generate new blood vessels and repair mechanisms.
“Age-related cognitive and functional decline has become a significant concern in the Western world. Major research efforts around the world are focused on improving the cognitive performance of the so-called ‘normal’ aging population,” said Professor Efrati. “In our study, for the first time in humans, we have found an effective and safe medical intervention that can address this unwanted consequence of our age-related deterioration.” 
The market for HBOT is growing rapidly. According to Transparent Market Research, the market is expected to grow at 7.4% year on year and reach a valuation of $284.8 million. More affordable prices, technological advancements and improved performance, as well as the search for solutions which can arrest cognitive decline, are just some of the reasons behind the rise .
As technology improves, it is possible to purchase at home devices for $5,000 or less if you have room, making it increasingly attractive for older people looking for ways to reduce age related cognitive decline and other issues.
Phil has over 25 years of C-level management, marketing and business development expertise in Europe and North America. His creative background has helped him shape unconventional strategies for commercial growth – garnering both awards and investor ROI.
Phil has wide experience of technology transfer and the commercialisation of innovations from both private and institutional sources and this led to his interest in Longevity and the founding of Longevity.Technology.
The microbiome is a collection of trillions of bacteria that reside in and on our bodies. Each person’s microbiome is unique—just like a fingerprint—and researchers are finding more and more ways in which it impacts our health and daily lives. One example involves an apparent link between the brain and the bacteria in the gut. This brain-gut “axis” is believed to influence conditions such as Parkinson’s disease, depression, and irritable bowel syndrome. However, many studies into the brain-gut axis have stalled because of one central problem: the lack of an adequate testable model of the gut.
Current testing platforms cannot emulate the human gut accurately and cheaply enough for large-scale studies. The research community needs something new, which is what a team at MIT Lincoln Laboratory is tackling in a project funded through the Technology Office. Researchers there aim to create the perfect artificial gut.
“The question from the mechanical side is, how do you emulate the colon?” says Todd Thorsen, the project’s principal investigator from the Biological and Chemical Technologies Group. “Bacteria in the colon occupy lots of ecological niches.”
Thorsen is referring to the complexity of the human gut, which includes a community of 100 trillion microbes that all have specific, and sometimes clashing, needs. For example, certain types of bacteria in the gut will die in the presence of oxygen, while others need it to survive. The gut also contains both hard and soft mucus that allows different types of bacteria to grow. All of these conditions need to be mimicked in a single platform in order to properly maintain and test microbiome samples—and that’s not an easy task.
“Until now, no one has been able to culture a microbiome sample and maintain it,” says David Walsh from the Biological and Chemical Technologies Group, who led the device’s development and fabrication. “If we can maintain a culture, we can do things like add toxins and therapeutics to see how they change the culture over time.”
To address the problem, the laboratory team developed a multimaterial platform made of permeable silicon rubber and other plastics, such as polystyrene, all of which are cheap and can be rapidly prototyped. The two components of the platform emulate the essential oxygen and mucosal gradients.
The above photo (left) shows the component that controls the oxygen gradient. Air diffuses through the plastic while the blue ports allow researchers to change the local oxygen concentrations at different positions within the adjacent microculture chambers. The right photo shows the component that controls mucus, which is welled up into the device from below. Both components implement careful geometry to yield the precise conditions found in the gut.
“The final system will allow us to tackle real-world problems,” Walsh says. Those problems, in addition to unraveling the brain-gut axis, include developing resilience to current and emerging pathogens, combating biological warfare, and more.
This year, the research team is partnering with the University of Alabama at Birmingham, Northeastern University, and the University of California at San Francisco to implement their first tests of microbiome samples to study links to Parkinson’s disease. The laboratory’s role is to use the artificial gut to culture microbiome samples taken from people with and without Parkinson’s disease and test what happens when different suspected adverse influencers are added. The goal is to correlate how changes in the microbiome caused by exposure to certain toxins may induce Parkinson’s-like nerve damage.
The laboratory will also continue advancing other aspects of the project. Some examples include building a tubular core-shell origami-like gut that rolls up during assembly to emulate the colon and the surrounding vascularized tissue, and developing modeling software to predict how microbial communities might change over time.
by Anne McGovern, Massachusetts Institute of Technology
Is this proof depression can be a physical illness? Matthew Leeming says he cured his depression with anti-inflammatory drugs
At the age of 47 I found myself living in Dubai, broke after a business venture went horribly wrong, and pole-axed with treatment-resistant depression.
I couldn’t work I felt so awful. Getting out of bed and into a taxi to a friend’s office where I pretended to occupy myself each day was an ordeal.
It was 2012 and for 20 years I’d been on a type of antidepressant called a tricyclic which, until then, had kept the depression which had only once before rendered me unable to work, at bay.
But it stopped being effective, I think through the shock of the business problems.
Trying to explain what depression feels like is difficult because it is in part an absence: an absence of feeling, an absence of self-respect, a lack of power to do anything and be optimistic.
I know of someone who had suffered depression and cancer and who said depression was worse. ‘When I had cancer, I wanted to live. But when I had depression I wanted to die,’ they said.
The brain itself has no pain receptors but I think everyone with depression would agree that the disease is the mental equivalent of pain — concentrated anguish, unrelieved negative thoughts, hatred of oneself.
But you also feel physically ill, as if you had been hit by a train. It’s not that you can’t be bothered to get out of bed: it is as physically difficult to do so, as when you have flu.
Living with depression is like carrying a large weight around. That weight is heavier in the morning perhaps because in many depressed people levels of cortisol (a stress hormone) are higher in the morning.
The cortisol levels and feelings of illness suggested to me that depression might be a physical disease. Although I didn’t know about the cortisol link at the time, when I first saw a doctor about the depression I said: ‘This is physical.’
But it meant nothing to him. He probably took this thought to be another symptom. However, 20 years later, I read about the work of Carmine Pariante, a professor of biological psychiatry — a brand new discipline — at King’s College, London, which suggested depression can indeed be an inflammatory physical illness.
‘In some cases, depression is due to normal bodily processes going wrong, the product of a malfunctioning immune system,’ Professor Pariante told me.
At the heart of his case are two well-attested observations. The first is the effects of interferon, a drug that stimulates the immune system to use inflammation to destroy the hepatitis virus lodged inside the liver.
One study Professor Pariante was involved with, which was published in the journal Neuropsychopharmacology in 2016, found that a third of patients given interferon for hepatitis treatment developed depression, and these were the patients who had the strongest inflammation.
‘This suggests that the depression in these patients might be caused by the inflammation,’ says Professor Pariante.
Second, people with rheumatoid arthritis often become depressed. Rheumatoid arthritis is an auto immune condition that occurs when the immune system perceives the body’s chemical messengers as invading bacteria and secretes an inflammatory chemical, tumour necrosis factor (TNF), in a bid to destroy them resulting in join pain and swelling.
Around 20 per cent of patients with this disease are also depressed according to Edward Bullmore, a professor of psychiatry at the University of Cambridge. Most doctors regard the depression as a response to the misery of the disease. But Professor Pariante believes the TNF causes the depression. ‘We now know that chemicals secreted by the body to signal the increased inflammation, such as TNF, can also directly affect brain cells and brain function, inducing depressive symptoms,’ he explains.
An anti-inflammatory drug called Remicade, developed to treat rheumatoid arthritis, that blocks the action of TNF has been a remarkably effective treatment for the disease he says.
In some patients it also caused an apparently miraculous lifting of the patient’s depression. The effect can be so dramatic that nurses call it the ‘Remicade high’.
Remicade — also known as infliximab — was recently trialled as an antidepressant but was only shown to be effective for patients with both depression and high inflammatory markers.
However TNF is just one of many inflammatory proteins in our bodies and according to Professor Pariante the resulting inflammation they bring causes ‘sickness behaviour’, something our body does to rid itself of damaging viruses and toxins while the lethargy and lack of motivation gives it a chance to recover.
‘Increased inflammation can affect our emotions and behaviour and induce symptoms that resemble depression, such as fatigue, malaise, aches and pains, bad mood and reduced interest in socialising,’ Professor Pariante says. ‘If you remember how you felt last time you had a really bad infection, you will recognise these symptoms. In fact, inflammatory chemicals change the function of brain areas that are important for anxiety and depression.’
If Professor Pariante is right, the inflammation theory suggests that in many cases depression is your mind telling your body you are ill when you are not — you are actually suffering inflammation.
Not all depression is caused like this but Professor Pariante estimates that 40 per cent of cases may involve inflammation.
Professor Pariante’s work turned on a mental lightbulb for me. A professor agreed that my disease was physical!
And because I was living in Dubai I was able to do something about it. That’s because you can buy Celebrex, a non-steroidal anti-inflammatory used for treating arthritis, over-the-counter there (but only on prescription in the UK). Internet research following reading about Pariante’s work produced papers showing its clinical effectiveness when used with antidepressants.
So I bought a packet. I took 200mg a day (I guessed at the dose) for a week with no effect but then one evening I took 400mg, the dose prescribed daily for arthritis. Within half an hour the ghastly feelings were leaving me, the anxiety in my stomach contracting as if after a strong drink following a bad day at work. Within two weeks I stopped taking the antidepressants — for the first time in 20 years. I felt normal.
Chekhov (a doctor as well as a writer) once said ‘If many remedies are prescribed for an illness, you may be certain that the illness has no cure’ and there are certainly a huge number of antidepressants on the market, none of which are universally effective. But this could be because depression has a number of causes, one of which it seems is inflammation.
Professor Pariante says that ‘depression could be like a fever — a symptom of a variety of underlying pathologies’.
So what does this mean for treatment? Professor Edward Bullmore in his book The Inflamed Mind predicts that future research will involve investigating drugs like Remicade and Celebrex rather than looking for new antidepressants in the mould of Prozac.
But despite my positive experience with anti-inflammatories Professor Bullmore warns: ‘Doctors and psychiatrists will want to see positive clinical trial data before recommending anti-inflammatory treatment for depression.
‘It is worth remembering that all anti-inflammatory drugs, including Celebrex, have side-effects and it is not advisable to start taking them until the evidence for therapeutic benefit is clearer. Hopefully, there will be further progress in the next few years to get us to that point but the current situation is still a scientific work in progress.’
I don’t think patients should suffer while there are effective drugs much less dangerous than lithium — which is what is generally prescribed for treatment-resistant depression — available.
If Professor Pariante is right, people with depression may gain more than a new treatment. We may receive sympathy. The inflammation theory provides depressed people with an acknowledgement that they are physically ill and can’t just pick up their mat and walk.
By MATTHEW LEEMING FOR THE DAILY MAIL – PUBLISHED: 17:42 EDT, 23 September 2019 | UPDATED: 03:27 EDT, 24 September 2019
She’s had endless disappointing visits with doctors. Some said they couldn’t help her. Others diagnosed her with everything from fibromyalgia to lipedema to the rare Ehlers-Danlos syndrome.
Pinkley has taken opioids a few times after surgeries but says they never helped her underlying pain.
“I hate opioids with a passion,” Pinkley says. “An absolute passion.”
Recently, she joined a growing group of patients using an outside-the-box remedy: naltrexone. It is usually used to treat addiction, in a pill form for alcohol and as a pill or a monthly shot for opioids.
As the medical establishment tries to do a huge U-turn after two disastrous decades of pushing long-term opioid use for chronic pain, scientists have been struggling to develop safe, effective alternatives.
When naltrexone is used to treat addiction in pill form, it’s prescribed at 50 mg, but chronic-pain patients say it helps their pain at doses of less than a tenth of that.
Low-dose naltrexone has lurked for years on the fringes of medicine, but its zealous advocates worry that it may be stuck there. Naltrexone, which can be produced generically, is not even manufactured at the low doses that seem to be best for pain patients.
Instead, patients go to compounding pharmacies or resort to DIY methods — YouTube videos and online support groups show people how to turn 50 mg pills into a low liquid dose.
Some doctors prescribe it off-label even though it’s not FDA-approved for pain.
University of Kansas pain specialist, Dr. Andrea Nicol has recently started prescribing it to her patients, including Pinkley. Nicol explains that for addiction patients, it works by blocking opioid receptors — some of the brain’s most important feel-good regions. So it prevents patients from feeling high and can help patients resist cravings.
At low doses of about 4.5 mgs, however, naltrexone seems to work completely differently.
“What it’s felt to do is not shut down the system, but restore some balance to the opioid system,” Nicol says.
Some of the hype over low-dose naltrexone has included some pretty extreme claims with limited research to back them, like using it to treat multiple sclerosis and neuropathic pain or even using it as a weight-loss drug.
In the past two years, however, there’s been a big increase in new studies published on low-dose naltrexone, many strengthening its claims as a treatment for chronic pain, though most of these were still small pilot studies.
Dr. Bruce Vrooman, an associate professor at Dartmouth’s Geisel School of Medicine, was an author of a recent review of low-dose naltrexone research. Vrooman says that when it comes to treating some patients with complex chronic pain, low-dose naltrexone appears to be more effective and well-tolerated than the big-name opioids that dominated pain management for decades.
“Those patients may report that this is indeed a game changer,” Vrooman says. “It may truly help them with their activities, help them feel better.”
So how does it work? Scientists think that for many chronic pain patients, the central nervous system gets overworked and agitated. Pain signals fire in an out-of-control feedback loop that drowns out the body’s natural pain-relieving systems.
They suspect that low doses of naltrexone dampen that inflammation and kick-start the body’s production of pain-killing endorphins — all with relatively minor side effects.
Despite the promise of low-dose naltrexone, its advocates say few doctors know about it.
The low-dose version is generally not covered by insurance, so patients typically have to pay out of pocket to have it specially made at compounding pharmacies.
Advocates worry that the treatment is doomed to be stuck on the periphery of medicine because, as a 50-year-old drug, naltrexone can be made generically.
Patricia Danzon, a professor of health care management at the Wharton School at the University of Pennsylvania, explains that drug companies don’t have much interest in producing a new drug unless they can be the only maker of it.
“Bringing a new drug to market requires getting FDA approval and that requires doing clinical trials,” Danzon says. “That’s a significant investment, and companies — unsurprisingly — are not willing to do that unless they can get a patent and be the sole supplier of that drug for at least some period of time.”
And without a drug company’s backing, a treatment like low-dose naltrexone is unlikely to get the big promotional push out to doctors and TV advertisements that have turned drugs like Humira or Chantix into household names.
“It’s absolutely true that once a product becomes generic, you don’t see promotion happening, because it never pays a generic company to promote something if there are multiple versions of it available and they can’t be sure that they’ll capture the reward on that promotion,” Danzon says.
The drugmaker Alkermes has had huge success with its exclusive rights to the extended-release version of naltrexone, called Vivitrol. In a statement for this story, the company says it hasn’t seen enough evidence to support the use of low-dose naltrexone to treat chronic pain and therefore is remaining focused on opioid addiction treatment.
Pinkley says she is frustrated that there are so many missing pieces in the puzzle of understanding and treating chronic pain, but she, too, has become a believer in naltrexone.
She has been taking it for about a year now, at first paying $50 a month out of pocket to have the prescription filled at a compounding pharmacy. In July, her insurance started covering it.
“I can go from having days that I really don’t want to get out of bed because I hurt so bad,” she says, “to within a half-hour of taking it, I’m up and running, moving around, on the computer, able to do stuff.”
This story is part of NPR’s reporting project with KCUR and Kaiser Health News.
This story is part of NPR’s reporting project with KCUR and Kaiser Health News.
A cocktail of drugs has been found to reverse a critical element of the ageing process for the first time.
Scientists said a clinical trial, carried out at Stanford University in California, suggested that growing old could one day become a treatable condition.
The study involved nine men aged 51 to 65 who took three existing drugs — a growth hormone and two diabetes medicines — for one year. The drugs appeared to alter chemical compounds attached to their DNA, reversing changes that accumulate over time.
The effect was equivalent to taking an average of two and a half years off their biological age, the researchers said. The subjects’ defences against infection and cancer also appeared to be boosted.
Steve Horvath, of the University of California, Los Angeles, said: “I was very surprised. I did not think it was possible to find age reversal. Our study is only a first step that demonstrates feasibility, but it suggests that a cocktail of relatively safe substances can already achieve what appeared to be a distant dream from science fiction novels.”
The work focuses on “epigenetic” changes inside cells, which involve chemicals that latch on to portions of DNA. These act like switches, controlling the activity of individual genes.
Epigenetic changes that accumulate with age appear to make people more vulnerable to diseases such as cancer.
Professor Horvath has developed techniques that can assess a person’s epigenetic status to predict with a high degree of accuracy how old they are and how long they have to live. People who smoke, for instance, are likely to be substantially older in epigenetic terms than their chronological age.
The main aim of the trial, which was carried out at the Stanford medical centre in California, was to rejuvenate the thymus gland, which plays an important role in fighting infection.
It was already thought that growth hormone could stimulate thymus regeneration but it can also promote diabetes, so the cocktail of drugs used in the trial included two widely used anti-diabetic medicines, dehydroepiandrosterone (DHEA) and metformin. The reversal of the ageing process was discovered as a side-effect.
Gregory Fahy, lead author of a study published in the journal Aging Cell, said: “The implication is that ageing may be a treatable condition.”
Professor Horvath said: “Our study results strongly suggest that these subjects are in a better shape to fight off infections because their thymus and immune system were in much better shape than before. The treatment actually lowered the risk of cancer.”
The researchers stress that the study was small and with no placebo control arm. A trial with 100 subjects is planned.