Cardiologists have long known that up to half of all heart attacks and strokes occur among apparently healthy individuals who do not smoke and do not have high blood pressure, high cholesterol, or diabetes, the “standard modifiable risk factors” which doctors often call “SMuRFs.” How to identify risk among the “SMuRF-Less” has been an elusive goal in preventive cardiology, particularly in women who are often under-diagnosed and under-treated.
A new study by Mass General Brigham researchers that leverages data from the Women’s Health Study has found hsCRP, a marker of inflammation, can help identify women who are at risk but are missed by current screening algorithms. Results are presented at a late-breaking clinical science session at the European Society of Cardiology Congress (ESC) and simultaneously published in The European Heart Journal.
“Women who suffer from heart attacks and strokes yet have no standard modifiable risk factors are not identified by the risk equations doctors use in daily practice,” said Paul Ridker, MD, MPH, a preventive cardiologist at Mass General Brigham’s Heart and Vascular Institute. “Yet our data clearly show that apparently healthy women who are inflamed are at substantial lifetime risk. We should be identifying these women in their 40s, at a time when they can initiate preventive care, not wait for the disease to establish itself in their 70s when it is often too late to make a real difference.”
As part of the federally funded study, researchers studied 12 530 initially healthy women with no standard modifiable risk factors who had the inflammatory biomarker hsCRP measured at study entry and who were then followed over 30 years. Despite the lack of traditional risks, women who were inflamed as defined by hsCRP levels > 3 mg/L had a 77% increased lifetime risk of coronary heart disease, a 39% increased lifetime risk of stroke, and a 52% increased lifetime risk of any major cardiovascular event.
Additionally, researchers released a new analysis of randomised trial data showing that “SMuRF-Less but Inflamed” patients can reduce their risk of heart attack and stroke by 38% using statin therapy.
“While those with inflammation should aggressively initiate lifestyle and behavioural preventive efforts, statin therapy could also play an important role in helping reduce risk among these individuals,” said Ridker.
Analysis of lipid blood levels in women with Alzheimer’s disease has shown noticeable loss of unsaturated fats, such as those that contain omega fatty acids, compared to healthy women.
In men with Alzheimer’s, no significant difference was found in the same lipid molecule composition disease compared to healthy men, which suggests that those lipids have a different role in the disease according to sex. Fats perform important roles in maintaining a healthy brain, so this study could indicate why more women are diagnosed with the disease.
The study, published today in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association by scientists from King’s College London and Queen Mary University London, is the first to reveal the important role lipids could have in the risk for Alzheimer’s between the sexes.
Women are disproportionately impacted by Alzheimer’s Disease and are more often diagnosed with the disease than men after the age of 80. One of the most surprising things we saw when looking at the different sexes was that there was no difference in these lipids in healthy and cognitively impaired men, but for women this picture was completely different. The study reveals that Alzheimer’s lipid biology is different between the sexes, opening new avenues for research.
Dr Cristina Legido-Quigley, Reader in Systems Medicine
The scientists took plasma samples from 841 participants who had Alzheimer’s Disease, mild cognitive impairment and cognitively health controls and and were measured for brain inflammation and damage.
They used mass spectrometry to analyse the 700 individual lipids in the blood. Lipids are a group of many molecules. Saturated lipids are generally considered as ‘unhealthy’ or ‘bad’ lipids, while unsaturated lipid, which sometime contains omega fatty acids, are generally considered ‘healthy’.
Scientists saw a steep increase in lipids with saturation – the ‘unhealthy lipids’ – in women with Alzheimer’s compared to the healthy group. The lipids with attached omega fatty acids were the most decreased in the Alzheimer’s group.
Now, the scientists say there is a statistical indication that there is a causal link between Alzheimer’s Disease and fatty acids. But a clinical trial is necessary to confirm the link.
Dr Legido-Quigley added: “Our study suggests that women should make sure they are getting omega fatty acids in their diet – through fatty fish or via supplements. However, we need clinical trials to determine if shifting the lipid composition can influence the biological trajectory of Alzheimer’s Disease.”
Dr Asger Wretlind, first author of the study from the School of Cancer & Pharmaceutical Sciences, said: “Scientists have known for some time that more women than men are diagnosed with Alzheimer’s disease.
Although this still warrants further research, we were able to detect biological differences in lipids between the sexes in a large cohort, and show the importance of lipids containing omegas in the blood, which has not been done before. The results are very striking and now we are looking at how early in life this change occurs in women.
Dr Asger Wretlind, School of Cancer & Pharmaceutical Sciences
Many diseases affect men and women differently. Asthma tends to strike men earlier in life, yet more women develop asthma as they get older. Parkinson’s is more common in men, but Alzheimer’s is more common in women.
The differences are even more stark when it comes to autoimmune disease. Women are around two and a half times more likely than men to develop multiple sclerosis and nine times more likely to develop lupus.
Why would some diseases strike one sex more than another? And why do some tissues, such as the lungs and brain, seem especially vulnerable to these sex-based differences?
To answer these questions, scientists at La Jolla Institute for Immunology (LJI) are leading new research into how our immune cells defend specific parts of the body.
“In just the last two years, LJI scientists have uncovered a whole new body of information about how the immune systems of men and women are very different,” says Saphire. “We’re looking at what is genetically encoded in our XX or XY chromosomes, and how hormones like oestrogen and testosterone affect what is genetically programmed into our immune cells.”
In the paper, the researchers define biological sex (in an immunology context) as the presence of XX chromosomes in females and XY chromosomes in males. “Every cell in your body is either XX or XY,” says Saphire. “That X chromosome has many, many immune-related genes. Women have two copies of each. That gives them, in a sense, twice the palette of colours to paint from in formulating an immune response. It can also give them a stronger immune response for those genes that are doubly active – active in both copies simultaneously.
Sex hormones are important for much more than reproductive function. Immune cells can also sense hormones such as oestrogen and testosterone and use them to determine which genes to turn on or off and which ones to turn on more brightly or dim. This means similar immune cells can do different things, depending on whether that cell is from a male or a female.
Further, female cells vary in which of their two copies of X is “turned on.” As a result, women have organs with a collage, or mosaic, of immune cells that work differently in different tissues. This innate “variety” of immune cells appears to be an effective way to ward off infectious disease (women are better than men at fighting off pathogens such as SARS-CoV-2).
But scientists have also found that having more genes from X chromosomes may predispose women to autoimmune disease. This increased X chromosome “dosage” is closely linked to a higher risk for autoimmune diseases such as Sjögren’s syndrome and scleroderma.
New research into sex-based immune system differences is also critical for developing new cancer immunotherapies, Sharma explains.
“We’re increasingly understanding how sex-based differences affect disease outcomes. When it comes to medicine, one size doesn’t fit everybody,” says Sharma, who directs LJI’s Center for Sex-Based Differences in the Immune System. “This is leading to new research, particularly in the cancer field, toward precision medicine. We’re asking how a person’s individual immune system is contributing to controlling that cancer through immunotherapy.”
Saphire and Sharma also highlight environmental factors, such as nutrition and chemical exposures, that may add to the complex interplay of chromosomes and sex hormones. Men and women also appear to have some signature differences in their skin and gut microbiomes.
The researchers hope these foundational discoveries can lead to medical advances for all, and they’re working with collaborators across the country to move this research forward. “It takes a team to translate these findings,” says Sharma.
The skeletal muscles of men and women process glucose and fats in different ways. A recently published study now provides the first comprehensive molecular analysis of these differences. The results possibly give an explanation why metabolic diseases such as diabetes manifest differently in women and men – and why they respond differently to physical activity.
Skeletal muscles are far more than just “movement driving motors.” They play a central role in glucose metabolism and therefore also in the development of type 2 diabetes. This is due to the fact that around 85% of insulin-dependent glucose uptake takes place in the muscles. This means that if muscle cells react less sensitively to insulin, for example in the case of insulin resistance, glucose is less easily absorbed from the blood. This process is specifically counteracted by physical activity.
Women’s and Men’s Muscles Work Differently
The degree to which muscles work differently in women and men has long been underestimated. It is precisely this issue which has now been investigated by researchers at the Institute for Diabetes Research and Metabolic Diseases at Helmholtz Munich, the University Hospital of Tübingen and the German Center for Diabetes Research (DZD) e.V. The researchers, led by Dr Simon Dreher and Prof Cora Weigert, examined muscle biopsies from 25 healthy but overweight adults (16 women, 9 men) aged around 30 years. The test subjects had not taken part in regular sporting activities beforehand. Over a period of eight weeks, they completed one hour of endurance training three times a week, consisting of 30 minutes of cycling and 30 minutes of walking on the treadmill.
Muscle samples were taken before they started, after they had the first training session and at the end of the program. Using state-of-the-art molecular biological methods, including epigenome, transcriptome and proteome analyses, the team investigated sex-specific differences at various levels.
Men React with more Stress to Exercise
The result: The first training session triggered a stronger stress response at the molecular level in men, which became manifest in the increased activation of stress genes and the increase in the muscle protein myoglobin in the blood. In addition, male muscles showed a distinct pattern of what are called fast-twitch fibers, which are designed for short-term, intensive exercise and preferably use glucose as an energy source.
Women had significantly higher amounts of proteins that are responsible for the absorption and storage of fatty acids: an indication of more efficient fat utilisation. After eight weeks of regular endurance training, the muscles of both sexes matched and the muscle fibre-specific differences decreased. At the same time, women and men produced more proteins that promote the utilisation of glucose and fat in the mitochondria.
“These adjustments indicate an overall improvement in metabolic performance, which can help to reduce the risk of type 2 diabetes,” says Weigert. “In future, our new findings might help to better predict individual diabetes risks and tailor recommendations for exercise therapies more specifically to women and men.”
The scientists next want to investigate the role sex hormones play in these differences – and how hormonal changes in old age influence the risk of metabolic diseases.
Original publication
Dreher et al., 2025: Sex differences in resting skeletal muscle and the acute and long-term response to endurance exercise in individuals with overweight and obesity. Molecular Metabolism. DOI: 10.1016/j.molmet.2025.102185
About the scientists
Prof. Cora Weigert is head of the research group “Molecular Diabetology and Exercise” at the Institute for Diabetes Research and Metabolic Diseases at Helmholtz Munich and Professor at the University of Tübingen.
Dr. Simon Dreher is scientist at the Institute for Diabetes Research and Metabolic Diseases at Helmholtz Munich and at the University of Tübingen.
Risks higher in women than in men with the same condition Chronic exposure to systemic inflammation may explain associations, say researchers
Photo by Sydney Sims on Unsplash
Living with an autoimmune disease is linked to a near doubling in the risk of persistent mental health issues, such as depression, generalised anxiety, and bipolar disorder, with these risks higher in women than in men, finds a large population-based UK study, published in the open access journal BMJ Mental Health.
Chronic exposure to the systemic inflammation caused by the autoimmune disease may explain the associations found, say the researchers.
A growing body of evidence suggests that inflammation is linked to mental ill health, but many of the published studies have relied on small sample sizes, limiting their statistical power, note the researchers.
In a bid to overcome this, they drew on data from 1.5 million participants in the recently established Our Future Health dataset from across the UK. Participants’ average age was 53; just over half (57%) were women; and 90% identified as White.
On recruitment to Our Future Health, participants completed a baseline questionnaire to provide personal, social, demographic, health and lifestyle information.
Health information included lifetime diagnoses–including for their biological parents–for a wide range of disorders, including autoimmune and psychiatric conditions.
Six autoimmune conditions were included in the study: rheumatoid arthritis; Graves’ syndrome (thyroid hormone disorder); inflammatory bowel disease; lupus, multiple sclerosis; and psoriasis.
The mental health conditions of interest were self-reported diagnoses of affective disorders, defined as depression, bipolar, or anxiety disorder.
In all, 37 808 participants reported autoimmune conditions and 1 525 347 didn’t. Those with autoimmune conditions were more likely to be women (74.5% vs 56.5%) and more likely to report lifetime diagnoses of affective disorders for their biological parents: 8% vs 5.5% for fathers; 15.5% vs 11% for mothers.
Chronic and pathogenic immune system activation—including the presence of markers of inflammation—is a hallmark of many autoimmune conditions. And in the absence of direct measurements of inflammatory biomarkers, an autoimmune condition was regarded as a proxy for chronic inflammation in this study.
The lifetime prevalence of any diagnosed affective disorder was significantly higher among people with an autoimmune disorder than it was among the general population: 29% vs 18%.
Similar associations in lifetime prevalence emerged for depression and anxiety: 25.5% vs just over 15% for depression; and just over 21% vs 12.5% for anxiety.
While the overall prevalence of bipolar disorder was much lower, it was still significantly higher among those with an autoimmune disorder than it was among the general population: just under 1% compared with 0.5%.
The prevalence of current depression and anxiety was also higher among people with autoimmune conditions.
And the prevalence of affective disorders was significantly and consistently higher among women than it was among men with the same physical health conditions: 32% compared to 21% among participants with any autoimmune disorder.
The reasons for this aren’t clear, say the researchers, but “theories suggest that sex hormones, chromosomal factors, and differences in circulating antibodies may partly explain these sex differences,” they write.
“Women (but not men) with depression exhibit increased concentrations of circulating cytokines and acute phase reactants compared with non-depressed counterparts. It is therefore possible that women may experience the compounding challenges of increased occurrence of autoimmunity and stronger effects of immune responses on mental health, resulting in the substantially higher prevalence of affective disorders observed in this study,” they add.
Overall, the risk for each of the affective disorders was nearly twice as high—87-97% higher—in people with autoimmune conditions, and remained high even after adjusting for potentially influential factors, including age, household income, and parental psychiatric history.
No information was available on the time or duration of illness, making it impossible to determine whether autoimmune conditions preceded, co-occurred with, or followed, affective disorders, note the researchers.
No direct measurements of inflammation were made either, and it was therefore impossible to establish the presence, nature, timing or severity of inflammation, they add.
“Although the observational design of this study does not allow for direct inference of causal mechanisms, this analysis of a large national dataset suggests that chronic exposure to systemic inflammation may be linked to a greater risk for affective disorder,” they conclude.
“Future studies should seek to determine whether putative biological, psychological, and social factors—for example, chronic pain, fatigue, sleep or circadian disruptions and social isolation—may represent potentially modifiable mechanisms linking autoimmune conditions and affective disorders.”
And they suggest that it may be worth regularly screening people diagnosed with autoimmune disease for mental health conditions, especially women, to provide them with tailored treatment early on.
Scanning electron micrograph of a T cell lymphocyte. Credit: NIH / NIAID
A study initiated by a University of Arizona Comprehensive Cancer Center physician-scientist has for the first time defined how loss of the Y chromosome in male immune cells negatively affects immune system function. The findings, published in Nature, may explain why loss of Y is associated with lower cancer survival rates.
In males, each cell in the body usually contains one X and one Y chromosome. “Loss of Y” is a common, nonhereditary genetic change in men in which an immune cell in the blood loses its Y chromosome. It is often associated with aging. Loss of Y has been linked to increased mortality from carcinomas for many years, though no one knew why.
This study is the first to identify and define the relationship between loss of Y in white blood cells, immune cells and tumours, providing insights as to why men with loss of Y have increased cancer risks and poorer outcomes.
“These findings represent a big step forward in our understanding of why men with loss of Y in their blood cells have a higher mortality from cancer. It turns out it’s because these cells make the immune system infiltrating the cancer less effective,” said Dan Theodorescu, MD, PhD, director of the Cancer Center and a professor in the College of Medicine – Tucson.
“We hope this provides a solid lead and framework for the nascent Y chromosome field to pursue so we can collectively better understand all the possible biological implications of this finding and how to use them to develop more effective approaches in prevention, treatment resulting in higher survival rates for patients.”
The research team discovered that loss of the Y chromosome – previously identified in malignant epithelial cells by the Theodorescu lab – also occurred in nearby noncancerous tissues, including connective tissue and immune cells.
Most notably, the team found that this chromosomal loss in helper and cytotoxic T cells, which are responsible for attacking cancer cells, was associated with a reduced ability to kill those cancerous cells. The findings suggest a mechanism by which tumours may evade immune detection and suppression.
Finally, the research team found that loss of Y in epithelial cells, combined with loss of Y in T cells, resulted in more aggressive cancers and lower survival rates in patients.
“The study has potential implications for current immunotherapies, including CAR T therapy,” Theodorescu said. “Further research is clearly needed but perhaps immunotherapies using cells from a patient’s immune system could be screened for loss of Y before being used in treatment.”
New research has found that men who carry a common genetic variant are twice as likely to develop dementia in their lifetime compared to women. The research, published in Neurology, used data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial to investigate whether people who had variants in the haemochromatosis (HFE) gene, which is critical for regulating iron levels in the body, might be at increased risk of dementia.
Co-author Professor John Olynyk, from the Curtin Medical School, said one in three people carry one copy of the variant, known as H63D, while one in 36 carry two copies.
“Having just one copy of this gene variant does not impact someone’s health or increase their risk of dementia. However, having two copies of the variant more than doubled the risk of dementia in men, but not women,” Professor Olynyk said.
“While the genetic variant itself cannot be changed, the brain pathways which it affects – leading to the damage that causes dementia – could potentially be treated if we understood more about it.”
Professor Olynyk said further research was needed to investigate why this genetic variant increased the risk of dementia for males but not females.
“The HFE gene is routinely tested for in most Western countries including Australia when assessing people for haemochromatosis – a disorder that causes the body to absorb too much iron. Our findings suggest that perhaps this testing could be offered to men more broadly,” Professor Olynyk said.
“While the HFE gene is critical for controlling iron levels in the body, we found no direct link between iron levels in the blood and increased dementia risk in affected men.
“This points to other mechanisms at play, possibly involving the increased risk of brain injury from inflammation and cell damage in the body.”
The ASPREE trial was a double-blind, randomised, placebo-controlled trial of daily low-aspirin in 19 114 healthy older people in Australia and the USA. Primarily undertaken to evaluate the risks versus benefits of daily low-dose aspirin in this cohort, it created a treasure trove of healthy ageing data that has underpinned a wealth of research studies.
A Geisinger study provides new insight into height differences between adult men and women, demonstrating that Y chromosome genes contribute more to height than their X chromosome counterparts, independent of male sex determination. The results were published this week in the Proceedings of the National Academy of Sciences.
Typical females have two X chromosomes, while typical males have one X and one Y chromosome. The differences between the X and Y chromosomes cause hormonal differences between males and females, but these differences have been insufficient to explain the average 13cm height difference between the sexes.
“Because height shows a large and reproducible difference between sexes and is widely measured, it serves as a valuable model for investigating the genomic factors underlying sex differences,” said Matthew Oetjens, Ph.D., assistant professor in Geisinger’s Department of Developmental Medicine and one of the study leads.
The Geisinger research team sought to determine the effects of sex-related factors on human height by examining height in people with an abnormal number of X or Y chromosomes, a genetic condition known as sex chromosome aneuploidy.
The team analysed genetic and clinical data on nearly one million participants enrolled in Geisinger’s MyCode Community Health Initiative, the National Institutes of Health’s All of Us cohort and the UK Biobank. Of these participants, 1225 had a sex chromosome aneuploidy. By incorporating people with more or fewer than two sex chromosomes into a model of height, they found that exchanging an X for a Y chromosome increased height by 3.1cm, independent of other sex-related factors, including hormonal differences. This result suggests that an estimated 23% of the average difference in height between men and women is explained by increased expression of shared genes on the Y chromosome relative to the X chromosome.
“Beyond its implications for understanding human height, this study provides broader insights into how sex chromosome aneuploidy research can uncover the mechanisms behind observed sex differences in various medical conditions,” said Alexander Berry, PhD, bioinformatics scientist and study co-lead.
SHOX, a gene found on both the X and Y chromosomes, is a known contributor to human height, but because two copies are found in both men and women, it has not been considered a likely contributor to the sex difference in height. However, recent studies have shown that SHOX is partially silenced on the second X chromosome in individuals with two or more X chromosomes. The Geisinger study’s results are consistent with the hypothesis that reduced SHOX expression in females results in a net difference in height between the sexes.
In many countries, males are more likely than females to get sick and die from three common conditions, and less likely to get medical care, according to a new study by Angela Chang of the University of Southern Denmark, and colleagues, published May 1st in the open-access journal PLOS Medicine.
Many health policies are the same for males and females, even though there is strong evidence that sex and gender can substantially influence a person’s health outcomes. In the new study, researchers gathered global health data for people of different sexes and ages for three conditions, hypertension, diabetes, and HIV and AIDS. By comparing rates of diseases between males and females and differences in diagnosis and treatment, the researchers sought to illuminate and reduce health inequities between the sexes.
The analysis identified significant differences between the sexes at each step in the “health pathway,” which includes exposure to a risk factor, development of the condition, diagnosis, treatment and death. Males and females received different care for hypertension, diabetes and HIV and AIDS in 200, 39, and 76 countries, respectively. Males had higher rates of disease and higher rates of death compared to females, and in some countries, were less likely to seek out health care and adhere to treatment. In most countries, males were also more likely to smoke, while females were more like to be obese and engage in unsafe sex.
Overall, the study suggests that public health professionals need to develop strategies to encourage males to participate in preventive and health care services. The researchers also highlight the importance of examining health data by sex to understand health inequities and guide appropriate interventions at multiple points along the health pathway. They conclude that we need more comprehensive datasets for these and other conditions so that we can monitor for sex differences and implement equitable health care policies.
Professors Kent Buse and Sarah Hawkes, co-founders and co-CEOs of Global 50/50 say, “We have long advocated the benefits of publishing sex disaggregated data. As our Gendered Health Pathways demonstrates, such data can reveal where the health journeys of men and women diverge be it in relation to the risk factors they are exposed to, their health care seeking behaviors or their experiences in health care systems. That is an important first step towards health equity. Most of these differences are not explained by sex (biology) alone, but by socially-constructed gender – highlighting the importance of taking a gender justice approach to reducing health inequities. A gender analysis can help to shape systems of health for all.”
Angela Chang, senior author, adds, “The evidence is clear: sex differences persist at nearly every point along the health pathway, from higher smoking rates in men to higher obesity prevalence in women, yet interventions rarely reflect this. Without sex-disaggregated cascade data, we’re flying blind – unable to detect who is falling through the cracks in prevention, diagnosis, and care.”
Some people living with chronic stress have a higher risk of stroke, according to a study published on online in Neurology®, the medical journal of the American Academy of Neurology. The study looked at younger adults and found a correlation between stress and stroke, with no known cause, in female participants, but not male participants.
“Younger people often experience stress due to the demands and pressures associated with work, including long hours and job insecurity, as well as financial burdens,” said Nicolas Martinez-Majander, MD, PhD, of the Helsinki University Hospital in Finland.
“Previous research has shown that chronic stress can negatively affect physical and mental health. Our study found it may increase the risk of stroke in younger women.”
For the study, researchers looked at 426 people aged 18 to 49 who had an ischaemic stroke with no known cause. They were matched for age and sex with 426 people who did not have stroke. Participants completed a questionnaire about stress levels over a one-month period. Those with stroke were asked after their stroke to record stress levels in the month prior to their stroke.
Participants were asked 10 questions, such as “In the last month, how often have you felt that you were unable to control the important things in your life?” Scores for each question ranged from zero to four, with four meaning “very often.” A total score of 0 to 13 represented low stress; 14 to 26, moderate stress; and 27 to 40, high stress.
Those with stroke had an average score of 13 compared to those without stroke who had an average score of 10. People with stroke were more likely to have at least moderate stress levels. Of those with stroke, 46% had moderate or high stress levels compared to 33% of those who did not have stroke. After adjusting for factors that could affect risk of stroke such as education level, alcohol use and blood pressure, researchers found for female participants, moderate stress was associated with a 78% increased risk of stroke and high stress was associated with a 6% increased risk.
Researchers did not find a link between stress and stroke in male participants. “More research is needed to understand why women who feel stressed, but not men, may have a higher risk of stroke,” said Martinez-Majander.
“In addition, we need to further explore why the risk of stroke in women was higher for moderate stress than high stress. Knowing more about how stress plays a role could help us to create better ways to prevent these strokes.”
A limitation of the study was that people experiencing higher levels of stress may have been less likely to enrol in the study, which could have affected the results.
