The trial was conducted at Peking Union Medical College Hospital in Beijing between 2020 and 2021. After a two-week run-in, participants were randomly assigned in a 1:1 ratio to berberine plus standard coronary disease therapy or standard therapy alone. The berberine dose was increased in three stages: 100 mg taken orally three times daily for approximately four weeks, then 200 mg three times daily for approximately four weeks, and finally 300 mg three times daily for approximately four weeks. Investigators monitored adherence with pill counts at three follow-up visits, and no participant fell below the prespecified 80% adherence threshold. One participant in the berberine group voluntarily withdrew before the final visit, leaving 11 participants with final clinical measurements in that group and 11 in the standard-therapy group.

Investigators assessed endothelial function using brachial flow-mediated dilation, with image analysts blinded to treatment assignment. Flow-mediated dilation increased numerically in the berberine group, from 6.7% to 9.7%, and the reported comparison did not meet the threshold for statistical significance at p = 0.07. The authors described the vascular result as a directional improvement rather than a demonstrated effect. The strongest lipid signal involved LDL cholesterol, which declined from 1.74 to 1.55 mmol/L with berberine plus standard therapy and from 2.33 to 2.01 mmol/L with standard therapy alone. A significant group-by-time interaction indicated a greater relative reduction in the berberine group, with a between-group difference at follow-up of p = 0.028. Total cholesterol showed only a marginal group-by-time interaction, so the LDL result was not accompanied by equally clear changes across the full lipid profile.

Triglycerides fell in the berberine group, while apolipoprotein B showed a similar direction of change that did not reach statistical significance. Several inflammatory mediators also decreased between baseline and week 12 in participants receiving berberine: interleukin-1α, interleukin-17, monocyte chemoattractant protein-1, macrophage inflammatory protein-1β and vascular endothelial growth factor. These were within-group observations, so the study does not establish that every decline was caused by berberine. High-sensitivity C-reactive protein declined in both groups, and the paper did not establish a significant between-group difference in that measure. Self-reported constipation assessment scale scores improved in the berberine group, whereas Bristol stool form scores showed no significant difference.

Shotgun metagenomic sequencing showed that berberine was associated with a broad restructuring of the fecal microbiome. The researchers sequenced 68 stool samples and assembled a catalog of 3,094,494 non-redundant microbial genes. Community diversity increased in the berberine group, while microbial community structure differed between baseline and follow-up within that group and between the groups at week 12. Forty-three species changed in relative abundance after treatment, and 17 were classified as berberine-responsive taxa after correction for multiple comparisons. Several organisms declined, including Megasphaera micronuciformis, Megasphaera elsdenii, a Clostridiales bacterium and an Azospirillum species, while Ruminococcus, Roseburia and Anaerostipes hadrus increased. The abundance of M. micronuciformis was negatively correlated with total cholesterol, lipoprotein(a) and C-reactive protein, although these correlations do not demonstrate that the bacterium caused the lipid differences.

The microbial response also involved organisms associated with fermentation and short-chain fatty acid production. Roseburia and Ruminococcus are capable of converting dietary polysaccharides or oligosaccharides into short-chain fatty acids, while Flavonifractor plautii and Eubacterium ventriosum, also associated with short-chain fatty acid production, increased in the combined berberine and standard-therapy group but declined in the standard-therapy group. Targeted fecal metabolomics detected a significant rise in butyric acid, from a median of 11.5 at baseline to 21.3 at week 12, with p = 0.04, and a smaller increase in isobutyric acid, from a median of 1.1 to 1.4, with p = 0.037. Acetic acid showed an upward trend during the middle of treatment before declining to a level only marginally above baseline. Gene profiles were consistent with this shift: pathways for acetate formation became progressively enriched, and the abundance of the but gene, which encodes an enzyme involved in terminal butyrate production, increased significantly after berberine treatment.

Berberine was particularly associated with changes in microbial aromatic amino acid catabolism rather than a simple increase in the amino acid precursors phenylalanine and tyrosine. Fecal L-dopa rose to 3.67 in the berberine group at follow-up, compared with 1.05 in the standard-therapy group, in a significant group-by-time interaction. L-arginine, 3-hydroxyphenylacetic acid and phenylpropionic acid followed a similar berberine-enriched pattern, with the reported follow-up L-arginine values being 22.6 and 9.8 in the berberine and standard-therapy groups, respectively. By contrast, tyrosine and L-tryptophan increased over time regardless of berberine exposure. The investigators interpreted those shared changes as a trajectory associated with standard therapy rather than a berberine-specific response.

A gene-level analysis offered a possible explanation for the metabolite shifts. The abundance of the microbial dopamine β-monooxygenase gene correlated with fecal L-dopa, the porA gene correlated with phenylacetic acid and the acdA gene correlated with phenylpropionic acid, with reported correlation coefficients of 0.6 to 0.7. Seventeen KEGG modules changed appreciably after berberine treatment, including pathways associated with tyrosine, phenylacetate, phenylalanine and tryptophan metabolism. The intervention increased several downstream products without a comparably clear rise in their upstream substrates. This pattern is consistent with the authors’ interpretation that berberine remodels microbial metabolic capacity, but the trial did not directly test whether those changes mediated the clinical outcomes.

Some fecal metabolites were statistically associated with circulating lipids, including L-dopa, hydroxyphenyl lactic acid, L-phenylalanine and imidazole propionic acid. These are associations within a small cohort, not evidence that any metabolite caused a lipid change. The authors noted that previous research had linked phenylpropionic acid to intestinal epithelial barrier function and aryl hydrocarbon receptor signaling, while L-dopa has a context-dependent relationship with cardiovascular biology. They also proposed that the observed fecal L-dopa enrichment might reflect a local gut–vascular axis, but acknowledged that dedicated tracer studies would be needed to determine whether the compound reaches the circulation or acts directly on host tissues. Berberine’s low oral bioavailability makes interactions with the gut microbiota plausible, yet direct effects on host tissues remain possible as well.

The trial is best understood as exploratory rather than definitive. Its two groups differed substantially in age and sex distribution, and potential residual confounding from smoking, alcohol consumption, diet and physical activity could not be fully excluded despite clinical annotation. Missing observations for some clinical parameters also prevented robust between-group comparisons of certain outcomes, while the limited cohort restricted analysis of downstream metabolites. The parallel design helped account for shared coronary disease secondary-prevention therapies, but the findings do not establish that berberine prevents heart attacks, improves survival or should replace established secondary prevention. The results instead identify measurable changes in LDL cholesterol, vascular function, inflammation and the gut ecosystem in a specific group of stable coronary artery disease patients after percutaneous coronary intervention, while leaving their clinical meaning for further investigation.

Subject of Research: Pilot randomized trial of berberine, vascular function, lipids, gut microbiota and fecal metabolites in stable coronary artery disease after percutaneous coronary intervention.

Article Title: Berberine improves lipid levels, vascular function, and gut microbial-dependent metabolites in stable coronary artery disease patients

Article References: Liu, H., Feng, S., Tang, M., Sun, J., Tian, R., & Zhang, S. (2026). Berberine improves lipid levels, vascular function, and gut microbial-dependent metabolites in stable coronary artery disease patients. Frontiers in Nutrition, 13, Article 1945710. https://doi.org/10.3389/fnut.2026.1945710

Image Credits: AI Generated

DOI: 10.3389/fnut.2026.1945710

Keywords: Berberine, Coronary artery disease, Gut microbiome, Short-chain fatty acids, LDL cholesterol, Endothelial function, Metabolomics, Metagenomics, Inflammation, Clinical trial, improves, lipid

The patient, a married recreational cyclist and strength trainer, initially had occasional blood-pressure readings as high as 140/90 mmHg and mixed hyperlipidaemia. Lifestyle measures, including a low-sodium diet and physical activity, did not provide satisfactory control. Treatment began in December 2021 with perindopril 5 mg and atorvastatin 40 mg. Poor adherence and inadequate control led to the temporary addition of indapamide 1.5 mg. Between June and September 2025, he received fixed-dose perindopril and amlodipine combinations of 5/5 mg and then 5/10 mg, but home measurements still reached 160/97 mmHg.

On 22 October 2025, the regimen was changed to a once-daily fixed-dose tablet containing valsartan 160 mg and amlodipine 10 mg. This treatment achieved home blood-pressure readings of 120/80 to 120/85 mmHg. Within a month, however, the patient developed substantial erectile dysfunction and was considering stopping the medication despite its favorable blood-pressure effect. Because preserving sexual function was a priority for him, he asked for a treatment change. Endocrine testing found total testosterone of 14.49 nmol/L, free testosterone of 1.7% and sex hormone-binding globulin of 43.7 nmol/L, all within the reported reference ranges, making a hormonal explanation less likely.

The clinicians therefore focused on the medicines as possible contributors. Amlodipine had been part of two earlier perindopril combinations, used at 5 mg and 10 mg, without erectile dysfunction, whereas the symptom began soon after valsartan was introduced. Those observations led the treating team to suspect valsartan, even though angiotensin receptor blockers as a class are generally considered neutral or potentially beneficial for sexual function. This is a clinically important departure from the expected class profile, but it remains a hypothesis based on temporal association and prior experience in the same individual, not a demonstrated pharmacological effect.

On 4 February 2026, the patient began half a tablet daily of a fixed-dose combination containing olmesartan 40 mg, amlodipine 5 mg and hydrochlorothiazide 12.5 mg. The resulting daily doses were therefore olmesartan 20 mg, amlodipine 2.5 mg and hydrochlorothiazide 6.25 mg. At a one-month follow-up, the patient reported that his erectile symptoms had disappeared. They did not recur, and home blood-pressure measurements remained between 104/75 and 123/81 mmHg, while the clinic reading was 120/80 mmHg. The authors described this sequence as a positive dechallenge following withdrawal of valsartan and successful substitution with olmesartan without relapse.

At an April 2026 assessment, the patient retrospectively rated his erectile function under valsartan therapy as 12 on the IIEF-5, a score categorized as moderate erectile dysfunction. Two months after the switch, he rated it as 22, which falls in the normal-function category, representing a 10-point increase. The questionnaire had not been officially validated in Croatian, so an ad hoc translation was used for clinical purposes. Retrospective self-report and a nonvalidated translation introduce potential recall and measurement uncertainty even though the patient reported high satisfaction and an improvement in quality of life.

Olmesartan and valsartan share a pharmacological class but differ in receptor behavior and several other properties. Olmesartan medoxomil is a prodrug converted during absorption to active olmesartan; the source reports that this modification raises bioavailability from 6% to 28.6% and that olmesartan has little inhibitory effect on cytochrome P450 enzymes, giving it a low potential for drug interactions. The active drug binds with high affinity to angiotensin II type 1, or AT1, receptors and has a slow dissociation rate. Crystallographic evidence described in the report indicates that olmesartan uses a double-chain binding arrangement involving the amino-acid residues Tyr113 and His256, whereas valsartan binds primarily to Lys199 and dissociates more rapidly.

Those molecular differences provide a possible explanation for why two drugs in the same class did not have the same observed effect in this patient, although the case cannot prove that mechanism. The report describes olmesartan as an inverse agonist that stabilizes AT1 receptors in an inactive state, potentially producing more sustained blockade of angiotensin II. It also cites evidence that olmesartan can reduce oxidative stress and microinflammation, influence resistance-vessel remodeling and suppress angiotensin-II-induced intracellular radical production. These vascular actions are relevant because endothelial dysfunction can impair the vasodilation needed for erection, but most of the supporting evidence summarized in the case report comes from broader pharmacological research and animal models rather than a controlled human comparison of valsartan and olmesartan for erectile function.

Experimental work in hypertensive animals provides the most direct evidence cited for a sexual-function effect. In those models, olmesartan reduced malondialdehyde concentrations, used as a marker of oxidative stress, in the corpus cavernosum and increased messenger RNA levels for endothelial and neuronal nitric oxide synthase in penile tissue. The authors propose that greater nitric-oxide availability could improve cavernosal vascular function and potentially counteract the vasoconstrictor effects of a thiazide diuretic. This mechanism remains a plausible hypothesis: the experiment involved animals, and the reported human outcome came from a single person whose treatment changed in several ways at the same time.

Three simultaneous medication changes prevent the improvement from being attributed uniquely to olmesartan: valsartan was replaced, amlodipine was reduced from 10 mg to 2.5 mg, and hydrochlorothiazide was introduced at 6.25 mg. The very low thiazide dose is also relevant because diuretics have historically been associated with erectile dysfunction and treatment discontinuation, although the cited studies used substantially larger doses. Adding a diuretic while function improved does not support the idea that hydrochlorothiazide caused the earlier problem, but it does further complicate identification of the active causal ingredient. The case therefore supports a clinical question—can individual responses differ within the angiotensin receptor blocker class?—rather than a general treatment claim. Larger controlled trials would be needed to determine whether the apparent difference between valsartan and olmesartan is reproducible and whether either drug directly affects erectile function in broader patient populations.

Subject of Research: A case report of improved erectile function after switching from valsartan to an olmesartan-based antihypertensive regimen in one 53-year-old man.

Article Title: Improvement of Erectile Function After Switching From Valsartan to Olmesartan Within a Fixed‐Dose Antihypertensive Combination: A Case Report

Article References: Ćurković, M., & Ćurković, N. (2026). Improvement of Erectile Function After Switching From Valsartan to Olmesartan Within a Fixed‐Dose Antihypertensive Combination: A Case Report. Clinical Case Reports, 14(10), Article e73718. https://doi.org/10.1002/ccr3.73718

Image Credits: AI Generated

DOI: 10.1002/ccr3.73718

Keywords: erectile dysfunction, antihypertensive therapy, olmesartan, valsartan, angiotensin receptor blockers, amlodipine, hydrochlorothiazide, case report, vascular function, Improvement, Erectile, Function

The trial enrolled 66 adults aged 60 to 75 with type 2 diabetes who had not been meeting recommended physical activity levels. Participants were randomly assigned in equal numbers to a morning exercise group, an evening exercise group, or a control group. Both exercise groups completed 12 weeks of moderate-intensity combined aerobic and resistance training delivered online three times per week, with the morning group training from 9:00 to 10:10 and the evening group from 19:00 to 20:10. The control group maintained usual lifestyle habits and attended weekly health education sessions without structured exercise. Fifty-eight participants completed the trial and were included in the final analysis.

The researchers measured four complementary indicators of vascular health: flow-mediated vasodilation, or FMD, which gauges how well the brachial artery expands in response to increased blood flow; brachial-ankle pulse wave velocity, or baPWV, the standard clinical marker of arterial stiffness; brachial blood pressure; and circulating plasma nitric oxide, the key vasodilator molecule produced by endothelial cells. Assessments were performed at baseline and after the intervention, with post-intervention testing conducted 48 to 72 hours after the final session to eliminate acute exercise effects, and always at the same time of day to control for circadian confounding.

The results showed that both exercise groups improved. FMD increased significantly from baseline in the morning group, rising from about 5.0 to 6.3 percent, and in the evening group, rising from about 5.5 to 7.2 percent, while systolic blood pressure and mean arterial pressure fell in both. Arterial stiffness also declined in both groups, but the magnitude differed strikingly: baPWV dropped by an average of 89.2 centimetres per second in the morning group and by 221.1 centimetres per second in the evening group. An exploratory analysis directly comparing the two exercise groups found a statistically significant interaction for baPWV, indicating a greater reduction with evening exercise.

Nitric oxide told a similar story. Plasma NO levels, measured indirectly through its metabolites nitrite and nitrate, increased significantly only in the evening group, from 31.75 to 46.30 micromoles per litre, whereas the morning group showed essentially no change. Post-intervention, the evening group exhibited higher FMD and NO levels and lower mean arterial pressure than the control group. The exploratory comparison of the two exercise groups for NO showed a numerically greater increase with evening exercise, although the interaction just missed statistical significance at p = 0.051.

Why might the clock matter? The answer lies in circadian physiology. In the early morning, sympathetic nervous system activity surges, accompanied by elevated cortisol, catecholamines, angiotensin II, platelet aggregates, and plasminogen activator inhibitor-1. Heart rate and blood pressure rise, serum nitric oxide falls, and brachial artery FMD is attenuated compared with other times of day. These alterations are thought to underlie the well-documented morning peak of cardiovascular events. By contrast, in the early evening most of these patterns reverse, creating a vascular environment with lower sympathetic tone and greater vasodilatory capacity, which may allow exercise-induced shear stress on endothelial cells to translate more effectively into nitric oxide synthesis and arterial adaptations.

The nitric oxide pathway is central to the trial’s mechanistic logic. Exercise increases blood flow and shear stress on the endothelium, which promotes endothelial nitric oxide synthase phosphorylation and NO production while reducing oxidative stress and proinflammatory signalling. NO, in turn, modulates vascular tone and arterial elasticity, so a larger training-induced NO response could plausibly contribute to the greater reduction in arterial stiffness observed after evening sessions. The authors note that plasma NO and FMD provide complementary biochemical and functional perspectives on vascular adaptation, and that considerable inter-individual variability in NO responses may reflect heterogeneity in vascular status within this population.

The trial has notable strengths. It is, to the researchers’ knowledge, the first randomised controlled trial to compare the long-term effects of morning versus evening combined aerobic and resistance exercise on endothelial function, arterial stiffness, and blood pressure in older adults with type 2 diabetes. Attendance was high in both exercise groups, at 95.3 percent in the morning and 97.5 percent in the evening, no exercise-related adverse events occurred, and outcome assessors and data analysts were blinded to group allocation. The consistent timing of vascular assessments before and after the intervention minimised the confounding influence of circadian variation on the outcome measures, a limitation that plagues many acute time-of-day studies.

Limitations temper the conclusions. The study did not include an afternoon exercise group, so whether midday sessions confer different vascular benefits remains unknown. Baseline use of lipid-lowering medication differed significantly among the three groups, an imbalance that likely arose by chance but may have influenced between-group vascular responses. Dietary intake was not strictly controlled, and sleep, physical activity outside prescribed sessions, and medication timing were not monitored during the intervention. Shear rate was not assessed during FMD measurement because the ultrasound system could not record brachial artery diameter and blood velocity simultaneously after cuff deflation. The authors call for future studies to monitor these variables and to include longer follow-up to determine whether the observed adaptations are sustained.

Even so, the findings carry practical weight. FMD is an independent predictor of future cardiovascular events, and evidence suggests that a 1 percent increase in FMD is associated with roughly a 13 percent reduction in cardiovascular risk. In this trial, FMD increased by an average of 1.45 percent across the two exercise groups, indicating potentially clinically relevant improvements in endothelial function. Current exercise guidelines for people with type 2 diabetes specify the type, intensity, frequency, duration, and progression of exercise but offer no clear guidance on timing within the day. This trial suggests that evening exercise may provide additional vascular benefits, particularly for arterial stiffness, and that exercise timing deserves consideration in exercise planning for this population. The study was registered in the Chinese Clinical Trial Registry under identifier ChiCTR2300073737.

Subject of Research: Exercise timing and vascular health in type 2 diabetes

Article Title: Effects of morning versus evening exercise on vascular function in older adults with type 2 diabetes: a randomised controlled trial

Article References: Ma, Z., Lin, Y., Zhu, Z., & Cao, Z.-B. (2026). Effects of morning versus evening exercise on vascular function in older adults with type 2 diabetes: a randomised controlled trial. Frontiers in Endocrinology, 17, Article 1976870. https://doi.org/10.3389/fendo.2026.1976870

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.1976870

Keywords: type 2 diabetes, exercise timing, vascular function, arterial stiffness, nitric oxide, randomised controlled trial, circadian rhythm, cardiovascular risk, Effects, morning, versus, evening

The motivation is demographic as much as scientific. The United States now counts nearly 60 million residents aged 65 and older, a figure projected to grow by another 42 percent by 2050, when more than 23 percent of Americans will be over 65. Age remains the single strongest risk factor for chronic disease, and for many older adults the burden is compounded by cognitive decline, including Alzheimer’s disease and related dementias. The researchers argue that promoting healthy aging and blunting the impact of age-related disease has become a major national social and economic challenge, one that demands biobehavioral data detailed enough to guide real public health interventions rather than isolated correlations.

To build that dataset, ASHA convenes experts spanning biomedical imaging, integrative physiology, biomechanics and exercise science, neuroscience, behavioral science, social work, public health, and biostatistics. Each participant completes two in-person visits lasting five to eight hours each. The protocol begins with informed consent and questionnaires delivered through Vibrent Health, a secure, HIPAA-compliant online platform that lets people complete medical histories remotely. Those histories cover medications, surgeries, physical activity, smoking, alcohol consumption, menstruation history, fall history, education, marital status, and even zip code, painting a social and environmental backdrop against which the biological measurements can later be interpreted.

The imaging centerpiece is a whole-body MRI protocol performed on a 3 Tesla Siemens MAGNETOM Vida scanner at the university’s Clinical Imaging Research Center, operated by a licensed radiologic technologist with breaks built in for comfort. The brain portion stacks structural and functional sequences: high-resolution T1-weighted MPRAGE anatomy, T2-weighted FLAIR to flag white matter lesions, and diffusion tensor imaging to probe the integrity of neural wiring. Cerebral blood flow is measured at rest with arterial spin labeling, while resting-state and task-based BOLD functional MRI, recorded alongside end-tidal CO2, quantify intrinsic brain networks, cerebrovascular reactivity, and activation during language, motor, and executive function tasks such as picture naming and finger tapping.

The rest of the body gets equal scrutiny. A head-to-toe stack of DIXON images separates water and fat signals to map skeletal muscle size and fat distribution across every anatomical region, while a multi-echo variant quantifies liver fat and iron, key markers for non-alcoholic fatty liver disease and iron overload. Thigh muscle imaging adds quantitative T1, T2, and fat-fraction mapping to detect intramuscular fat infiltration, a hallmark of muscle degeneration. Cardiac MRI rounds out the session with cine imaging of ventricular function, tissue tagging to measure strain, T1 and T2 mapping for fibrosis and edema, diffusion tensor imaging of heart muscle architecture, aortic distensibility and pulse wave velocity as markers of vascular stiffness, 4D flow imaging of aortic hemodynamics, and oxygen-sensitive sequences that probe coronary endothelial function without ever threading a catheter.

On a separate day, after a six-hour fast, participants undergo a vascular battery that spans macro- and microcirculation. Blood pressure is measured sitting, standing, and supine to assess postural regulation; ankle-brachial and toe-brachial indices screen for peripheral artery disease; and the SphygmoCor system derives central pulse wave analysis and pulse wave velocity. Beat-to-beat pressure is captured from a finger cuff via photoplethysmography, and brachial artery flow-mediated dilation, the standard noninvasive test of endothelial health, is measured with Doppler ultrasound and rapid cuff inflation. Near-infrared diffuse correlation spectroscopy over the forearm adds a window into microvascular reactivity and tissue oxygenation kinetics, complementing the larger-vessel measures.

Following an approximately 80-milliliter blood draw, part of which goes to clinical testing and the rest to a biorepository of PAXgene tubes and frozen plasma and serum for future genetic and transcriptomic work, participants refuel with a snack and face a cognitive battery. It includes the Montreal Cognitive Assessment for global screening, the NIH Toolbox Cognition Battery and an odor identification test for domain-specific evaluation, and a prospective memory test probing the ability to act on future intentions cued by the environment. Physical function testing then begins with the Short Physical Performance Battery and grip strength dynamometry, followed by gait analysis on an instrumented ZenoMat walkway under both normal conditions and cognitive load, counting backward by ones or sevens or naming animals while walking. A six-minute walk test and a DEXA scan for lean mass, fat mass, and bone density close the visit.

Between clinic visits, the study follows participants into daily life. For seven days they wear a Fitbit Inspire 3 tracking steps, activity intensity, and sleep stages; a cuffless Hilo bracelet, formerly known as Aktiia, that captures blood pressure fluctuations around the clock; and a FreeStyle Libre continuous glucose monitor sampling interstitial glucose every fifteen minutes. Together these devices record glycemic variability, postprandial responses, nocturnal glucose trends, and autonomic cardiovascular rhythms in real-world settings, adding ecological validity that clinic snapshots cannot provide. The design also builds in safeguards: incidental MRI findings are reviewed by the imaging center’s medical director and communicated to participants with recommendations for follow-up, and the study itself offers no diagnosis or treatment.

What may set ASHA apart most is its deliberate diversity and equity focus. The 600 participants, recruited beginning in November 2024 with completion expected by late 2028, will be evenly distributed across Non-Hispanic Black, Non-Hispanic White, Hispanic or Latino, and Asian residents of Tarrant County, one of the largest and most demographically diverse counties in the country, with balanced sex representation in each group. Concentrating recruitment in a single county trades some generalizability for rigor: the same instruments and personnel assess every participant, minimizing measurement noise. Exclusions screen out active cancer treatment, advanced chronic disease, dementia, non-ambulatory status, severe gait disorders, and other conditions that would confound the healthy-aging signal. The investigators acknowledge the single-site limitation and plan controlled-access data sharing so that qualified researchers elsewhere can test whether the patterns hold. Ultimately, by measuring organ systems in concert rather than isolation, the team hopes to build biological age metrics, from frailty indices to imaging-derived biomarkers, that reveal why some people age with resilience while others decline, and to identify the modifiable factors that keep more of us independent for longer.

Subject of Research: A multidisciplinary community cohort study investigating biological, psychological, and social mechanisms of age-related functional decline through multi-organ imaging and monitoring.

Article Title: The Arlington study of healthy aging: a multidisciplinary community cohort study of functional decline with age

Article References: Davis, D. L., Shah, R., Pixler, L., Mai, D. M., Santos, J., Chandler, C., White, K., Nguyen, J., Moradi, A. S., Choudhari, J., Arena-Marshall, C., Johnson, C., Kamel, L., Liao, Y., Greer, T. L., Cooper, C., Ball, H., Fields, N. L., Wang, X., … Nelson, M. D. (2026). The Arlington study of healthy aging: a multidisciplinary community cohort study of functional decline with age. GeroScience, 48(5), 6409-6420. https://doi.org/10.1007/s11357-026-02498-z

Image Credits: AI Generated

DOI: 10.1007/s11357-026-02498-z

Keywords: healthy aging, cohort study, whole-body MRI, functional decline, vascular function, cognitive aging, wearable monitoring, sarcopenia, biological age, older adults, geroscience, health equity

The system in question is autophagy, the cellular recycling program that engulfs damaged proteins and organelles in double-membraned vesicles and delivers them to lysosomes for degradation. Within mitochondria, a specialized form of this process, known as mitophagy, selectively removes dysfunctional mitochondria before they leak reactive oxygen species and trigger cell death. When autophagic flux runs smoothly, the endothelium stays clean and energetic. When it stalls, debris accumulates, mitochondria fragment into dysfunctional shards, and the cell’s metabolic machinery begins to misfire. The French-led research team, working across institutions in Paris and Angers with collaborators in Japan, set out to determine whether calpains, enzymes best known for degrading structural proteins under stress, might be the hidden hand jamming this recycling machinery in diabetes.

The investigators began with human umbilical vein endothelial cells and primary lung endothelial cells exposed to high glucose concentrations in the laboratory. Under these diabetic-mimicking conditions, they observed a clear activation of calpains, detectable through the characteristic cleavage of their substrates. More importantly, they documented a full-blown autophagic flux blockade. The cargo receptor protein SQSTM1, also known as p62, accumulated to abnormal levels because it was no longer being efficiently cleared, while expression of LC3B, the lipidated protein that decorates autophagosomal membranes, was reduced. In practical terms, the conveyor belt carrying cellular waste to the lysosome had ground to a halt, and the mitochondria within these cells responded by fragmenting, losing the elongated, interconnected network architecture that healthy endothelial cells depend upon for efficient energy production.

To test whether calpains were truly the drivers of this collapse rather than innocent bystanders, the team deployed two complementary strategies. The first was pharmacological: small-molecule inhibitors that block calpain enzymatic activity. The second was genetic: overexpression of calpastatin, the endogenous protein that naturally inhibits calpains and serves as the body’s built-in brake on these proteases. Remarkably, both approaches produced the same result. Blocking calpain activity restored autophagic flux, allowing SQSTM1 to be cleared and LC3B-mediated autophagosome formation to resume, and it preserved the mitochondrial network, preventing the pathological fragmentation that hyperglycemia would otherwise induce. The convergence of drug-based and gene-based evidence strengthens the causal argument considerably, ruling out the possibility that the inhibitor was working through some unrelated off-target pathway.

To understand the broader consequences of calpain inhibition at the level of gene expression, the researchers performed transcriptomic profiling of endothelial cells subjected to high glucose with and without calpain blockade. The results revealed that calpain inhibition counteracted several major hyperglycemia-driven transcriptional programs. Among the most prominent were pathways governing oxidative phosphorylation, the mitochondrial process that generates most of the cell’s ATP; reactive oxygen species signaling, which spirals dangerously upward when mitochondria fail; and the unfolded protein response, a stress program activated when the endoplasmic reticulum is overwhelmed. In other words, restraining calpains did not merely patch one leak in the diabetic endothelium but appeared to rebalance an entire constellation of stress responses that high glucose had pushed out of alignment.

The mechanistic picture that emerges is elegant in its simplicity. Hyperglycemia floods endothelial cells with calcium signals and oxidative stress, which overactivate calpains. These proteases then disrupt the autophagy-mitophagy axis, either by directly degrading components of the autophagic machinery or by damaging the lysosomal system that completes the degradation process. With mitophagy impaired, damaged mitochondria escape removal, fragment, and pour out reactive oxygen species, which in turn inflict further damage on proteins and organelles, creating a self-reinforcing cycle of dysfunction. Calpain inhibition breaks this vicious cycle at its upstream point, restoring the cell’s capacity for self-renewal before the downstream damage becomes irreversible. This positions calpains not as one among many secondary casualties of diabetes but as a genuine regulatory node in the pathogenesis of vascular disease.

Crucially, the team did not confine their work to cell culture dishes. They extended their findings into living animals, using mouse models of diabetes to ask whether calpain inhibition could preserve vascular function in the intact organism. The answer was affirmative: treatment that restrained calpain activity preserved vascular reactivity in diabetic mice, the ability of blood vessels to dilate and constrict appropriately in response to physiological cues. This functional rescue is the metric that matters most for translational relevance, because endothelial dysfunction in patients is measured precisely by the loss of this dynamic responsiveness, whether in the coronary arteries feeding the heart or the glomerular capillaries sustaining the kidneys. The study also made use of mitoQC reporter mice, a sophisticated genetic tool developed in Ian Ganley’s laboratory at the University of Dundee, which allows mitophagy to be visualized directly in tissues, providing in vivo confirmation of the cellular findings.

The implications for diabetic patients are significant but must be weighed with appropriate caution. Calpains have been implicated in a wide range of physiological processes, including platelet activation, muscle remodeling, and neuronal function, which means that systemic calpain inhibition carries potential risks that will need careful evaluation. The study’s use of both pharmacological inhibitors and calpastatin overexpression suggests that even partial or tissue-targeted modulation of calpain activity might be sufficient to confer vascular protection, which could open the door to therapeutic strategies that maximize benefit while limiting collateral effects. It is also worth noting that the work was supported by the Société francophone du diabète, Laboratoire Servier, and the EFSD/Novo Nordisk Programme for Diabetes Research in Europe, reflecting a serious institutional commitment to translating basic endothelial biology into clinical applications.

What makes this research resonate beyond the diabetes field is its contribution to a growing appreciation of autophagy as a master regulator of vascular health. Endothelial cells are among the longest-lived cells in the body, exposed continuously to mechanical forces, metabolic fluctuations, and inflammatory insults over decades. Their survival depends on relentless intracellular housekeeping, and any mechanism that compromises that housekeeping, whether it is a protease gone rogue or a lysosome gone sluggish, accelerates vascular aging. By identifying calpain overactivation as a specific and druggable point of failure in the diabetic endothelium, Salemkour, Lenoir, and their colleagues have added a precise new entry to the molecular map of diabetic vascular disease, and they have demonstrated that the map can be redrawn toward health with the right molecular intervention.

The road from a mouse study to a bedside therapy is long, and the authors themselves frame calpain inhibition as a promising strategy rather than a finished treatment. Nevertheless, the convergence of cellular mechanistics, transcriptomic breadth, and intact-animal functional data makes this one of the more complete preclinical demonstrations in the endothelial autophagy literature. For the hundreds of millions of people worldwide living with diabetes, whose risk of cardiovascular death is roughly doubled compared with the general population, the finding that a single enzymatic family stands between high glucose and the collapse of mitochondrial quality control offers something genuinely new: a target that, if safely inhibited, could preserve the vessels that diabetes slowly destroys. The next chapter will be written in the clinic, but the molecular groundwork has now been firmly laid.

Subject of Research: The role of calpain-mediated autophagy and mitophagy blockade in diabetic endothelial dysfunction

Article Title: Calpain inhibition prevents high-glucose-induced autophagy blockade and mitochondrial fragmentation in endothelial cells and preserves vascular functions in diabetic mice

Article References: Salemkour, Y., Dionet, L., Vessieres, E., Saito, R., Le Gall, M., Letavernier, E., Henrion, D., Tharaux, P.-L., & Lenoir, O. (2026). Calpain inhibition prevents high-glucose-induced autophagy blockade and mitochondrial fragmentation in endothelial cells and preserves vascular functions in diabetic mice. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06433-5

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06433-5

Keywords: diabetes, endothelial dysfunction, calpain, autophagy, mitophagy, mitochondria, hyperglycemia, vascular function, calpastatin, oxidative stress, endothelium, diabetic complications

The research team recruited 21 adults aged 35 to 68, dividing them into 11 controls and 10 individuals with long COVID. Every participant had a documented history of SARS-CoV-2 infection, but the two groups differed sharply in the severity of the acute illness and in their recovery. The controls had all experienced asymptomatic or mild infections and reported no lingering symptoms. The long COVID group, by contrast, had suffered moderate-to-critical disease: 60 percent required hospitalization, 60 percent needed oxygen therapy, and one person required mechanical ventilation. At the time of testing, roughly three years after infection, they continued to report fatigue, exercise intolerance, breathlessness, and headaches, and their scores on the Post-COVID-19 Functional Status Scale indicated substantially greater functional limitation than the controls.

To disentangle the possible mechanisms behind this persistent limitation, the investigators designed a three-visit protocol that separated each measurement from the others. On the first visit, participants completed a symptom-limited cardiopulmonary exercise test on a cycle ergometer, with breath-by-breath gas exchange analysis, continuous electrocardiography, and blood pressure monitoring. The second visit was devoted to transthoracic echocardiography, including advanced speckle-tracking analyses of myocardial work. The third visit assessed endothelial function using brachial artery flow-mediated dilation, a noninvasive ultrasound technique in which a blood pressure cuff is inflated for five minutes to induce ischemia and the subsequent surge of blood upon release is used to probe how well the artery dilates. Participants abstained from caffeine, alcohol, and strenuous activity before each session to prevent interference between measurements.

The exercise testing revealed clear and quantifiable deficits. Compared with controls, the long COVID group achieved a lower peak oxygen uptake, a lower predicted peak oxygen uptake relative to reference values, and a lower oxygen uptake at the first ventilatory threshold, the point during incremental exercise where metabolism begins to shift toward anaerobic contribution. These differences carried large effect sizes, indicating that the impairment was not marginal. Because both maximal and submaximal aerobic capacity were reduced, the results suggest that everyday activities, not just athletic performance, demand more physiological effort from these individuals than from their fully recovered counterparts.

The vascular findings were even more striking. Flow-mediated dilation was dramatically lower in the long COVID group, with a Cohen’s d of 2.30, an effect size that is exceptionally large for a between-group comparison in human vascular physiology. Crucially, the team also measured the shear-rate stimulus, the frictional force that flowing blood exerts on the vessel wall and that normally triggers the endothelium to release nitric oxide and other vasodilators. Peak shear rate, the area under the shear-rate curve during the hyperemic period, and the area under the curve up to maximal vasodilation were all significantly reduced in the long COVID participants. This means the problem involves not only a blunted vasodilatory response but also a diminished hyperemic signal, a double hit to the mechanisms that normally match blood flow to metabolic demand.

The researchers took care to ensure that the difference in flow-mediated dilation was not an artifact of differing artery sizes. Allometric scaling of log-transformed baseline and peak diameters showed no significant group-by-diameter interaction, and the between-group difference remained significant after adjustment for baseline diameter. The difference also persisted after statistical adjustment for age, sex, body composition, and comorbidities, strengthening the conclusion that the vascular impairment is a genuine feature of the long COVID phenotype rather than a byproduct of the higher body mass index and obesity prevalence observed in this group.

Perhaps the most informative result came from the correlation analyses. Within the long COVID group, flow-mediated dilation was positively and significantly associated with both peak oxygen uptake and predicted peak oxygen uptake, meaning that individuals with better endothelial function tended to have better aerobic capacity. No such association appeared among the controls, whose vascular function was uniformly good. This pattern supports the idea that, in long COVID, the state of the peripheral vasculature becomes a rate-limiting factor for exercise performance, constraining oxygen delivery to skeletal muscle in a way that does not occur in healthy vasculature with reserve capacity to spare.

The heart, meanwhile, told a different story. Conventional echocardiographic measures, including left ventricular ejection fraction, volumes, and global longitudinal strain, were indistinguishable between groups, as were the myocardial work indices derived from pressure-strain analysis: global work index, global constructive work, global wasted work, and global work efficiency. Myocardial work integrates ventricular deformation with afterload and can detect subtle dysfunction that conventional parameters miss, yet even this sensitive approach found no group differences. Exploratory analyses did reveal intriguing internal patterns: in the long COVID group, lower global work index was associated with greater ventilatory drive and poorer ventilatory efficiency during exercise, and with higher body mass index, hinting at interactions between metabolic status, breathing mechanics, and cardiac mechanics that deserve further study in larger cohorts.

Taken together, the data sketch a coherent physiological account of long COVID exercise intolerance. Persistent endothelial injury after SARS-CoV-2 infection, plausibly driven by chronic inflammation, oxidative stress, and reduced nitric oxide bioavailability, compromises the ability of conduit and resistance vessels to dilate appropriately during exercise. The result is a peripheral limit on oxygen delivery that manifests as reduced aerobic capacity, while the central pump continues to function within normal limits. This peripheral mechanism aligns with earlier studies conducted one and two years after infection, but the present work extends the timeline considerably, showing that these abnormalities persist well into the third year after the acute illness.

The authors are careful to note the limitations of their study. It was observational, cross-sectional, and single-center, with a modest sample size, so the findings are hypothesis-generating rather than definitive. The long COVID cohort consisted predominantly of people with previous moderate-to-critical illness, and the controls all had prior asymptomatic or mild infection, so the results may not generalize to the full spectrum of post-COVID conditions. The cohort was also predominantly composed of individuals with overweight or obesity, and the study was not powered to detect sex or race differences. Even so, the large effect sizes and the a priori power calculation lend credibility to the central conclusion. Clinically, the work argues for evaluating vascular health, not just cardiac function, in patients with persistent post-COVID exercise intolerance, and for cardiometabolic risk management alongside structured rehabilitation. Whether improving endothelial function can restore exercise tolerance remains a critical question for future interventional trials.

Subject of Research: Persistent endothelial dysfunction and exercise intolerance in long COVID three years after SARS-CoV-2 infection

Article Title: Persistent endothelial dysfunction is associated with exercise intolerance in adults despite preserved myocardial work 3 years after SARS‐CoV‐2 infection

Article References: de Araújo Alves, C. C., Goulart, C. D. L., D'Ávila, L., de Souza Silva, B. H. E., Alves, I. M., Aguiar, B. V. S., Conde, C., Stein, R., & Cipriano, G., Jr. (2026). Persistent endothelial dysfunction is associated with exercise intolerance in adults despite preserved myocardial work 3 years after SARS‐CoV‐2 infection. Physiological Reports, 14(19), Article e71103. https://doi.org/10.14814/phy2.71103

Image Credits: AI Generated

DOI: 10.14814/phy2.71103

Keywords: long COVID, endothelial dysfunction, flow-mediated dilation, exercise intolerance, myocardial work, cardiopulmonary exercise testing, SARS-CoV-2, vascular function, peak oxygen uptake, echocardiography, nitric oxide, post-COVID condition

The research team, led by investigators at Trinity College Dublin and collaborating institutions, focused on two distinct but related markers of exercise tolerance. The first was peak oxygen uptake, or VO2peak, the maximal amount of oxygen the body can consume during incremental exercise to exhaustion. VO2peak is not merely a laboratory curiosity; it is one of the strongest independent predictors of cardiovascular and all-cause mortality, and people with type 2 diabetes consistently show reductions of roughly twelve to twenty-two percent compared with healthy peers. The second marker was the time constant of the primary phase of the oxygen uptake response, abbreviated as tau VO2p, which describes how quickly oxygen consumption rises toward its steady state when a person transitions from rest to moderate exercise. Slower kinetics mean a larger oxygen deficit at the onset of activity, greater reliance on anaerobic metabolism, and earlier fatigue during everyday tasks such as climbing stairs or carrying groceries.

Participants were stratified into two age cohorts: an early middle-aged group aged thirty-seven to fifty-nine years and a late middle-aged group aged sixty to seventy years. All had been diagnosed with type 2 diabetes for fewer than ten years and had glycated hemoglobin values below ten percent, indicating reasonably well-controlled disease. After an initial treadmill electrocardiogram stress assessment, volunteers were assigned to one of four groups: exercising or non-exercising controls in each age band. The allocation was not random, primarily because of differences in participants’ ability to travel to the training facility, a limitation the authors acknowledge. Those in the exercise arms completed a twelve-week supervised program of up to thirty-six sessions, combining continuous cycling at seventy to eighty percent of maximal heart rate, resistance training for major upper and lower body muscle groups at sixty to seventy percent of one-repetition maximum, core strengthening, flexibility work, and brief high-intensity intervals at approximately ninety percent of maximal heart rate. Adherence was exceptional, with participants averaging thirty-five of a possible thirty-six sessions.

The testing protocol was rigorous. Before and after the intervention, participants performed a graded exercise test on a cycle ergometer to determine VO2peak, peak power output, the power output at the gas exchange threshold, and the oxygen pulse, an indirect marker of stroke volume. In a separate session, they completed six constant-load cycling bouts at a workload corresponding to eighty percent of their individually determined gas exchange threshold, with breath-by-breath gas exchange measured continuously. Cardiac output was assessed by an inert gas rebreathing technique at rest and at thirty and two hundred forty seconds of exercise, allowing the researchers to calculate stroke volume, mean arterial pressure, and systemic vascular conductance. The oxygen uptake data were fitted with monoexponential or biexponential mathematical models to extract the time constant of the primary response, the parameter that captures how efficiently the oxidative system adjusts to a sudden metabolic demand.

The results were unambiguous for the exercising groups. Both the early and late middle-aged training cohorts showed statistically significant increases in absolute and relative VO2peak, rising from roughly twenty-five milliliters per kilogram per minute at baseline to about twenty-eight after training, an improvement of approximately twelve percent. Peak power output, the power output at the gas exchange threshold, and oxygen pulse all rose in parallel, while heart rate at exhaustion was unchanged, indicating genuine physiological adaptation rather than simply greater effort or familiarization with the test. Crucially, the magnitude of these gains did not differ between the two age groups. The non-exercising controls, by contrast, showed no meaningful changes in any of these variables over the twelve weeks, and body mass and HbA1c remained stable across all groups, meaning the fitness improvements could not be attributed to weight loss or better glycaemic control.

The oxygen uptake kinetics data told a similarly encouraging story. The time constant of the primary VO2 response fell from approximately forty seconds at baseline to around thirty-four to thirty-five seconds after training in both exercise groups, representing an acceleration of roughly twelve percent in the late middle-aged cohort and twenty-one percent in the early middle-aged cohort. Although the numerical difference between the age groups was noticeable, statistical testing showed it did not reach significance, and the authors concluded that the improvement in submaximal oxygen kinetics was essentially equivalent across ages. This matters because faster kinetics reduce the oxygen deficit at the start of exercise, limit the accumulation of metabolites that contribute to fatigue, and translate directly into better tolerance of the repetitive, moderate-intensity activities that define daily life, an effect that is particularly relevant for adults in their sixties who may be approaching the threshold of functional decline.

Perhaps the most intriguing mechanistic finding was what did not change. The researchers had hypothesized that faster oxygen uptake kinetics might be driven by improved central cardiovascular delivery of oxygen, reflected in more rapid adjustments of cardiac output, stroke volume, or systemic vascular conductance during the first seconds of exercise. Instead, when they quantified the dynamic responses of these variables by comparing the change at thirty seconds with the change at two hundred forty seconds, they found no significant alterations following training in either age group. The improvements in cardiac output and vascular conductance that were observed at fixed time points largely reflected the higher workloads participants could sustain after training rather than a fundamentally altered cardiovascular response profile. This pattern suggests that the acceleration of oxygen uptake kinetics was more likely mediated by peripheral adaptations, such as enhanced matching of oxygen delivery to metabolic demand within the contracting skeletal muscle, improved vasodilatory capacity, or better dynamic microvascular function, although the study did not directly measure muscle oxygenation.

The clinical implications are considerable. Type 2 diabetes prevalence rises sharply with age, and as populations grow older and more sedentary, the burden of the disease is projected to escalate. Previous work by the same group had shown that middle-aged adults with diabetes in their forties and fifties exhibit slowed oxygen uptake kinetics compared with healthy controls, whereas those in their sixties do not, hinting that age might modify the exercise phenotype of the disease. The new data extend that picture by demonstrating that, regardless of these baseline differences, the responsiveness to structured training, in both maximal and submaximal measures of exercise tolerance, is preserved across early and late middle age. In practical terms, clinicians can reasonably expect a sixty-three-year-old with well-controlled type 2 diabetes to gain as much fitness from a twelve-week combined program as a fifty-four-year-old with the same disease duration, which argues strongly against the assumption that older middle-aged patients are somehow less trainable.

The authors are careful to note the boundaries of their conclusions. The participants had relatively mild, uncomplicated diabetes with mean HbA1c values between 6.3 and 7.0 percent, so the findings may not generalize to people with poorer glycaemic control or advanced disease, who typically show greater impairments in fitness. The age gap between the two cohorts was only about ten years, limiting inferences about broader age-related differences in trainability, and the sex distribution differed between groups, although prior evidence indicates that training adaptations in VO2peak and oxygen kinetics are not influenced by sex in type 2 diabetes. The inert gas rebreathing technique also lacked the temporal resolution to detect subtle changes in central hemodynamics. Even so, the study provides a valuable benchmark for expected training responses in adults with type 2 diabetes in their forties through sixties, and it reinforces a message that exercise physiologists have long championed: the aging body, even one carrying a metabolic disease, retains a striking capacity to grow fitter when given the right stimulus. Whether the same plasticity extends to people over seventy or with longer disease duration remains an open and clinically urgent question.

Subject of Research: Effects of structured exercise training on cardiorespiratory fitness and oxygen uptake kinetics in early versus late middle-aged adults with type 2 diabetes

Article Title: Exercise training improves cardiorespiratory fitness and oxygen uptake kinetics to a similar extent in early and late middle‐aged adults with type 2 diabetes

Article References: Kiely, C., O'Connor, E., O'Shea, D., Green, S., & Egaña, M. (2026). Exercise training improves cardiorespiratory fitness and oxygen uptake kinetics to a similar extent in early and late middle‐aged adults with type 2 diabetes. Physiological Reports, 14(18), Article e71107. https://doi.org/10.14814/phy2.71107

Image Credits: AI Generated

DOI: 10.14814/phy2.71107

Keywords: type 2 diabetes, exercise training, cardiorespiratory fitness, oxygen uptake kinetics, VO2peak, middle age, cardiac output, skeletal muscle, aging, physical activity, Physiological Reports, vascular function

The research, led by Leandro C. Brito and colleagues at Oregon Health & Science University, set out to answer a deceptively simple question: does the baroreflex system itself follow a circadian rhythm, and if so, does that rhythm line up with the circadian rhythm of blood pressure? Previous studies had hinted at a daily pattern in baroreflex function, with sensitivity appearing greatest around three in the morning in both normotensive and hypertensive individuals. But those studies measured people during their normal sleep-wake cycles, meaning the results were hopelessly entangled with behavior. Sleep, posture, meals, and physical activity all influence blood pressure and autonomic function, making it impossible to separate the effect of the internal clock from the effect of simply being asleep.

To untangle this knot, the team turned to one of the most powerful tools in human circadian physiology: the forced desynchrony protocol. In this design, volunteers live on a behavioral schedule that is too short for their internal circadian pacemaker to follow. Because the human circadian clock runs on an intrinsic period of roughly 24.1 hours and cannot entrain to cycles far outside its entrainment range, the internal rhythm is forced to free-run at its own pace while the behavioral cycle marches to a different drummer. When physiological measurements are later plotted against circadian phase rather than clock time, any rhythm that emerges must be driven by the endogenous circadian system rather than by sleep, meals, or activity.

Eleven healthy young adults, aged 20 to 39, completed a 30-hour laboratory stay built around five consecutive six-hour cycles, each containing four hours of wakefulness followed by a two-hour sleep opportunity. Every aspect of their environment was tightly controlled. Wake periods took place in dim light below eight lux, sleep occurred in total darkness, and no time cues were provided. Identical isocaloric meals of roughly 322 kilocalories, composed of about 35 percent fat, 50 percent carbohydrate, and 15 percent protein, were delivered every three hours. Participants remained supine except during meals, scheduled restroom visits, and supervised exercise. Polysomnography confirmed that they slept an average of 114 minutes during each two-hour window, with no significant differences in sleep duration across the protocol. Circadian phase was anchored to the dim light melatonin onset, the gold-standard marker of the biological clock, determined from hourly salivary samples.

During each wake period, the researchers recorded beat-to-beat blood pressure with finger photoplethysmography and cardiac electrical activity with a standard three-lead electrocardiogram. From these continuous signals they extracted two distinct measures of baroreflex function. The first, baroreflex sensitivity, quantifies how strongly the heart rate responds to a given change in systolic pressure, expressed as the slope of the relationship between the two. The second, the baroreflex effectiveness index, counts how often the baroreflex actually intervenes: it is the ratio of validated baroreflex sequences, in which pressure and heart interval change in the appropriate opposing directions across at least three consecutive cardiac cycles, to the total number of spontaneous systolic pressure sequences observed. Sensitivity measures the strength of the reflex when it fires; effectiveness measures how frequently it fires at all.

The results were striking in their asymmetry. Systolic blood pressure showed a clear circadian rhythm with a peak-to-trough amplitude of ten millimeters of mercury, bottoming out at a circadian phase corresponding to roughly 1:40 in the morning and peaking near 11:40 in the morning. Diastolic pressure showed no significant rhythm. Baroreflex sensitivity, perhaps surprisingly, also showed no significant circadian variation. But the baroreflex effectiveness index told a different story entirely. It peaked at a circadian phase corresponding to about one in the morning, averaging 34 percent above its overall mean, and fell to its lowest value, 48 percent below the mean, at around nine in the morning. In other words, the reflex was most active precisely when systolic pressure was at its circadian minimum.

Deeper analysis of the directionality of the reflex added an important nuance. When the researchers separated the data into up-up sequences, in which the reflex slows the heart in response to rising pressure, and down-down sequences, in which it accelerates the heart as pressure falls, they found that the nocturnal advantage came almost entirely from the up-up responses. During the circadian night, the baroreflex was 110 percent more effective at correcting increases in blood pressure than during the circadian morning. This asymmetry carries real clinical weight. Prior work has shown that in women with a family history of hypertension, the ability to correct pressure rises is selectively impaired, and in people with established hypertension, a deficient baroreflex response to pressure increases independently predicts death and adverse cardiovascular events.

The study also mapped the circadian rhythms of the vasculature. Brachial artery vascular conductance, an index of skeletal muscle vasodilation, peaked around two in the morning at 27 percent above its mean, immediately preceding the systolic pressure trough, and fell to its lowest point around six in the evening. Vascular endothelial function, measured as flow-mediated dilation of the brachial artery, peaked later, at around ten in the morning, 34 percent above the mean, and was lowest at six in the evening. Notably, this morning peak in endothelial function occurred about five hours earlier than previously reported in middle-aged adults studied with the same technique, raising the possibility that aging shifts the circadian phase of vascular protection. The authors suggest this morning peak may help explain why, paradoxically, adverse cardiovascular events cluster between six in the morning and noon in epidemiological studies.

Why did sensitivity fail to rhythm while effectiveness did? The authors offer several possibilities. Their participants were exceptionally healthy, young, and recreationally active, conditions that may have created a ceiling effect masking a true rhythm in sensitivity. Alternatively, sensitivity and effectiveness may act in counterphase, as earlier work by di Rienzo and colleagues proposed when the effectiveness index was first introduced. It is also possible that the circadian system exerts a stronger influence on the spontaneous engagement of the reflex than on its gain. Importantly, the findings held up when the total number of pressure sequences and validated baroreflex sequences were included as covariates, ruling out the trivial explanation that more opportunities to detect sequences arose at night.

The implications extend well beyond basic physiology. No currently available antihypertensive medication acts directly on the baroreflex, but non-pharmacological interventions, including exercise training, respiratory muscle training, and non-invasive vagal nerve stimulation, are known to improve baroreflex function. If the circadian system genuinely gates baroreflex effectiveness, these therapies might be timed to exploit that rhythm, opening a chronotherapy-based avenue for treating non-dipping blood pressure. The authors are careful to note the limits of their work: the sample was small and predominantly young and healthy, the 30-hour protocol offers only six-hour phase resolution, and the findings must be reproduced in older adults and in people with hypertension before they can inform clinical practice. Still, by rigorously isolating the internal clock from the noise of daily behavior, the study elevates the baroreflex from a passive bystander to a leading suspect in the mystery of nocturnal blood pressure regulation, and it hands researchers a concrete, testable target in the search for why some hearts fail to dip when night falls.

Subject of Research: Circadian variation in cardiac baroreflex effectiveness and its alignment with the nocturnal trough in systolic blood pressure in young healthy adults

Article Title: Nocturnal peak in cardiac baroreflex effectiveness aligns with nocturnal trough in systolic blood pressure in young healthy adults: Possible circadian effects

Article References: Brito, L. C., Jones, M. L., Chaudhary, N., Shea, S. A., & Thosar, S. S. (2026). Nocturnal peak in cardiac baroreflex effectiveness aligns with nocturnal trough in systolic blood pressure in young healthy adults: Possible circadian effects. Physiological Reports, 14(17), Article e71092. https://doi.org/10.14814/phy2.71092

Image Credits: AI Generated

DOI: 10.14814/phy2.71092

Keywords: circadian rhythm, baroreflex, blood pressure, nocturnal dipping, forced desynchrony, autonomic nervous system, vascular function, hypertension, melatonin, flow-mediated dilation, cardiovascular physiology, chronotherapy