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Hypertonic Saline Plus Furosemide Improves Heart Failure Biomarkers in Randomized Trial

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“Our findings revealed that in subjects with ADHF, treatment with i.v. furosemide plus HSS significantly decreased the serum levels of IL-6, sST2, hsTnT, galectin-3, and NT-proBNP and modulated some miRNA expression.”

Heart failure remains one of the leading causes of hospitalization among older adults worldwide. During episodes of acute decompensated heart failure (ADHF), excess fluid builds up in the lungs and body, making breathing difficult and increasing the risk of serious complications. Although intravenous loop diuretics such as furosemide are the standard treatment for relieving congestion, many patients continue to experience persistent inflammation, ongoing cardiac remodeling, and worsening heart function despite therapy.

A research paper published in Volume 18 of Aging titled “Effects of intravenous furosemide plus small-volume hypertonic saline solutions on inflammatory, remodelling markers and epigenetics signatures of patients with congestive acute decompensated heart failure (ADHF),” investigated whether combining intravenous furosemide with small volumes of hypertonic saline solution (HSS) could improve biological markers associated with heart failure compared with furosemide alone. 

The study was led by first author Mario Daidone from University Hospital, Policlinico, Paolo Giaccone, and the University of Palermo, with corresponding author Antonino Tuttolomondo from the same institutions. 

Why Add Salt to a Diuretic?

At first glance, combining a salt solution with a diuretic may seem counterintuitive because heart failure treatment typically focuses on removing excess fluid and limiting sodium intake.

However, previous studies have suggested that administering a small volume of hypertonic saline together with high-dose furosemide may temporarily improve intravascular volume and kidney perfusion during aggressive diuresis. This could enhance the effectiveness of the diuretic while helping maintain circulation, potentially leading to better fluid removal and improved clinical outcomes. The current study was designed to examine not only these clinical effects but also whether the combination therapy influenced inflammation, cardiac remodeling, and circulating microRNAs linked to heart failure.

Testing a New Treatment Strategy

The investigators conducted a randomized controlled trial involving 200 patients hospitalized with acute decompensated heart failure caused by heart failure with reduced ejection fraction (HFrEF).

Participants were randomly assigned to receive either:

  • intravenous furosemide plus small-volume hypertonic saline solution, or
  • intravenous furosemide alone.

Patients were evaluated at hospital admission, after six days of treatment, and again after undergoing a standardized saline challenge designed to assess how well the heart responded after treatment. At each time point, the researchers measured several biomarkers associated with heart failure, including:

  • NT-proBNP, a marker of cardiac wall stress,
  • high-sensitivity troponin T (hsTnT), a marker of myocardial injury,
  • soluble ST2 (sST2) and galectin-3, which are associated with cardiac remodeling and fibrosis,
  • interleukin-6 (IL-6) and C-reactive protein (CRP), markers of inflammation,
  • and several circulating microRNAs involved in heart failure biology.

Greater Improvements in Selected Heart Failure Biomarkers

After six days of treatment, several biomarkers declined in both groups. When the researchers compared the magnitude of these changes, patients receiving furosemide plus hypertonic saline showed significantly greater reductions in IL-6, sST2, and NT-proBNP than those receiving furosemide alone. Although hsTnT and galectin-3 also decreased during treatment, the magnitude of their reduction did not differ significantly between the two groups in the absolute change analysis. CRP likewise did not show a significant treatment-related difference between groups.

The researchers also observed that patients treated with hypertonic saline produced more urine and experienced greater weight loss during hospitalization, findings consistent with more effective decongestion. In addition, symptoms such as exertional shortness of breath and peripheral edema improved in a greater proportion of patients receiving the combination therapy.

The Heart Responded Differently to a Saline Challenge

One distinctive feature of the study was that, after completing treatment, all participants underwent an acute saline challenge.

Patients treated with furosemide alone experienced larger increases in biomarkers such as IL-6, sST2, hsTnT, galectin-3, and NT-proBNP following the saline infusion.

In contrast, patients who had received furosemide plus hypertonic saline showed smaller increases in these biomarkers after the saline load. The authors interpreted this pattern as suggesting a more favorable response to acute volume loading after decongestive treatment.

Changes Extended to Epigenetic Markers

Beyond conventional biomarkers, the investigators also examined several circulating microRNAs, small regulatory RNA molecules that influence gene expression and have been implicated in inflammation, fibrosis, and cardiac remodeling.

The treatment groups also differed in the expression patterns of several microRNAs, particularly miR-214, miR-365, and miR-181b. The direction and timing of these changes varied across the treatment and saline-challenge phases, indicating that the combination regimen altered selected circulating microRNA profiles rather than producing a uniform effect across all markers.

Although the biological significance of these changes remains uncertain, the authors propose that circulating microRNAs may eventually serve as biomarkers for monitoring treatment response in patients with heart failure. However, they emphasize that additional research is needed before these markers can be incorporated into routine clinical practice.

Why These Findings Matter

Heart failure is driven by more than excess fluid alone. Persistent inflammation, myocardial injury, neurohormonal activation, and structural remodeling all contribute to disease progression and worsening outcomes.

This study suggests that combining small-volume hypertonic saline with intravenous furosemide may improve multiple biological processes associated with heart failure rather than simply increasing urine output. Improvements in selected biomarkers related to inflammation, cardiac stress, and remodeling raise the possibility that this approach could provide broader benefits during treatment of acute decompensated heart failure.

However, improvements in biomarkers do not necessarily translate into better long-term clinical outcomes, and further studies are needed to determine whether these biological effects lead to sustained reductions in hospitalization or mortality.

Looking Ahead

The authors conclude that, in patients with acute decompensated heart failure and reduced ejection fraction, intravenous furosemide plus small-volume hypertonic saline reduced several biomarkers associated with inflammation, myocardial injury, cardiac remodeling, and ventricular wall stress more effectively than furosemide alone. The combination therapy also altered circulating microRNA profiles linked to heart failure biology, suggesting potential effects on molecular pathways involved in disease progression.

While these findings are encouraging, the study was conducted at a single center, and larger multicenter randomized trials will be needed to determine whether these improvements in biomarkers translate into better long-term patient outcomes. Future research will also help clarify whether circulating microRNAs can become reliable tools for monitoring treatment response and guiding personalized therapy in heart failure.

Click here to read the full research paper published in Aging.

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Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Brain Flexibility Is Linked to Hand Coordination During Aging

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“These findings underscore an age-related shift in the neural dynamics underpinning motor adaptability with aging, pointing to increased BOLD variability modulation as a potential marker of compensatory reorganization in late adulthood.”

Coordinating both hands is something most people take for granted. Everyday activities such as buttoning a shirt, preparing a meal, driving, or using a knife and fork all depend on the brain’s ability to precisely control movements on both sides of the body. As people age, however, these tasks often become more difficult, especially when they require both hands to perform different movements at the same time.

A research paper published in Volume 18 of Aging titled “Age-specific relationship between the modulation of brain dynamics in response to task demands and bimanual performance,” investigated how aging affects the brain’s ability to adapt to increasingly complex hand-coordination tasks. The study was led by first author Sara Magalhães Ferreira from Hasselt University, with corresponding author Koen Cuypers from Hasselt University and KU Leuven.

Looking Beyond Brain Activation

For many years, scientists studying healthy aging have focused primarily on which brain regions become more or less active during movement. However, brain activity is not static. Even while performing the same task, activity naturally fluctuates from moment to moment.

These fluctuations, known as Blood Oxygen Level-Dependent (BOLD) variability, may provide important information about how flexibly the brain adapts to changing demands. Rather than measuring average brain activity alone, BOLD variability reflects the dynamic changes in neural activity over time and has emerged as a potential indicator of neural adaptability and efficiency.

Although previous studies have linked BOLD variability to cognitive aging, its role in complex motor functions such as coordinating both hands had remained largely unexplored.

Testing How the Aging Brain Responds to Increasing Motor Demands

To investigate this question, the researchers recruited 22 younger adults and 23 older adults, who performed a series of increasingly challenging bimanual tracking tasks while undergoing functional magnetic resonance imaging (fMRI).

The tasks required participants to coordinate both hands under three levels of difficulty. While some tasks involved moving both hands together in relatively simple patterns, others required different movement speeds and timing between the hands, placing greater demands on motor control and executive function.

As expected, older adults performed less accurately than younger adults, particularly during the most complex coordination task.

The Brain Responded Differently With Age

Rather than simply comparing overall brain activity, the researchers examined how BOLD variability changed as task difficulty increased.

Older adults showed greater BOLD variability in a cerebellar region and greater modulation of BOLD variability across several sensorimotor and cerebellar regions as task demands increased. These findings suggest that the aging brain adjusts its neural activity differently when faced with more challenging movements.

Importantly, these findings suggest that the changes reflected different strategies for adapting to increasing motor demands rather than simply indicating reduced brain function.

Different Brain Strategies Predicted Better Performance

One of the study’s most interesting findings was that the relationship between brain dynamics and motor performance differed between younger and older adults.

Among younger adults, smaller changes in BOLD variability within several sensorimotor and visuospatial brain regions were associated with better task performance. This suggests that younger brains may already operate efficiently and require relatively little adjustment as task difficulty increases.

In contrast, older adults who showed greater modulation of BOLD variability in regions of the parietal cortex generally performed better on the coordination tasks. These brain areas help integrate sensory information, guide movement, and support attention during complex motor activities.

Across both age groups, greater modulation in the middle occipital gyrus—a region involved in visual processing—was associated with better performance, whereas greater modulation in the cerebellar Crus I was linked to poorer performance. These findings suggest that the contribution of individual brain regions to successful movement changes with age.

How the Aging Brain May Adapt

Although the study was not designed to determine the precise biological mechanisms behind these findings, the results support the idea that the aging brain can reorganize its activity to compensate for age-related changes.

Rather than relying on the same neural strategies used by younger adults, older individuals may recruit additional brain networks and dynamically adjust neural activity as task demands increase. This flexible reorganization may help preserve motor function despite the structural and physiological changes that naturally occur with aging.

The findings are consistent with theories suggesting that healthy aging involves both gradual neural decline and compensatory adaptations that help maintain everyday function.

What Makes This Study Different?

Most previous neuroimaging studies of aging have focused on average brain activation. In contrast, this study examined how fluctuations in brain activity change as movement tasks become more demanding.

It is also among the first studies to investigate BOLD variability during complex bimanual coordination rather than cognitive tasks alone. By combining advanced functional MRI analyses with increasingly difficult motor challenges, the researchers were able to identify age-specific patterns of neural adaptability that traditional measures of brain activation may overlook.

Looking Ahead

The authors conclude that aging is associated with important changes in how the brain dynamically responds to increasing motor demands. Rather than reflecting simple decline, greater modulation of brain activity in certain regions may represent a compensatory strategy that helps older adults maintain coordinated movement.

Although larger studies will be needed to confirm these findings, the results suggest that measuring BOLD variability may provide new insights into healthy brain aging and motor adaptability. As researchers continue to investigate the neural mechanisms underlying movement, these findings may help guide future strategies aimed at preserving coordination, independence, and quality of life throughout aging.

Click here to read the full research paper published in Aging.

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Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Plant-Based Dietary Patterns Are Associated With Slower Biological Aging

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“The present study found that dietary patterns higher in plant foods and lower in animal products were consistently associated with decelerated DNA methylation-derived aging biomarkers, specifically GrimAge2 and PhenoAge.”

As people live longer, maintaining good health is becoming just as important as extending lifespan. While chronological age simply reflects the number of years a person has lived, biological age measures how well the body is functioning and may better predict future health. Researchers have increasingly focused on lifestyle factors that may slow biological aging, and diet has emerged as one of the most promising.

A research paper published in Volume 18 of Aging titled “Plant-based dietary patterns are associated with slower epigenetic aging,” investigated whether diets emphasizing plant foods are associated with slower biological aging as measured by DNA methylation-based epigenetic clocks.

Looking Beyond Chronological Age

Not everyone ages at the same rate. While two individuals may share the same chronological age, one may remain healthier and more resilient than the other because their biological age is lower.

One of the most widely used approaches involves measuring DNA methylation, a natural chemical modification of DNA that changes throughout life. These patterns can be analyzed using so-called epigenetic clocks, including GrimAge2, PhenoAge, and HannumAge, which have been shown to predict future risks of chronic disease, disability, and mortality more accurately than chronological age alone.

Previous studies have suggested that healthy dietary patterns may help slow epigenetic aging. However, it remained unclear whether plant-based diets in people who do not necessarily follow vegetarian or vegan lifestyles are associated with these biological aging markers.

Comparing Different Types of Plant-Based Diets

To investigate this question, the researchers analyzed data from two large U.S. population studies: the Atherosclerosis Risk in Communities (ARIC) Study and the National Health and Nutrition Examination Survey (NHANES). Together, the analysis included more than 4,800 middle-aged and older adults.

Rather than simply comparing vegetarians with non-vegetarians, the investigators evaluated four different plant-based dietary patterns:

  • Overall Plant-Based Diet Index (PDI), which rewards greater intake of plant foods and lower intake of animal foods.
  • Provegetarian Diet Index, which emphasizes relatively higher consumption of plant foods while reducing animal products.
  • Healthy Plant-Based Diet Index (healthy PDI), which favors nutrient-rich foods such as fruits, vegetables, whole grains, legumes, and nuts.
  • Unhealthy Plant-Based Diet Index (unhealthy PDI), which reflects greater intake of refined grains, sugary foods, and other less nutritious plant-derived foods.

The researchers then examined whether these dietary patterns were associated with three widely used measures of epigenetic aging after accounting for age, lifestyle, socioeconomic factors, smoking, alcohol use, physical activity, and other potential confounding variables.

Healthier Plant-Based Diets Were Linked to Slower Epigenetic Aging

The study found that greater adherence to overall plant-based diets, provegetarian diets, and healthy plant-based diets was consistently associated with slower biological aging.

Participants with higher scores for the overall plant-based diet and provegetarian diet showed slower GrimAge2 and PhenoAge acceleration. Higher adherence to the overall plant-based diet was also associated with slower HannumAge. Healthy plant-based diets were linked to slower GrimAge2, although the associations with the other epigenetic clocks were less consistent.

In contrast, unhealthy plant-based diets showed no significant association with any of the biological aging measures.

These findings suggest that the quality of plant foods matters. Simply consuming fewer animal products may not be enough if the diet relies heavily on refined carbohydrates, added sugars, and other less nutritious plant-based foods.

How Diet Influences Biological Aging

Although this study was not designed to identify the underlying biological mechanisms, the authors discuss several possibilities.

Plant-based diets are typically rich in dietary fiber, vitamins, minerals, antioxidants, and other bioactive compounds that are thought to help reduce oxidative stress and chronic inflammation, two processes believed to contribute to biological aging. These diets have also been associated with improved blood pressure, healthier cholesterol levels, better glucose regulation, and reduced risk of cardiovascular disease.

Over time, these favorable metabolic effects may influence DNA methylation patterns, resulting in slower progression of biological aging as measured by epigenetic clocks.

The researchers also note that plant-based diets are not all alike. Diets centered on whole, minimally processed plant foods appear to offer greater health benefits than those dominated by refined grains, sugary beverages, and highly processed plant-derived products.

What Makes This Study Different?

Unlike many previous studies that focused on vegetarian or vegan diets, this investigation evaluated plant-based eating patterns in a largely non-vegetarian population.

This distinction is important because many people adopt diets that increase plant food consumption without completely eliminating animal products. The findings suggest that even moderate shifts toward healthier plant-based eating patterns may be associated with measurable differences in biological aging.

Another strength of the study is its use of two large, independent U.S. cohorts and multiple validated epigenetic aging measures, increasing confidence that the observed associations were consistent across different populations.

Looking Ahead

The authors conclude that dietary patterns emphasizing healthy plant foods and limiting animal products are associated with slower epigenetic aging. While the study cannot establish cause and effect, it adds to growing evidence that long-term dietary habits may influence biological processes linked to aging and future health.

Additional research, including long-term intervention studies, will be needed to determine whether adopting healthier plant-based diets can directly slow biological aging over time. As scientists continue exploring the relationship between nutrition and longevity, this study suggests that everyday food choices may play an important role in promoting healthier aging at the molecular level.

Click here to read the full research paper published in Aging.

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Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Do Exergames Improve Mood and Mental Well-Being in Older Adults?

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“The results indicated that exergames positively impacted mood in older adults, reducing tension, anger, fatigue, confusion, and depressive symptoms, while promoting engagement, immersion, and socialization.”

As people live longer, maintaining mental well-being has become an increasingly important part of healthy aging. While regular physical activity is known to support both physical and psychological health, many older adults face barriers that make traditional exercise programs difficult to sustain. Researchers have therefore been exploring new approaches that combine physical activity with enjoyment, social interaction, and cognitive engagement.

A review published in Volume 18 of Aging titled “What are the effects of exergames on the mood states of older people? A systematic review of experimental studies, impacts on mental health and recommendations,” examined whether exergames—video games that require physical movement to play—can improve mood and mental health in older adults. The study was led by authors from the Laboratory of Sport and Exercise Psychology, Human Movement Sciences Graduate Program, College of Health and Sport Science of the Santa Catarina State University (UDESC) in Florianópolis, Brazil. 

Turning Exercise Into Play

Exergames combine exercise with interactive digital gaming. Unlike traditional video games that are played while sitting, exergames require players to move their bodies to control gameplay. Popular examples include Nintendo Wii Fit, Wii Sports, Kinect Sports, Dance Central, and virtual reality-based exercise platforms.

These systems have attracted growing interest among researchers because they may help overcome some of the challenges that limit exercise participation among older adults. By incorporating game-like rewards, social interaction, and enjoyable activities, exergames may increase motivation and long-term adherence to physical activity programs.

Previous research has already suggested that exergames can improve physical fitness, balance, mobility, and cognitive function. However, less was known about their effects on mood and emotional well-being in older populations.

Reviewing the Evidence

To better understand these effects, the researchers conducted a systematic review following PRISMA guidelines and registered the study in PROSPERO before completing the analysis. They searched four major scientific databases and identified 651 studies. After applying strict eligibility criteria, nine experimental studies involving 325 participants aged 61 to nearly 79 years were included in the final review.

The studies examined a wide variety of exergaming interventions, including dance-based games, sports simulations, balance-training activities, virtual reality cycling, and cognitive-motor training programs. Intervention lengths ranged from a single session to multi-week programs lasting up to 36 sessions.

Improvements Across Multiple Mood States

The review found that exergames generally produced positive effects on mood. Six of the nine studies reported significant improvements in mood-related outcomes, while the remaining studies reported neutral findings. Importantly, none of the included studies found evidence that exergames worsened mood or mental health.

Several studies reported reductions in:

  • Depressive symptoms
  • Tension
  • Anger
  • Fatigue
  • Mental confusion

At the same time, participants frequently reported improved overall mood and emotional well-being.

One study found that a single Wii-based exercise session produced immediate positive mood changes. Another reported that exergames reduced depression scores more effectively than conventional physical activity programs.

More Than Just Exercise

The researchers suggest that the benefits of exergames extend beyond physical activity alone.

Unlike many traditional exercise programs, exergames combine movement with mental stimulation and interactive challenges. Players must make decisions, react to visual cues, solve problems, and coordinate movements in real time. This cognitive engagement may contribute to positive emotional responses and increased enjoyment during exercise.

Social interaction may also play a major role. Several studies reported that exergames encouraged communication, cooperation, and shared experiences among participants. Some older adults described the activities as enjoyable opportunities to connect with family members and friends. Others reported that the games reduced boredom and created a sense of immersion that made exercise feel less like a chore.

One group of participants even compared exergaming to an “emotional therapy” experience because of its positive effects on mood and well-being.

Reducing Depressive Symptoms

One of the most consistent findings involved depression-related outcomes.

Several studies specifically examined depressive symptoms in older adults. While not all studies reached statistical significance, most reported a favorable trend, and one study demonstrated a significant reduction in depression scores among participants who used Nintendo Wii Fit-based exergames. In that study, the benefits were greater than those observed with conventional physical activity alone.

Given that depression, loneliness, and social isolation are common concerns among aging populations, these findings suggest that exergames may offer a valuable complementary approach to supporting mental health.

Why Exergames May Be Particularly Appealing for Older Adults

One practical advantage of exergames is accessibility.

Many systems can be used at home, reducing barriers such as transportation difficulties, mobility limitations, weather conditions, or lack of access to exercise facilities. This flexibility may be particularly important for older adults who have difficulty participating in traditional fitness programs.

The review also highlighted another important factor: adherence. Because exergames are interactive and enjoyable, participants may be more likely to continue exercising over time. Long-term adherence is often one of the greatest challenges in health promotion programs, making enjoyment a critical component of successful interventions.

Recommendations for Practice

Based on the available evidence, the authors suggest that exergames can serve as a useful alternative or complement to traditional exercise programs for older adults. They recommend adapting gameplay to individual preferences and abilities, incorporating appropriate rest periods, and ensuring that exercise intensity remains safe while still providing meaningful health benefits.

The researchers also note that exergames may be particularly useful in residential care settings, rehabilitation programs, community centers, and home-based health interventions.

Looking Ahead

The authors conclude that exergames represent a promising tool for promoting both physical activity and psychological well-being in older adults. Across the studies reviewed, exergames consistently demonstrated positive effects on mood while also encouraging social interaction, cognitive engagement, and enjoyment.

Although larger and longer-term studies are still needed, the current evidence suggests that interactive exercise games may help address some of the emotional and mental health challenges associated with aging. By combining movement, technology, and social engagement, exergames may offer an innovative way to support healthy aging and improve quality of life in older populations.

Overall, the findings suggest that staying active does not always require a gym or structured exercise class. For many older adults, stepping into a virtual bowling alley, dance floor, or sports arena may provide meaningful benefits for both body and mind.

Click here to read the full review published in Aging.

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Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

Click here to subscribe to Aging publication updates.

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Blood Tests and Gut Bacteria May Help Reveal Your Biological Age

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“Biological age reflects the current state of the body, considering the aspects of lifestyle, environment, and hereditary component.”

Why do some people appear to age faster than others, even when they are the same age? Researchers increasingly believe that chronological age tells only part of the story. Biological age attempts to capture how well the body’s systems are functioning and may provide a more meaningful picture of overall health.

A research paper on this topic was published in Volume 18 of Aging titled “Blood biochemical and gut microbiotic neural network models forecasting human biological age.” In the study, Russian researchers explored whether information from routine blood tests and the gut microbiome could be used to estimate biological age.

Looking Beyond the Calendar

For decades, researchers have searched for reliable ways to measure biological aging. Some of the most well-known aging clocks rely on DNA methylation patterns, but these approaches often require specialized laboratory equipment and can be difficult to implement in routine clinical practice.

The researchers aimed to develop alternatives to DNA methylation clocks using blood biomarkers and gut microbiome characteristics. They investigated whether blood chemistry measurements and gut microbiome profiles could be used to estimate biological age with high accuracy.

To do this, they analyzed data from 637 adults ranging in age from 18 to 99 years, combining laboratory blood measurements with microbiome sequencing data obtained from stool samples.

Building an Aging Clock From Blood Markers

The first model focused on biochemical indicators measured in blood. After evaluating dozens of laboratory parameters, the researchers identified a small set of biomarkers that showed strong associations with age.

Three markers were important for both men and women:

  • Cystatin C
  • Insulin-like growth factor 1 (IGF-1)
  • Dehydroepiandrosterone sulfate (DHEAS)

Additional sex-specific markers were incorporated for each group. In women, the model included homocysteine, urea, glucose, and zonulin. In men, the model included HbA1c, NT-proBNP, free testosterone, and high-sensitivity C-reactive protein (hs-CRP).

Using these biomarkers as inputs, the team trained neural-network models designed to predict biological age. The resulting models predicted age with an average error of roughly six years and showed strong agreement with chronological age.

The Aging Signature Hidden in the Gut Microbiome

The second model focused on the trillions of microorganisms that inhabit the human digestive tract.

Previous studies have shown that the gut microbiome changes with age, leading researchers to investigate whether these microbial shifts could serve as indicators of biological aging. Some bacterial species become more abundant with age, while others decline. Because the microbiome influences metabolism, immune function, inflammation, and gut barrier integrity, researchers have increasingly viewed it as a potential window into the aging process.

After analyzing microbial sequencing data, the investigators selected 45 bacterial species that were associated with age and used them to train a microbiome-based aging model.

Despite relying on a very different set of biological measurements, the microbiome-based model also showed strong predictive performance. Its estimates closely tracked chronological age and showed substantial agreement with both the blood-based model and an established aging measure known as PhenoAge.

Making Artificial Intelligence Explainable

Because neural networks are often difficult to interpret, the researchers also examined which variables contributed most to the predictions. To do this, they used an explainable AI approach called SHAP (SHapley Additive exPlanations). This method allowed them to determine how much each blood biomarker or bacterial species contributed to an individual’s biological age estimate.

DHEAS, a hormone known to decline with age, emerged as one of the most influential predictors of biological age in both sexes, with its contribution varying substantially across age groups. In older individuals, markers such as cystatin C and NT-proBNP became particularly important indicators of aging-related physiological changes.

The microbiome model showed a more complex pattern. Rather than relying on a single dominant bacterial species, the model incorporated information from dozens of microbes whose collective behavior reflected age-related shifts in gut health and metabolism.

What Changes in the Body Are Being Captured?

According to the authors, the blood-based model appears to capture aging-related changes across multiple biological systems, including metabolism, hormone regulation, inflammation, cardiovascular health, and kidney function. Age-related increases in glucose, HbA1c, hs-CRP, homocysteine, and NT-proBNP were associated with biological aging, while declines in IGF-1, DHEAS, and testosterone reflected reduced anabolic and endocrine function.

The microbiome model identified a different but interconnected aspect of aging. As people grow older, some beneficial bacteria involved in producing metabolites such as butyrate and acetate decline, while certain potentially harmful or inflammatory species become more abundant. These microbial shifts can influence immune responses, metabolic regulation, and intestinal barrier function.

The researchers suggest that common biological pathways may link the two models, including chronic low-grade inflammation, metabolic dysregulation, insulin resistance, and changes in gut barrier integrity. Rather than being independent processes, these mechanisms may interact to drive biological aging throughout the body.

Why These Findings Matter

A practical advantage of the study is that biological age could be estimated using a relatively small number of biomarkers. The blood-based model required only seven laboratory measurements, while the microbiome model relied on 45 bacterial species. Both approaches achieved strong predictive accuracy while remaining more interpretable than many previous aging clocks.

Although additional validation in diverse populations will be needed, these tools could eventually help researchers monitor the effects of lifestyle interventions, medical treatments, or anti-aging therapies. Because the models provide information about which factors contribute most to an individual’s biological age estimate, they may also offer insights into the specific biological processes driving accelerated aging.

Looking Ahead

The authors conclude that both blood biochemistry and gut microbiome composition contain valuable information about biological aging. Their neural-network models achieved strong predictive performance and showed substantial agreement with each other, suggesting that different aspects of human biology may converge on common aging pathways.

As biological age becomes an increasingly important concept in longevity research and preventive medicine, practical and interpretable aging clocks may help clinicians move beyond simply counting years and toward understanding how well the body is truly aging. The findings highlight how advances in laboratory medicine, microbiome research, and artificial intelligence may help researchers better understand why people age differently and how healthy aging can be measured more precisely.

Click here to read the full research paper published in Aging.

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Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

Click here to subscribe to Aging publication updates.

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Glutathione Pathway May Hold the Key to Safer Anti-Obesity Interventions

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“Despite its anti-obesity effects, BSO did not exert any detrimental effects on bones.”

Efforts to improve metabolic health through dietary interventions often come with trade-offs. Some approaches that reduce obesity or extend lifespan in laboratory models can also negatively affect other tissues, including bone.

One example is sulfur amino acid restriction (SAAR), a diet low in methionine and lacking cysteine that has repeatedly shown strong anti-obesity effects in animal studies. However, despite these promising metabolic benefits, SAAR has also been associated with reduced bone mineral density, weaker bones, and increased marrow fat accumulation.

This has led researchers to ask whether the metabolic benefits of SAAR can be separated from its harmful skeletal effects.

A new research paper was published in Volume 18 of Aging-US, titled “D, L-Buthionine-(S, R)-sulfoximine recapitulates the anti-obesity effects of sulfur amino acid restriction without the associated deleterious effects on bone in male mice.” The researchers investigated whether those metabolic benefits could be achieved without the same harmful effects on bone. The study was led by first author Naidu B. Ommi and corresponding author Sailendra N. Nichenametla from the Orentreich Foundation for the Advancement of Science Inc., in collaboration with Dwight A. L. Mattocks from the same institution and Mark C. Horowitz from the Yale University School of Medicine.

Understanding the Trade-Off

SAAR has attracted attention because of its strong anti-obesity effects in laboratory animals. But the same diet can also weaken the skeleton. In previous studies, SAAR reduced fat mass while increasing bone marrow adipocytes and decreasing bone strength. This complicates the idea of using SAAR as a long-term metabolic intervention without first understanding why those bone-related side effects occur.

The researchers focused on cysteine restriction and glutathione metabolism. Cysteine is a sulfur-containing amino acid and a key building block of glutathione, an important molecule involved in antioxidant defense, redox balance, and cell signaling. Because SAAR removes cysteine from the diet, the authors wanted to determine whether cysteine restriction was responsible not only for the anti-obesity effects, but also for bone-related side effects.

Testing a Different Approach

To investigate this, the team studied obese male mice fed high-fat diets under different conditions. One group received a control diet, another received the SAAR diet, a third received the SAAR diet with N-acetylcysteine (NAC), and another received the control diet with D, L-buthionine-(S, R)-sulfoximine (BSO), a compound that inhibits glutathione biosynthesis.

The results showed a clear difference between the dietary intervention and the pharmacological approach. Mice on the SAAR diet had lower trabecular and cortical bone mineral density, fewer osteoblasts, reduced bone strength, and more marrow adipocytes. However, mice treated with BSO did not show these harmful skeletal effects, even though BSO reproduced several anti-obesity effects seen with SAAR.

NAC also reversed the bone-related changes caused by SAAR, suggesting that cysteine restriction was a major driver of the skeletal side effects.

Bone, Fat, and Cysteine Restriction

One of the most important parts of the study is the connection between bone-forming cells and marrow fat. Osteoblasts, which build bone, and marrow adipocytes, which store fat inside bone marrow, can arise from related skeletal progenitor cells. When more of these cells shift toward fat formation, bone formation can decline.

In the SAAR-fed mice, the researchers observed fewer osteoblasts, weaker bone structure, and more marrow fat. When NAC was added, many of these effects were reversed. This supported the idea that cysteine restriction plays a central role in the bone loss associated with SAAR.

BSO, however, behaved differently. Although it affected body composition, it did not reduce bone mineral density, weaken mechanical strength, or increase marrow adipocytes in the same way as SAAR.

Why BSO May Act Differently

The finding that BSO did not harm bone was especially important. The authors suggest that this may be due to tissue-specific effects. In other words, BSO may lower glutathione more strongly in some tissues than in others. The paper notes that bone marrow may be more resistant to glutathione depletion by BSO than tissues such as the liver or kidney.

This could help explain why BSO was able to produce anti-obesity effects without reproducing the bone damage seen with SAAR. Still, the authors were careful to emphasize that more research is needed before BSO can be considered for broader therapeutic use. The authors also note that long-term studies will be necessary to better understand potential toxicity and tissue-specific effects.

Looking Ahead

This study is preclinical and was conducted in male mice, so the findings cannot yet be applied directly to humans. Future studies will need to examine long-term safety, effects in female mice, tissue-specific responses, optimal dosing, and possible off-target effects.

Still, the findings point to an important idea: the metabolic benefits of sulfur amino acid restriction may be separable from its harmful effects on bone. If researchers can better understand that separation, it may become possible to design safer interventions for obesity, aging, and metabolic health.

Conclusion

This study provides new insight into how sulfur amino acid metabolism, cysteine restriction, glutathione biology, obesity, and bone health are connected. By showing that BSO can reproduce anti-obesity effects without the bone deterioration seen with SAAR, the findings point toward a possible new direction for future research in nutrition, aging, and metabolic disease.

This study provides the first evidence that CysR mediates the adverse effects of the SAAR diet on bone health, while BSO induces beneficial changes in body composition without detectable adverse effects on bone.

Click here to read the full research paper published in Aging-US.

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Aging-US is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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P38 MAPK–Driven Epigenetic Regulation Identified as a Key Mechanism in Lung Fibrosis

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“Pharmacological inhibition of p38 MAPK significantly reduced α-SMA and Col3A1 expression in both TGF-β1-stimulated fibroblasts and primary IPF cells. Mechanistically, TGF-β1-induced expression of α-SMA and Col3A1 was mediated by histone H4K16 acetylation (H4K16ac), which was enriched at gene promoter regions and attenuated by p38 MAPK inhibition.”

Aging has long been linked to a range of biological processes, including cellular senescence, epigenetic changes, and chronic tissue remodeling. Yet, these explanations often describe what happens during aging rather than why certain age-related diseases, such as fibrosis, continue to progress over time. In conditions like idiopathic pulmonary fibrosis (IPF), a key question remains: what drives the persistent activation of cells that should normally return to a resting state after injury? Increasing attention has turned to the interaction between cellular signaling pathways and epigenetic regulation as a potential explanation. Understanding how these processes work together to control gene expression and cell behavior is becoming an important focus in uncovering the mechanisms behind age-related disease.

A new research paper was published in Volume 18 of Aging-US, titled “P38 MAPK is involved in epigenetic regulation of fibrotic genes in replication induced senescence in lung fibroblasts.” The study was led by first author Shan Zhu and corresponding author Yan Y. Sanders from the Department of Biomedical and Translational Sciences, Eastern Virginia Medical School (Macon & Joan Brock Virginia Health Sciences at Old Dominion University), in collaboration with Jennifer Q. Zhou, Kan Wang, and Ming-lei Guo from the same institution.

A Closer Look at Aging, Senescence, and Lung Disease

Aging is often described as a gradual accumulation of cellular damage, but that explanation alone does not fully capture how age-related diseases develop. In conditions like IPF, the problem is not just damage—it is how cells respond to that damage over time. Increasingly, researchers are focusing on cellular senescence, a state in which cells stop dividing but remain metabolically active and can influence their environment in harmful ways.

Understanding how these senescent cells drive disease—and what controls their behavior—has become an important question in aging biology.

Linking Senescence to Fibrosis

IPF is a progressive lung disease strongly associated with aging. One of its defining features is the abnormal activation of fibroblasts, the cells responsible for producing structural components of tissue. When these cells remain activated for too long, they begin to deposit excessive extracellular matrix, leading to scarring and loss of lung function.

In this study, the researchers explored how young (low population doubling level, LPDL) and near-senescent/senescent (high population doubling level, HPDL) lung fibroblasts respond to transforming growth factor-β1 (TGF-β1), a key driver of fibrosis.

Interestingly, both young and senescent cells showed similar increases in fibrotic markers such as α-SMA and Col3A1, suggesting that senescence does not prevent fibroblast activation—but may alter how it is regulated.

A Distinct Role for p38 MAPK Signaling

While canonical SMAD signaling behaved similarly in both cell types, the p38 MAPK pathway told a different story. The researchers found a clear difference between the two cell types: p38 MAPK activation was rapid and short-lived in young fibroblasts, but slower and more sustained in senescent cells. 

This prolonged signaling in aging cells may help explain why fibrosis becomes persistent and difficult to resolve over time.

Blocking Fibrosis at the Molecular Level

To test whether p38 MAPK plays a functional role, the team used a pharmacological inhibitor (SB202190). The results were clear. Inhibition of p38 MAPK significantly reduced the expression of key fibrotic genes, including α-SMA and Col3A1, and this effect was observed in both experimental fibroblasts and primary IPF patient cells. 

These findings suggest that p38 MAPK is not just active during fibrosis but plays an important role in sustaining the fibrotic response.

Epigenetics: The Missing Link

Beyond signaling pathways, the study uncovered an important epigenetic mechanism. The researchers showed that TGF-β1 increases histone H4K16 acetylation (H4K16ac), enriches this modification at fibrotic gene promoters, and that blocking p38 MAPK reduces this effect. 

In simple terms, p38 MAPK helps “switch on” fibrosis-related genes by modifying chromatin structure, making them more accessible for transcription.

Why This Matters

Fibrosis is notoriously difficult to treat, in part because it involves multiple overlapping pathways. This study highlights a key intersection between cellular aging (senescence), signal transduction (p38 MAPK), and epigenetic regulation (H4K16ac). 

By linking these processes together, the authors provide a more integrated understanding of how fibrosis develops and persists.

Looking Ahead

While this work is preclinical, it points to an important therapeutic opportunity. Targeting p38 MAPK—or the epigenetic mechanisms it controls—could help disrupt the cycle of fibroblast activation and slow disease progression.

Future studies will be needed to explore how these findings translate into clinical settings and whether similar mechanisms operate in other age-related fibrotic diseases.

Conclusion

This study sheds light on how aging-related changes in cell signaling and chromatin structure work together to drive fibrosis. By identifying p38 MAPK as a key regulator of epigenetic activation in fibroblasts, the authors offer a compelling framework for understanding—and potentially targeting—fibrotic disease.

Click here to read the full research paper published in Aging-US.

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Aging-US is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Decline in Glycolytic ATP Production Proposed as a Fundamental Mechanism Limiting Lifespan

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“Glycolytic ATP production declines with age, contributing to common aging phenotypes such as reduced cell division and impaired DNA & mitochondria repair.”

Aging has long been attributed to a range of biological processes, including DNA damage, telomere shortening, and mitochondrial dysfunction. Yet, these frameworks often describe downstream consequences rather than a single unifying cause. Despite decades of research, a central question remains unresolved: what ultimately determines lifespan across species? Increasing attention has turned to cellular energy metabolism—particularly pathways responsible for rapid ATP generation—as a potential key driver. Understanding how these metabolic changes unfold over time, and how they influence survival, regeneration, and disease, remains a major challenge in aging biology.

A new research perspective published in Volume 18 of Aging-US introduces a unifying concept in aging biology, titled “A decline in glycolytic ATP production is the fundamental mechanism limiting lifespan; species with an optimal rate of decline over time survived.”

The study was led by first and corresponding author Akihiko Taguchi and co-author Yuka Okinaka, both from the Department of Regenerative Medicine Research, Foundation for Biomedical Research and Innovation at Kobe, Hyogo, Japan, in collaboration with Carsten Claussen and Sheraz Gul from the Fraunhofer Institute for Translational Medicine and Pharmacology, Hamburg, Germany.

A New Concept in Aging Biology

Rather than viewing aging as the result of accumulated damage alone, the authors propose that a gradual decline in glycolytic ATP production represents a central mechanism underlying aging across species. Glycolysis plays a critical role in supporting rapid energy demands, cell division, DNA repair, and mitochondrial maintenance. A reduction in this pathway over time may therefore contribute directly to many of the functional declines observed with aging.

An Evolutionary Perspective on Lifespan

The authors put forward a simple but compelling hypothesis: species that evolved with an optimal rate of decline in glycolytic ATP production were more likely to survive through natural selection.

In environments with limited food resources, increased energy efficiency—achieved through a shift toward oxidative metabolism—may provide a survival advantage. While this adaptation may benefit the species as a whole, it may also come at the cost of reduced cellular repair capacity and regenerative potential over time.

Linking Metabolism to Aging Phenotypes

Glycolytic ATP production is approximately 100 times faster than oxidative phosphorylation and is essential for high-demand cellular processes. Its decline with age is associated with impaired tissue repair, reduced cellular turnover, and increased vulnerability to stress. In contrast, cells that maintain high glycolytic activity—such as cancer cells—exhibit sustained proliferation and extended survival, highlighting the central role of metabolism in determining cellular lifespan.

Explaining Differences in Lifespan Across Species

Taken together, this framework may help explain several longstanding observations, including the wide variation in lifespan among species, the absence of biological immortality in most organisms, and the exceptional longevity of certain species such as the naked mole rat. According to the authors, differences in the rate of glycolytic decline may underlie these biological distinctions.

Implications for Aging and Disease

The authors also point to links between reduced glycolytic activity and age-related conditions, including neurodegenerative diseases, chronic kidney disease, and sarcopenia. Evidence from experimental and clinical studies suggests that enhancing glycolysis may help preserve cellular function and slow disease progression, supporting the relevance of this metabolic framework.

Future Directions

While the study is largely conceptual, it opens new directions for research into aging and longevity. Targeting glycolytic pathways—through metabolic, genetic, or cell-based approaches—may represent a promising strategy for promoting healthy aging. Further studies will be required to determine how these insights can be translated into safe and effective therapeutic interventions.

Conclusion

This study proposes a shift in how aging is understood, positioning the decline in glycolytic ATP production as a fundamental determinant of lifespan shaped by evolutionary pressures. By integrating metabolism, evolution, and cellular biology, the authors provide a cohesive framework that may guide future research and therapeutic development in aging science.

Click here to read the full research perspective published in Aging-US.

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Aging-US is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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IL6 and IL6R: Opposing Forces of Inflammation That Shape Human Survival

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“The IL6 axis plays a pivotal role in both acute and chronic inflammatory responses, operating through two distinct pathways: classical signalling via a membrane-bound IL6 receptor and trans-signalling mediated by a soluble IL6 receptor (IL6R), which enables IL6 activity in cells lacking the membrane receptor.”

Inflammation is a double-edged sword. It defends the body against infection and injury, yet when it becomes chronic, it can accelerate aging and fuel the very diseases that shorten human life. For decades, scientists have observed that people with higher levels of inflammatory markers like interleukin-6 (IL6) and C-reactive protein (CRP) tend to have shorter lifespans. But the critical question has always been: does inflammation cause mortality, or does it merely reflect underlying disease?

A research paper, titled “Causal effects of inflammation on long-term mortality: A mendelian randomization study” was published in  Volume 18 of Aging-US by an international team of researchers, provides a definitive answer by using a powerful genetic technique to untangle cause from effect.

The team’s investigation demonstrates that the IL6 inflammatory pathway has a direct causal impact on human survival—but with a surprising twist: two components of the same pathway pull in opposite directions.

The Method: Mendelian Randomization

To establish causation, the researchers employed Mendelian randomization (MR), a technique that uses genetic variants as natural experiments. Because genes are randomly assigned at conception and fixed throughout life, they are not subject to the confounding factors—such as lifestyle, diet, or socioeconomic status—that plague traditional observational studies.

The team analyzed genetic data from approximately 750,000 individuals of European ancestry, focusing on four inflammatory biomarkers: interleukin-6 (IL6), its soluble receptor (IL6R), C-reactive protein (CRP), and growth differentiation factor-15 (GDF15). The primary outcome was all-cause mortality over a median follow-up of 11.7 years, with secondary outcomes including cardiovascular events and cancer.

Key Findings: Opposing Forces in the IL6 Pathway

The results revealed a remarkable biological duality. Genetically higher levels of the soluble IL6 receptor (IL6R) were associated with a reduced risk of all-cause mortality (odds ratio 0.95 per 1-standard deviation increase; p = 0.007). Higher IL6R levels also lowered the risk of atrial fibrillation, coronary artery disease, stroke, and lung cancer.

In stark contrast, genetically higher levels of IL6 itself were linked to an increased risk of mortality (odds ratio 1.05; p = 0.002). These findings suggest that IL6 and IL6R are biological opposites: IL6 drives harm, while IL6R protects.

The protective effects of IL6R were consistent across multiple sensitivity analyses, with no evidence of pleiotropy (where genetic variants influence outcomes through unintended pathways). A cis-Mendelian randomization analysis restricted to variants within the IL6R gene locus confirmed the protective association, reinforcing the causal relevance of this pathway.

CRP and GDF15: Biomarkers, Not Drivers

Notably, neither CRP nor GDF15 showed any significant causal effect on mortality or cardiovascular outcomes. Despite their well-established epidemiological associations with disease, these markers appear to be downstream indicators of inflammation rather than active drivers. As the authors note, this distinction is critical: CRP and GDF15 may be useful for predicting risk, but they are not themselves targets for intervention.

The Biological Mechanism: Classical vs. Trans-Signaling

The opposing effects of IL6 and IL6R are explained by the unique biology of the IL6 pathway. IL6 signals through two distinct routes. Classical signaling occurs when IL6 binds to membrane-bound IL6 receptors on certain cell types. Trans-signaling, however, occurs when IL6 binds to soluble IL6 receptors (sIL6R), allowing it to act on cells that lack membrane-bound receptors—including vascular and myocardial cells.

The genetic variants associated with higher sIL6R levels shift the balance away from trans-signaling, effectively dampening the inflammatory effects of IL6 in cardiovascular tissues. This reduces vascular inflammation, endothelial dysfunction, and thrombotic risk—mechanisms that directly contribute to atrial fibrillation, coronary artery disease, and stroke.

Clinical Implications: A Precision Target for Prevention

These findings have direct implications for drug development. IL6 receptor antagonists such as tocilizumab are already approved for inflammatory conditions like rheumatoid arthritis and giant cell arteritis, and have shown survival benefits in severe COVID-19. The genetic evidence presented here suggests that targeting IL6R could be an effective strategy for preventing cardiovascular disease and reducing mortality in high-risk populations.

Importantly, the neutral findings for CRP and GDF15 argue against broad anti-inflammatory approaches that target downstream markers. Instead, precision targeting of the IL6 signaling pathway—specifically through modulation of trans-signaling—appears to offer a more focused and potentially safer therapeutic avenue.

Limitations and Future Directions

The authors acknowledge several limitations. The analysis was restricted to individuals of European ancestry, which may limit generalizability to other populations. Additionally, while the study identified cardiovascular mechanisms as key mediators of IL6R’s mortality benefits, other potential pathways—such as metabolic or inflammatory diseases—remain to be explored.

Future research should focus on validating these findings in more diverse populations and conducting dedicated cardiovascular prevention trials with IL6R antagonists. The long-term safety of such interventions also warrants careful evaluation.

Future Perspectives and Conclusion

This study does not merely confirm that inflammation matters for longevity. It goes further, identifying a specific molecular axis—IL6 and its receptor—as a causal driver of human survival, with one component harming and the other protecting.

The perspective that emerges is one where the immune system’s inflammatory machinery can be precisely tuned. Rather than broadly suppressing inflammation—which could impair host defense—targeting IL6 trans-signaling offers a way to reduce cardiovascular risk while preserving essential immune functions.

As the authors conclude, “These results support IL6R antagonism as a potential strategy for cardiovascular disease prevention.” In an era where cardiovascular disease remains the leading cause of death globally, this genetic evidence provides a clear roadmap for translating inflammation biology into clinical practice.

Click here to read the full research paper published in Aging-US.

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Aging-US is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Mitochondrial Circular RNAs: New Players in Human Aging

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“During mammalian aging, there are changes in abundance of noncoding RNAs including microRNAs, long noncoding RNAs, and circular RNAs.”

The aging of an organism is reflected not only in the function of its organs but also in the molecular signatures written into its cells. For years, scientists have cataloged the changes in protein-coding genes and various non-coding RNAs that occur as we grow older. However, one class of molecules—circular RNAs originating from the genome of our cellular power plants, the mitochondria—has remained largely unexplored.

A new research paper, titled “Aging-associated mitochondrial circular RNAs” published in Volume 18 of Aging-US by a multi-institutional team of researchers, provides the first detailed profile of these molecules and reveals a surprising link to cellular energy metabolism. 

The team’s investigation demonstrates that a specific mitochondrial circular RNA, circMT-RNR2, is depleted in older individuals and plays a direct role in regulating the TCA cycle, the engine of cellular energy production.

The Discovery: A Mitochondrial Circular RNA Lost with Age

The researchers began by analyzing circular RNA junctions in peripheral blood mononuclear cells (PBMCs) from 11 young adults (average age 30) and 11 older adults (average age 64). Using RNA sequencing data, they identified hundreds of circular RNA species.

The most striking finding was the source of these molecules. In young individuals, the vast majority of circular RNA junctions originated from the mitochondrial chromosome (chrM). Specifically, the most abundant circular RNAs were derived from a mitochondrial ribosomal RNA gene called MT-RNR2. In older individuals, however, these same circular RNA junctions were sharply depleted—a loss of nearly 90%.

This age-associated decline was not just a statistical observation. When the team examined human fibroblasts (skin cells) as they aged in culture, they saw the same pattern: levels of circMT-RNR2 dropped progressively as the cells approached senescence, the point at which they permanently stop dividing.

The Regulator: An RNA-Binding Protein Called GRSF1

If circMT-RNR2 disappears with age, what controls its production? The team turned their attention to GRSF1, a protein known to localize to mitochondrial RNA granules—specialized compartments where mitochondrial RNAs are processed.

Using a split-GFP system, they confirmed that GRSF1 resides within mitochondria. They then performed a PAR-CLIP analysis, a technique that identifies precisely which RNAs a protein binds to. The results showed that GRSF1 binds directly to several mitochondrial transcripts, including both the linear and circular forms of MT-RNR2. A specific RNA motif—UGxxGGUU—was identified as the recognition sequence for GRSF1 on its target RNAs.

When the researchers depleted GRSF1 from human fibroblasts, circMT-RNR2 levels plummeted. This established GRSF1 as a critical factor for maintaining the abundance of this mitochondrial circular RNA.

The Function: Scaffolding the TCA Cycle

The discovery that a circular RNA is lost with age raised an obvious question: what does it actually do? Given that MT-RNR2 originates from the mitochondria, the team hypothesized it might be involved in mitochondrial metabolism.

They performed RNA immunoprecipitation assays to see if circMT-RNR2 interacts with metabolic enzymes. The results revealed that both linear and circular MT-RNR2 bind to two key enzymes of the TCA cycle: SUCLG1 (part of succinyl-CoA synthetase) and SDHA (a component of succinate dehydrogenase complex II).

This binding appears to have functional consequences. When the team depleted MT-RNR2 from cells, levels of the TCA cycle metabolites fumarate and alpha-ketoglutarate declined. Conversely, reintroducing circMT-RNR2 restored fumarate levels. The circular RNA seemed to be acting as a scaffold, helping to assemble or stabilize the enzyme complexes that drive the TCA cycle.

The Consequence: Suppressing Cellular Senescence

If circMT-RNR2 supports energy production, its loss should accelerate aging at the cellular level. To test this, the team measured markers of cellular senescence—p16 and p21—after manipulating GRSF1 and circMT-RNR2.

Depleting GRSF1, which reduced circMT-RNR2, caused a sharp increase in p16 and p21 mRNA levels. However, when they reintroduced circMT-RNR2 into these GRSF1-depleted cells, the senescence markers returned to normal. The circular RNA alone was sufficient to reverse the senescence phenotype.

Further analysis showed that GRSF1 depletion broadly suppressed mitochondrial transcripts, and reintroducing circMT-RNR2 partially rescued this defect. The model that emerges is one where GRSF1 promotes the production of circMT-RNR2, which then scaffolds TCA cycle enzymes to maintain efficient energy production and keep cells in a proliferating, non-senescent state.

Implications for Future Research

This study opens several new avenues for investigation. First, it establishes that mitochondria produce circular RNAs with distinct functions, expanding our understanding of mitochondrial biology. Second, it identifies GRSF1 as a key regulator of these molecules, linking RNA-binding proteins to mitochondrial metabolism.

The finding that a single circular RNA can influence the entire TCA cycle suggests that non-coding RNAs may play broader roles in metabolism than previously appreciated. The authors propose that circMT-RNR2 may act similarly to other scaffold non-coding RNAs, like NEAT1, which assemble metabolic enzymes to accelerate biochemical reactions.

The mechanism by which MT-RNR2 produces a circular RNA remains intriguing. Since the gene lacks introns, conventional back-splicing cannot explain its circularization. The authors speculate that trans-splicing—a process more common in plants and trypanosomes—may be at work, potentially mediated by GRSF1 within mitochondrial RNA granules.

Future Perspectives and Conclusion

This research does not claim to have fully mapped the landscape of mitochondrial circular RNAs or their functions. Rather, it offers a compelling proof-of-concept that these molecules exist, change with age, and have measurable biological effects.

By integrating transcriptomic profiling, biochemical analysis, and functional studies, the team demonstrates that circMT-RNR2 is depleted during human aging and senescence, that it is regulated by GRSF1, and that it supports the TCA cycle by scaffolding metabolic enzymes.

The perspective that emerges is one where the mitochondria are not just passive energy generators but active participants in the aging process through their non-coding RNA output. Continued research will be needed to determine whether other mitochondrial circular RNAs have similar functions, how precisely they are generated, and whether they might serve as therapeutic targets to preserve metabolic health in older age.

Click here to read the full research paper published in Aging-US.

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Aging-US is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

Click here to subscribe to Aging-US publication updates.

For media inquiries, please contact [email protected].

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