Each month, we will highlight a paper published in Aging chosen as the “Editors’ Choice.” These selections are handpicked by our editors and accompanied by a brief summary, showcasing research with significant impact and novel insights in aging and age-related diseases.
A research paper recently published in Volume 18 of Aging, titled “Slowing intervertebral disc aging in mice through long-term systemic treatment with the senolytic BCL-2/BCL-xL proteolysis targeting chimera (PROTAC) 753b,” examines whether the senolytic PROTAC 753b can slow age-related intervertebral disc degeneration (IDD) in mice. Long-term systemic treatment with 753b reduced key features of disc degeneration in 22-month-old male mice, including matrix breakdown, loss of disc aggrecan, age-related structural changes, and inflammatory markers such as IL-6 and TNFα. These benefits, however, were not observed in female mice, highlighting potential sex-based differences in the role of cellular senescence in IDD and the response to senolytic therapies.
Click here to read the full research paper published in Volume 18 of Aging.
______
To learn more about the journal, please visit www.Aging-US.com and connect with us on social media:
“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.
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.
___
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.
“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.
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.
___
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.
Each month, we will highlight a paper published in Aging chosen as the “Editors’ Choice.” These selections are handpicked by our editors and accompanied by a brief summary, showcasing research with significant impact and novel insights in aging and age-related diseases.
Cellular senescence is a hallmark of aging and age-related disease, yet the diverse mechanisms that trigger this cellular state remain incompletely understood. The review recently published in Volume 18 of Aging, titled “The multifaceted inducers of cellular senescence,” examines the many intrinsic and extrinsic stimuli that induce senescence, including DNA damage, oxidative and mitochondrial stress, telomere attrition, oncogene activation, cell–cell fusion, and developmental signals. The authors, Hilah Gal and Valery Krizhanovsky, explain how these distinct pathways converge on a stable cell-cycle arrest. By highlighting the complexity and heterogeneity of senescent cells, the authors provide valuable insights that may guide the development of future therapies targeting senescence to promote healthy aging and combat age-related diseases.
Click here to read the full review published in Volume 18 of Aging.
______
To learn more about the journal, please visit www.Aging-US.com and connect with us on social media:
“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.
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.
___
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.
“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.
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.
___
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.
Each month, we will highlight a paper published in Aging chosen as the “Editors’ Choice.” These selections are handpicked by our editors and accompanied by a brief summary, showcasing research with significant impact and novel insights in aging and age-related diseases.
The researchers found a significant slowing of the DNA methylation-based pace of aging measure DunedinPACE in overweight men aged 50 and older, suggesting that feasible lifestyle changes may be associated with short-term improvements in selected epigenetic aging biomarkers.
Click here to read the full research paper published in Volume 18 of Aging.
______
To learn more about the journal, please visit www.Aging-US.com and connect with us on social media:
“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.
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.
___
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.
Each month, we will highlight a paper published in Aging-US chosen as the “Editors’ Choice.” These selections are handpicked by our editors and accompanied by a brief summary, showcasing research with significant impact and novel insights in aging and age-related diseases.
In the research paper, titled “Association of epigenetic age acceleration with MRI biomarkers of aging and Alzheimer’s disease neurodegeneration,” researchers investigated whether epigenetic clocks of biological aging are associated with MRI markers of brain aging and Alzheimer’s disease-related neurodegeneration in 1,196 older women. While none of the five epigenetic clocks examined were linked to accelerated overall brain aging, one measure—AgeAccelGrim2—was associated with MRI patterns related to neurodegeneration.
The findings suggest this relationship was largely driven by DNA methylation markers linked to smoking history and changes in frontal and temporal brain regions rather than areas typically affected early in Alzheimer’s disease.
Overall, the study indicates that epigenetic aging and brain aging may reflect different aspects of the aging process, while highlighting the potential role of smoking-related biological aging in increasing dementia risk.
Click here to read the full research paper published in Aging-US.
______
To learn more about the journal, please visit www.Aging-US.com and connect with us on social media:
“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.
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.
___
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.