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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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EDITORS’ CHOICE: Epigenetic Aging Biomarkers Respond to Exercise and Dietary Intervention

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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.

This exploratory randomized controlled trial, titled “Short-term responsiveness of DNA methylation–based aging biomarkers to a multimodal intervention comprising exercise and dietary guidance involving daily consumption of yogurt containing Bifidobacterium longum BB536: an exploratory randomized controlled trial,” investigated whether a 12-week lifestyle intervention combining exercise, dietary guidance, and daily consumption of yogurt containing Bifidobacterium longum BB536 could influence biological aging.

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.

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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.

For media inquiries, please contact [email protected].

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EDITORS’ CHOICE: Association of epigenetic age acceleration with MRI biomarkers of aging and Alzheimer’s disease neurodegeneration

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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.

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To learn more about the journal, please visit www.Aging-US.com​​ and connect with us on social media:

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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).

Click here to subscribe to Aging-US publication updates.

For media inquiries, please contact [email protected].

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EDITORS’ CHOICE: Plant-based dietary patterns are associated with slower epigenetic aging

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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 this study, titled “Plant-based dietary patterns are associated with slower epigenetic aging,” the researchers examined whether plant-based dietary patterns are linked to biological aging in large, diverse U.S. populations. Using data from the Atherosclerosis Risk in Communities (ARIC) Study and National Health and Nutrition Examination Survey (NHANES), they analyzed several versions of plant-based diet scores that reflect higher intake of plant foods and lower intake of animal products, as well as distinctions between healthy and less healthy plant-based foods. They then compared these dietary patterns with DNA methylation-based “epigenetic clocks,” which estimate biological age, including GrimAge2, PhenoAge, and HannumAge.

The results showed that greater adherence to overall plant-based diets, provegetarian diets, and especially healthy plant-based diets was consistently associated with slower epigenetic aging, meaning participants appeared biologically younger than their chronological age. In contrast, diets higher in less healthy plant-based foods did not show the same benefits.

The findings suggest that diets emphasizing whole plant foods and limiting animal products may help slow biological aging at the molecular level.

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

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To learn more about the journal, please visit www.Aging-US.com​​ and connect with us on social media:

Click here to subscribe to Aging-US publication updates.

For media inquiries, please contact [email protected].

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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).

Click here to subscribe to Aging-US publication updates.

For media inquiries, please contact [email protected].

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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).

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EDITORS’ CHOICE: Single-cell transcriptomics reveal intrinsic and systemic T cell aging in COVID-19 and HIV

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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.

Biomarkers of aging help researchers understand how diseases influence the body over time. However, most current biomarkers rely on measurements from mixed cell populations, making it difficult to distinguish between changes caused by shifts in cell types and aging processes occurring within individual cells.

In this study, titled “Single-cell transcriptomics reveal intrinsic and systemic T cell aging in COVID-19 and HIV” and published in Volume 18 of Aging-US, researchers used single-cell RNA sequencing to analyze aging-related changes in human T cells. They developed Tictock, a single-cell transcriptomic clock that predicts both cellular age and T cell type across six human T cell subsets.

Applying this tool, the researchers found that acute COVID-19 was associated with increased proportions of CD8⁺ cytotoxic T cells, while T cell composition remained relatively stable in individuals with HIV receiving antiretroviral therapy (HIV+ART). Despite these differences, both conditions showed signs of accelerated transcriptomic aging, particularly in naïve CD8⁺ T cells.

Further analysis identified shared aging-related genes and biological pathways linked to ribosomal components and TNF receptor binding. These findings demonstrate how single-cell transcriptomic biomarkers can help separate systemic immune changes from cell-intrinsic aging processes, providing new tools to measure immune aging in disease.

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

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Tictock: A Single-Cell Clock Measures Immune Aging in Viral Infections

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“Biomarkers of aging offer insights into how diseases and interventions affect biological systems. However, most current biomarkers are based on bulk cell measurements, making it difficult to distinguish between changes driven by shifts in cell type composition (systemic effects) versus intrinsic changes within individual cells.”

Aging reshapes the immune system in two fundamental ways: it alters the proportions of different immune cell types circulating in the blood, and it induces molecular changes within each individual cell. For years, researchers have struggled to disentangle these two intertwined processes using standard “bulk” measurements, which average signals across millions of cells and obscure what is happening at the single-cell level.

A new research paper, titled “Single-cell transcriptomics reveal intrinsic and systemic T cell aging in COVID-19 and HIV” published in Volume 18 of Aging-US by researchers at the Buck Institute for Research on Aging in California, the University of Southern California, and the University of Copenhagen, introduces an innovative solution. 

The team of Alan Tomusiak, Sierra Lore, Morten Scheibye-Knudsen, and corresponding author Eric Verdin, developed a novel tool called Tictock (T immune cell transcriptomic clock) that uses single-cell RNA sequencing to separately measure systemic and cell-intrinsic components of immune aging, and then applied it to understand how COVID-19 and HIV affect T cells.

The Tictock Model

The challenge the researchers addressed is akin to a chicken-and-egg problem. When we see a change in the average gene expression of a T cell population with age, is it because the cells themselves are aging, or because the composition of the population has shifted to contain more aged cell types?

To solve this, the researchers built Tictock, a two-part model using a massive dataset of two million peripheral blood mononuclear cells from 166 individuals. The first component is an automated cell type predictor that classifies T cells into six canonical subsets with 97% accuracy. It identifies naïve CD8+ T cells, central memory CD8+ cells, effector memory CD8+ cells, naïve CD4+ cells, central memory CD4+ cells, and regulatory T cells based on the expression of key marker genes like CD4, CD8A, CCR7, and FOXP3.

The second component consists of six distinct age-prediction models—one trained specifically for each T cell subset. By applying the cell type predictor first, the researchers can isolate a pure population of, say, naïve CD8+ T cells, and then apply the age model for that specific cell type to calculate its “transcriptomic age.” This dual-layer design allows Tictock to separate the signal of aging cell populations from the signal of aging within a cell.

Evidence from Laboratory and Human Studies

The researchers first validated their model by confirming known trends in immune aging. They observed a significant increase in the CD4/CD8 ratio with age, a well-established phenomenon. More specifically, they found a sharp decline in the proportion of naïve CD8+ cytotoxic T cells as people grow older, which aligns with decades of immunological research.

Having validated the tool, the authors then applied Tictock to two disease contexts: acute COVID-19 and HIV infection managed with antiretroviral therapy (HIV+ART). The results revealed distinct patterns. In acute COVID-19, the model detected a significant change in cell type composition—a systemic shift toward increased proportions of CD8+ cytotoxic T cells, likely reflecting the body’s acute immune response to the virus.

However, both diseases shared a striking commonality at the cell-intrinsic level. In people with acute COVID-19 and in those with HIV+ART, Tictock detected a significant increase in the transcriptomic age of naïve CD8+ T cells. In other words, these naïve cells appeared biologically older than expected for the individual’s chronological age. This accelerated aging signature was specific; it was not observed in other T cell subsets like CD4+ helper cells.

Insights into Mechanisms

To understand what was driving these age predictions, the team analyzed the 209 genes that were consistently included across the six different cell-type age models. Gene Ontology enrichment analysis revealed that these shared genes were heavily involved in fundamental cellular processes, including components of the cytosolic small and large ribosomal subunits and pathways related to TNF receptor binding.

This points to a central role for protein synthesis machinery and inflammatory signaling in T cell aging. The authors also discovered a correlation between aging and mean transcript length within cells, suggesting that changes in RNA processing or stability may be a general feature of the aging process at the single-cell level. Across these examples, the recurring theme is the power of single-cell resolution to reveal distinct layers of aging—systemic shifts in cell populations versus intrinsic molecular aging within specific cell types.

Implications for Future Research

The development of Tictock opens several avenues for future investigation. One immediate application is as a tool to measure how different interventions, such as drugs or lifestyle changes, affect immune aging. Because the model can distinguish between effects on cell composition and effects on cell-intrinsic age, it could provide a more nuanced readout of whether a therapy is truly rejuvenating immune cells or simply altering their proportions.

The finding that both a chronic viral infection (HIV) and an acute viral infection (COVID-19) accelerate aging in naïve CD8+ T cells raises important questions about the long-term consequences of severe infections. It suggests that the immune system may carry a “memory” of these encounters in the form of prematurely aged T cells, which could impact future immune responses.

Future Perspectives and Conclusion

Tictock does not claim to be a universal clock for all tissues or all immune cells. Rather, it offers a proof-of-concept for a powerful approach: using single-cell transcriptomics to build interpretable biomarkers that can disentangle the multiple layers of a complex process like aging. By integrating automated cell typing with cell-type-specific age predictors, the model clarifies how systemic and intrinsic factors combine to shape the aging immune system.

This perspective suggests that immune aging is not a single process but a composite of changes at different levels of biological organization. Continued research will be needed to determine how broadly this model applies to other cell types and other diseases, and how it might guide future efforts to monitor and modulate immune health in older adults and in people living with chronic viral infections.

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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