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Aging-US Supports the NOVA Conference 2026

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Aging-US proudly sponsored the NOVA (Neuroscience of Vitality and Aging) Conference, hosted by the Aging Initiative on Saturday, April 25 in Boston, MA.

Highlights from the NOVA (Neuroscience of Vitality and Aging) Conference

On April 25, 2026, the NOVA (Neuroscience of Vitality and Aging) Conference brought together a dynamic and interdisciplinary audience in Boston, MA. With over 600 attendees spanning students, researchers, clinicians, investors, and patient advocates, the event highlighted both the complexity of brain aging and the growing momentum behind efforts to better understand and treat neurodegenerative diseases.

In the opening keynote, Dr. Joanne Smikle of the American Brain Foundation emphasized the need to remember the “why” behind this research. She highlighted the power of intentional collaboration and the belief that breakthroughs in one neurological disease may translate to others. Even small monthly contributions as little as $10.00 can collectively drive meaningful progress.

Clinical Progress in Neurodegeneration

Dr. John Sims of Eli Lilly & Company, noted that traditional measures, such as clinical dementia ratings, may be too blunt to capture early cognitive decline. Emerging approaches, such as learning-based assessments and digital cognitive tools, aim to detect subtle changes sooner and more accurately.

Studying the Biology of Brain Aging with New Tools

This breakout session showcased cutting-edge tools transforming how scientists study the aging brain.  Researchers included Dr. Stuart Lipton from Scripps Research, Dr. Eric Sun from MIT, Dr. Jiang He from Vizgen, Dr. Ed Boyden from the McGovern Institute at MIT, and Dr. David Salat from Harvard Medical School. Overall, the researchers are focused on causal models, the importance of needing more high-quality data, and spatial mapping technologies to better understand cellular interactions and disease mechanisms. Additionally, continued advances in molecular imaging, organoid development, and neuroimaging enable more detailed insights into how the brain changes over time. The speakers did stress the importance of rigor (particularly in validating experimental models and ensuring data quality) to draw any meaningful conclusions.

Mainstage Presentations

These presentations highlighted both the promise and challenges of advancing longevity science. Raiany Romanni-Klein of Amaranth emphasized a critical paradox: while human lifespan continues to increase, many individuals spend more years in declining health. From an investment perspective, Michael Reisman of Centerview Partners and Second Century Foundation noted that longevity science is increasingly attracting attention from the financial sector. While past biotech ventures in aging have seen mixed outcomes, the field continues to evolve, with increasing focus on translating biological insights into real-world interventions.

Neurotechnology and Brain-Computer Interfaces

One of the most forward-looking discussions centered on neurotechnology and brain-computer interfaces (BCIs), panelists included Christian Howell of Cognito Therapeutics, Dr. Oliver Armitage from Axoft, Dr. Daniel Rizzuto of Nia Therapeutics, Dr. Alan Mardinly from Science Corp., and Dr. Leigh Hochberg from BrainGate and Massachusetts General Hospital.

The speakers described emerging approaches that use sensory stimulation or implantable devices to preserve or restore brain function. Innovations in this space are already demonstrating tangible benefits. Early studies suggest that closed-loop neurostimulation systems may significantly improve memory performance, while implantable BCIs are enabling patients with severe impairments to communicate and interact with their environment. Despite these advances, challenges remain, including regulatory pathways, reimbursement models, the need for scalable and  patient-centered deployment, and collaboration in terms of sharing ideas between industries and regulators, in technology, and throughout our community.

Still, the outlook is promising. As Dr. Hochberg noted, the field is moving quickly, envisioning a future where, in just ten years, patients with conditions such as ALS may retain the ability to communicate through advanced neurotechnologies.

Investment Landscape

The conference also explored the evolving investment landscape in aging and longevity science. Speakers of this panel included Dr. Alex Colville of age1, Dr. Daniel Carbonero from PsyMed Ventures, Dr. Jarod Rutledge from Starbloom Capital, and Karen Harris from the Alzheimer’s Drug Discovery Foundation.

Although previous biotech efforts have yielded mixed results, confidence is growing that targeting the biology of aging is both scientifically feasible and financially promising. Investors emphasized the importance of strong founding teams and highlighted areas of interest such as neuroinflammation, genetic medicine, and biomarker development. Blood-based biomarkers, in particular, were identified as critical tools for improving clinical trial design and patient stratification.

Repair and Regeneration

Panelists of this important discussion included Dr. Mark Tomishima of BlueRock Therapeutics, Dr. Jean Hebert from ARPA-H, Dr. Nabiha Saklayen of Cellino, Dr. Parastoo Khoshakhlagh of GC Therapeutics, and Dr. Abdulkader Rahmo from SMS Biotech, Inc.

Speakers on repair and regeneration highlighted the potential of cell and tissue-based therapies to address age-related decline. Advances in automation, scalability, and precision are making neuroreplacement strategies more feasible, though cost and access remain significant challenges, and prevention remains key.

Equally important was the focus on patient advocacy. Speakers stressed the need to incorporate patient and caregiver perspectives into research and clinical trials, ensuring that scientific progress aligns with real-world needs and experiences.

Patient Advocacy

A powerful breakout session on patient advocacy emphasized the importance of integrating lived experiences into research and clinical development.

Kevin Rhodes of the Association for Frontotemporal Degeneration (AFTD), who is living with frontotemporal dementia, highlighted the session as he underscored the challenges of diagnosis and access. With advanced imaging often required for confirmation, many patients face barriers to timely diagnosis. He emphasized the need for stronger connections between patients and biotechnology companies, enabling researchers to better understand patient needs while helping individuals identify and access clinical trials.

The perspectives discussed overall highlighted a critical shift in the field: advancing brain aging research will require not only scientific innovation, but also meaningful engagement with the individuals most directly affected.

Looking Ahead

The conference concluded with a keynote by Dr. Dennis Selkoe from the Ann Romney Center for Neurologic Diseases, discussing the biology of Alzheimer’s disease and ongoing efforts to target amyloid-related mechanisms through immunotherapy. With millions affected worldwide, the urgency of advancing effective treatments remains clear.

Next year’s event will be the Cardiovascular Aging Research & Development (CARD) Symposium on May 6, 2027, with Opening Keynote Speaker Dr. John Maraganore of Alnylam.

Overall, the NOVA Conference highlighted a field that is rapidly evolving and is driven by technological innovation, interdisciplinary collaboration, and a shared commitment to improving outcomes for aging populations. As research continues to advance, the integration of science, investment, and patient engagement will be essential to translating discoveries into meaningful impact.

Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang
Photo Credit: Tony Zhang

Our Continued Commitment to Advancing Aging Research

Founded in 2008 by visionary scientists—the late Dr. Mikhail (Misha) Blagosklonny, the late Dr. Judith Campisi, and Dr. David Sinclair, Aging-US was created as a journal by scientists, for scientists, to publish innovative ideas and studies in the rapidly developing field of aging research. Since then, it has remained dedicated to advancing the understanding of aging and age-related diseases.

Supporting initiatives such as the NOVA Conference reflects our belief that progress in aging science depends on collaboration, mentorship, and the open exchange of ideas between academia, industry, and young innovators. By investing in the next generation of researchers, we aim to accelerate discoveries that will lead to longer, healthier lives for all.

Sponsoring this initiative is more than an investment, it’s a commitment to the future of aging science and to the vision of a world where longevity and well-being advance hand in hand.

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

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

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

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

A Closer Look at Aging, Senescence, and Lung Disease

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

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

Linking Senescence to Fibrosis

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

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

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

A Distinct Role for p38 MAPK Signaling

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

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

Blocking Fibrosis at the Molecular Level

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

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

Epigenetics: The Missing Link

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

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

Why This Matters

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

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

Looking Ahead

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

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

Conclusion

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

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

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

Click here to subscribe to Aging-US publication updates.

For media inquiries, please contact [email protected].

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

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

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

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

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

A New Concept in Aging Biology

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

An Evolutionary Perspective on Lifespan

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

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

Linking Metabolism to Aging Phenotypes

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

Explaining Differences in Lifespan Across Species

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

Implications for Aging and Disease

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

Future Directions

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

Conclusion

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

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

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

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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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).

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Acknowledgment of 2025 Reviewers

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Aging-US sincerely thanks all reviewers who contributed their expertise and time during 2025.

Rigorous and constructive peer review is essential to scientific progress. Through their careful evaluations, our reviewers played a central role in maintaining the scientific quality, integrity, and credibility of the journal.

Their efforts also directly support one of the core missions of Aging-US, which is to increase the visibility and impact of high-quality research in the biology of aging and age-related disease.

We are deeply grateful for this commitment to excellence and to the aging research community, and we look forward to continued collaboration in the coming year.

–Marco Demaria
Editor-in-Chief, 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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How Aging Leads to Chronic Disease: A Two-Stage Model

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“Aging (senescence) is characterized by development of diverse senescent pathologies and diseases, leading eventually to death.”

Aging has long been explained in different ways. One traditional view is that it results from the gradual accumulation of molecular damage over time. Another perspective, based on evolutionary theory, suggests that natural selection strongly protects health during youth and reproductive years but becomes less effective later in life. As a result, biological effects that appear in older age may persist because they have little impact on reproduction. 

Over the past two decades, researchers have also explored the idea that biological programs beneficial early in life may continue operating later in ways that become harmful. Processes that once supported growth, repair, and reproduction may, with time, contribute to chronic disease.

A recent review article, titled “Aging as a multifactorial disorder with two stages,” published in Aging-US by researchers at University College London and Queen Mary University of London, brings these different perspectives together into a unified model, to propose a broader explanation of how aging-related diseases develop. The review appears in a special issue honoring the late scientist Misha Blagosklonny, whose theoretical work on programmatic aging significantly influenced the field. 

The Two-Stage Model

The review by David Gems, Alexander Carver from University College London, and Yuan Zhao from Queen Mary University of London, brings together evidence from evolutionary biology, laboratory research, and human disease. It argues that most diseases associated with aging are multifactorial, meaning they arise from multiple interacting causes rather than a single trigger. The authors describe aging as a process that often develops in two main stages.

The first occurs earlier in life and involves disruptions in normal biological functions. It can include infections, physical injuries, environmental exposures, or DNA mutations. In many cases, the body repairs the damage or contains it effectively. However, not all disruptions are fully eliminated. Some remain in tissues in a controlled or dormant state without causing immediate symptoms.

The second stage takes place later in life, when normal age-related biological changes alter the body’s internal environment. Immune function tends to decline, inflammatory activity may increase, and tissue repair processes shift. Cells may enter a state known as senescence, in which they stop dividing but release signaling molecules that influence surrounding tissues. According to the review, these later-life changes can weaken the body’s ability to contain earlier disruptions. As a result, previously silent injuries or latent conditions may begin to develop into clinically recognizable disease.

In this model, aging is not explained only by accumulated damage or exclusively by genetic programming. Instead, disease emerges from the interaction between earlier disruptions and later biological changes.

Evidence from Laboratory and Human Studies

Part of the conceptual foundation for this model comes from studies in the roundworm Caenorhabditis elegans. In this organism, early mechanical damage to tissue can later contribute to fatal infections in old age, illustrating how early disruption and later biological change may interact. The authors suggest that similar patterns may occur in humans.

Several human conditions also fit this model. In shingles, the virus responsible for chickenpox remains dormant in nerve cells after childhood infection and may reactivate decades later as immune control weakens. Tuberculosis provides another example, as latent infections can become active in older age when immune defenses decline.

Osteoarthritis is more common in individuals who experienced joint injury earlier in life. Although the joint may initially recover, age-related changes in cartilage and surrounding tissues may allow earlier structural damage to progress. Traumatic brain injury in youth has also been associated with increased risk of dementia later in life, suggesting that early injury may interact with aging processes.

Cancer risk rises sharply with age as well. While genetic mutations accumulate over time, changes in the aging tissue environment, including altered inflammatory signaling and the presence of senescent cells, may increase the likelihood that mutated cells progress into tumors.

Across these examples, the recurring theme is the interaction between earlier contained disruption and later biological vulnerability.

Implications for Prevention and Intervention

The authors outline two broad approaches to reduce age-related disease. One approach focuses on preventing or minimizing early disruptions, for example through vaccination, injury prevention, and reduction of harmful environmental exposures. The other aims to modify later-life biological processes that contribute to loss of containment, including pathways involved in inflammation or excessive cellular activity.

At present, the most reliable and widely implemented measures in humans focus on preventing early disruptions. Interventions that directly target fundamental aging processes remain under investigation and require further research to establish their safety and effectiveness.

Future Perspectives and Conclusion

The two-stage model does not claim to provide a complete explanation of aging. Rather, it offers a structured model for understanding how multiple causes may combine over time to produce late-life disease. By integrating evolutionary theory, laboratory findings, and clinical observations, the review clarifies how early-life events and later biological changes may interact.

This perspective suggests that aging is neither purely passive decline nor solely genetically programmed deterioration. Instead, it may reflect a lifelong interaction between accumulated disruptions and evolving biological conditions. Continued research will be needed to determine how broadly this model applies and how it might guide future efforts to reduce the burden of chronic disease in older adults.

Click here to read the full review 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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