Aging-US

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.

Full blog - https://aging-us.org/2026/04/p38-mapk-driven-epigenetic-regulation-identified-as-a-key-mechanism-in-lung-fibrosis/

Paper DOI - https://doi.org/10.18632/aging.206357

Corresponding author - Yan Y Sanders - [email protected]

Abstract video - https://www.youtube.com/watch?v=yP0CwWMUhnY

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Keywords - aging, senescence, fibroblast activation, p38 MAPK, lung fibrosis, H4K16Ac

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BUFFALO, NY — April 27, 2026 — A new #hypothesis paper was #published in Volume 18 of Aging-US on April 8, 2026, titled “From Hydra to rotifer and beyond: implications for human aging and delayed senescence.”

The study was led by first and corresponding author Michael Bordonaro from the Geisinger College of Health Sciences. In this work, the author explores a bold and testable hypothesis centered on two very different invertebrate models of aging: the freshwater cnidarian Hydra and the rotifer Brachionus manjavacas. Hydra are well known for their remarkable ability to maintain tissue integrity over time through continuous stem cell renewal, effectively avoiding many of the hallmarks of aging under laboratory conditions. In contrast, rotifers represent the opposite end of the biological spectrum, with short lifespans, fixed somatic cell numbers, and a predictable pattern of age-related decline.

Building on these contrasts, the paper proposes that introducing Hydra-like gene expression patterns into rotifers could delay senescence and extend healthspan. The hypothesis focuses in particular on conserved molecular pathways, including the transcription factor FoxO, which plays a central role in maintaining stem cell function and cellular resilience. Rather than attempting to recreate full stem cell renewal in rotifers—an organism with a fixed adult cell number—the proposed strategy emphasizes improving cellular maintenance, stress resistance, and proteostasis within existing cells.

The paper outlines an iterative experimental framework, beginning with targeted genetic manipulation in rotifers and extending to more complex organisms such as Daphnia and mouse models. This stepwise approach is designed to identify which elements of the Hydra genetic program are truly responsible for its resistance to aging, while also allowing researchers to monitor potential trade-offs, including increased risk of uncontrolled cell growth.

“We hypothesize that delayed senescence at the organismal level is possible through recapitulation of Hydra-like patterns of gene expression in rotifers, and that data obtained may help generate hypotheses for somatic interventions and prioritize pathways for mammalian validation in future studies.”

Importantly, the author emphasizes that complete elimination of aging is unlikely in complex organisms due to evolutionary and biological constraints. Instead, the goal is more realistic: extending healthspan and delaying the onset of age-related decline. The paper also highlights the importance of balancing potential benefits with risks, particularly the possibility that enhancing cellular renewal pathways could increase susceptibility to neoplasia.

Overall, this study presents a conceptual and experimental roadmap for translating insights from simple organisms into strategies that may eventually inform human aging research. By bridging the gap between negligible senescence and rapid aging models, the work provides a fresh perspective on how conserved biological mechanisms might be harnessed to improve health across the lifespan.

DOI - https://doi.org/10.18632/aging.206370

Corresponding author - Michael Bordonaro - [email protected]

Abstract video - https://www.youtube.com/watch?v=YGzYf3W5jNA

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BUFFALO, NY — April 23, 2026 — A new #research paper was #published in Volume 18 of Aging-US on April 7, 2026, titled “Association of epigenetic age acceleration with MRI biomarkers of aging and Alzheimer’s disease neurodegeneration.”

The study was led by first and corresponding author Linda K. McEvoy from the Kaiser Permanente Washington Health Research Institute, in collaboration with a multidisciplinary team of researchers across leading institutions in the United States and Europe.

In this study, the researchers examined whether epigenetic measures of biological aging are associated with structural brain changes linked to aging and Alzheimer’s disease. Using data from 1,196 older women enrolled in the Women’s Health Initiative Memory Study, they analyzed five widely used epigenetic clocks and compared them with MRI-derived measures obtained approximately eight years later.

The findings revealed a clear distinction between different aspects of aging. None of the epigenetic clocks were associated with accelerated brain aging as measured by the SPARE-BA index, a composite MRI marker of brain age. However, one specific clock—AgeAccelGrim2—was significantly associated with the Alzheimer’s Disease Pattern Similarity Score (AD-PS), a validated imaging biomarker linked to increased risk of dementia.

Further analyses suggested that this association was largely driven by epigenetic signatures related to smoking exposure. In particular, a DNA methylation marker reflecting cumulative smoking history was linked to reduced frontal and temporal lobe volumes—regions commonly affected in age-related neurodegeneration. Notably, no significant associations were observed with hippocampal or entorhinal cortex volumes, areas more directly implicated in early Alzheimer’s pathology.

“Taken together with prior findings, these results suggest that measures of epigenetic and brain age acceleration capture different aspects of biological aging, and that AgeAccelGrim2 is predictive of neurodegenerative changes associated with smoking that increase risk of dementia.”

The study highlights the complexity of biological aging and underscores that not all aging biomarkers reflect the same underlying processes. While epigenetic clocks are increasingly used to estimate biological age, their relationship with brain structure appears to depend on the specific pathways they capture—particularly those influenced by environmental exposures such as smoking.

Overall, these findings provide important insight into how molecular measures of aging relate to neuroimaging markers of brain health. By distinguishing between general brain aging and disease-related neurodegeneration, this work helps refine the use of epigenetic biomarkers in aging research and may support future efforts to identify individuals at risk for cognitive decline.

DOI - https://doi.org/10.18632/aging.206369

Corresponding author - Linda K. McEvoy - [email protected]

Abstract video - https://www.youtube.com/watch?v=kZiRjlKnnsI

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Keywords - aging, epigenetic clocks, brain age, biological aging, smoking, frontal lobe

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BUFFALO, NY — April 21, 2026 — A new meeting report was published in Volume 18 of Aging-US on April 6, 2026, titled “Toward actionable interventions in human aging (12th ARDD meeting, 2025).”

The report was led by corresponding authors Aleksandr Dekan and Daniela Bakula from the University of Copenhagen, Denmark, in collaboration with an international group of researchers spanning academia, industry, and biotechnology.

Bringing together experts from across the global aging research community, the 12th ARDD meeting focused on one central goal: moving beyond descriptive studies of aging toward interventions that can actively improve human healthspan. The discussions reflected a clear shift in the field—from understanding the hallmarks of aging to identifying the molecular mechanisms that can be targeted to modify them.

Key presentations explored whether biological age can be reversed, highlighting the epigenome as a central regulator of cellular identity. Emerging evidence suggests that partial cellular reprogramming may restore youthful function, while systemic effects observed in preclinical models point to the possibility of organ-wide or even whole-body rejuvenation.

The meeting also emphasized the importance of maintaining genomic integrity, with accumulating DNA damage linked to widespread transcriptional stress and age-associated functional decline. At the same time, chronic inflammation, metabolic dysfunction, and cellular senescence were consistently identified as major drivers of aging, reinforcing the need for integrated, multi-targeted therapeutic strategies.

Advances in biomarker development were another major focus. Researchers presented new generations of biological aging clocks—ranging from organ-specific proteomic signatures to single-cell and imaging-based approaches—capable of predicting disease risk and monitoring intervention outcomes with increasing precision.

In parallel, the integration of artificial intelligence into drug discovery is accelerating the development of novel therapeutics. From generative AI-designed proteins to platform-based identification of new drug targets, these approaches are helping bridge the gap between basic research and clinical application.

“This focus is predicated on the hypothesis that aging is not solely a result of stochastic damage accumulation but may be a tractable, modifiable, and potentially reversible biological process amenable to intervention.”

Beyond laboratory science, the meeting highlighted the growing importance of translational strategies, regulatory pathways, and investment models in bringing anti-aging therapies to market. A consensus emerged around a “disease-first” approach, in which targeting specific age-related conditions may provide a practical pathway for validating interventions that also influence underlying aging biology.

Overall, the ARDD 2025 meeting underscored a major turning point in the field. Aging research is no longer confined to observation—it is increasingly positioned to deliver actionable interventions that could reshape how age-related diseases are prevented and treated.

DOI - https://doi.org/10.18632/aging.206368

Corresponding authors - Aleksandr Dekan - [email protected], and Daniela Bakula - [email protected]

Video abstract - https://www.youtube.com/watch?v=LntAWVQMKqE

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BUFFALO, NY — April 17, 2026 — A new #research paper was #published in Volume 18 of Aging-US on April 3, 2026, titled “Modeling premature aging in yeast via the expression of Progerin.”

The study was led by first author Zachery R. Belak from the University of Saskatchewan, and corresponding author Troy A.A. Harkness from the University of Saskatchewan and the University of Alberta. The team developed a yeast-based model to study premature aging by expressing Progerin, the toxic protein responsible for Hutchinson–Gilford Progeria Syndrome. Using genetically engineered yeast cells, they compared the effects of Progerin with its normal counterpart, Lamin A, to better understand how protein accumulation impacts cellular aging.

Their findings show that Progerin expression leads to slower cell growth, increased genome instability, and a significant reduction in chronological lifespan. In contrast, Lamin A did not produce the same harmful effects, highlighting the specific role of Progerin in driving premature aging phenotypes.

The study also demonstrates that Progerin accumulates in aging mother cells and remains more stable than Lamin A, suggesting a mechanism by which damaged or toxic proteins are retained during the aging process. These observations mirror what has been reported in human cells, reinforcing the relevance of this model system.

“Taken together, expression of Progerin in yeast cells mimics what is observed in human cells, establishing yeast as a powerful model to discover genetic mechanisms driving premature and normal aging.”

Overall, the researchers present a practical and efficient model for studying the biological mechanisms underlying premature aging. Their work provides a valuable platform for testing new strategies aimed at reducing toxic protein accumulation and improving cellular health during aging.

DOI - https://doi.org/10.18632/aging.206367

Corresponding author - Troy AA. Harkness - [email protected]

Abstract video - https://www.youtube.com/watch?v=VYQKAJjgIb8

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Keywords - aging, Hutchinson-Gilford Progeria Syndrome, yeast, Progerin, Lamin A, premature aging

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BUFFALO, NY — April 15, 2026 — A new #research paper was #published in Volume 18 of Aging-US on March 30, 2026, titled “A manually curated gene–phenotype catalogue for progeroid syndromes and premature aging.”

The study was led by Nuša Likar and Tanja Kunej from the University of Ljubljana, Slovenia. The researchers developed a comprehensive, manually curated catalogue integrating data from 84 scientific publications and the OMIM database. The resulting resource systematically organizes genetic and clinical information on progeroid syndromes, linking 144 genes to 56 syndromes and 160 distinct clinical entities, making it one of the most extensive datasets in this field to date.

Using genome–phenome association analysis and protein–protein interaction networks, the study reveals the complex genetic and phenotypic heterogeneity underlying premature aging disorders. The findings highlight strong enrichment in genome maintenance and DNA repair pathways, reinforcing their central role in aging biology.

The catalogue also demonstrates how single genes, such as LMNA, can be associated with multiple syndromes, illustrating the pleiotropic nature of genetic variants in progeroid conditions and their broader relevance to human aging mechanisms.

“Overall, this study provides a reference resource and framework to support future research into premature aging syndromes and their broader implications for understanding physiological aging.”

Overall, the authors present a valuable framework for improving the classification, diagnosis, and study of rare premature aging disorders. Their work not only advances understanding of progeroid syndromes but also offers important insights into the biological processes that drive normal human aging.

DOI - https://doi.org/10.18632/aging.206366

Corresponding author - Tanja Kunej - [email protected]

Abstract video - https://www.youtube.com/watch?v=Ov6Saz34ZpE

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Keywords - aging, premature aging, progeroid syndromes, DNA repair, LMNA gene

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In this episode of the Longevity & Aging Series (S4, E3), Dr. Ricardo Costeira of King’s College London joins host Dr. Yuan Zhao of Queen Mary University of London to discuss a research paper he co-authored in Volume 17, Issue 12 of Aging-US, titled “Theobromine is associated with slower epigenetic ageing.”

DOI - https://doi.org/10.18632/aging.206344

Corresponding authors - Ramy Saad - [email protected], and Jordana T. Bell - [email protected]

Video interview - https://www.youtube.com/watch?v=in0z_QApqWQ

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Abstract video - https://www.youtube.com/watch?v=S0P1USM8L6E

Abstract

Theobromine, a commonly consumed dietary alkaloid derived from cocoa, has been linked to extended lifespan in model organisms and to health benefits in humans. We examined associations between circulating levels of theobromine intake, measured using serum metabolomics, and blood-based epigenetic markers of biological ageing in two European human population-based cohorts. Serum theobromine levels were significantly associated with reduced epigenetic age acceleration, as measured by GrimAge (p < 2e-7) and DNAmTL (p < 0.001) in 509 individuals from the TwinsUK cohort, and both signals replicated in 1,160 individuals from the KORA cohort (p = 7.2e-08 and p = 0.007, respectively). Sensitivity analyses including covariates of other cocoa and coffee metabolites suggest that the effect is specific to theobromine. Our findings indicate that the reported beneficial links between theobromine intake on health and ageing extend to the molecular epigenetic level in humans.

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Keywords - aging, theobromine, epigenetic aging, DNA methylation, metabolomics, nutrition

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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.”

Full blog - https://aging-us.org/2026/04/decline-in-glycolytic-atp-production-proposed-as-a-fundamental-mechanism-limiting-lifespan/

Paper DOI - https://doi.org/10.18632/aging.206356

Corresponding author - Akihiko Taguchi - [email protected]

Abstract video - https://www.youtube.com/watch?v=rA23radaoqI

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Keywords - hypothesis, aging, glycolytic ATP production, lifespan, Heterocephalus glaber

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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.

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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.

DOI - https://doi.org/10.18632/aging.206362

Corresponding author - Hyunju Kim - [email protected]

Abstract video - https://www.youtube.com/watch?v=FcJ7oEZ-KFk

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Keywords - aging, plant-based diets, DNA methylation, epigenetic aging, all-cause mortality, middle-aged adults

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BUFFALO, NY — April 9, 2026 — A new #research paper was #published in Volume 18 of Aging-US on March 27, 2026, titled “ATF5 is required for the maintenance of mitochondrial homeostasis and skeletal muscle health during aging.”

Led by first author Victoria C. Sanfrancesco and corresponding author David A. Hood, both from the Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada, the study investigated the role of activating transcription factor 5 (ATF5) in regulating mitochondrial quality control and skeletal muscle function during aging.

Using young and aged mouse models with and without ATF5 expression, the researchers examined how this transcription factor contributes to mitochondrial homeostasis, protein turnover, and stress response pathways. The analysis focused on key mechanisms such as the integrated stress response (ISR) and mitochondrial unfolded protein response (UPRmt), which are essential for maintaining mitochondrial integrity.

The authors found that ATF5 plays a critical role in coordinating mitochondrial quality control and adaptive stress signaling in skeletal muscle. Notably, the absence of ATF5 prevented the typical age-related decline in muscle mass but resulted in increased muscle fatigability and elevated mitochondrial reactive oxygen species (ROS) production. Additionally, the loss of ATF5 disrupted normal stress-response signaling and altered protein degradation pathways, highlighting its importance in maintaining muscle function with age.

“Collectively, these results suggest that ATF5 functions to maintain mitochondrial quality control and muscle endurance at the expense of muscle mass, and its absence attenuates the normal compensatory stress response to contractile activity with age.”

The authors conclude that while ATF5 contributes to preserving mitochondrial function and endurance capacity, its role in regulating muscle mass and stress adaptation is complex. Further studies are needed to clarify how modulation of ATF5 and related pathways could be leveraged to improve muscle health and mitigate age-related decline in mitochondrial function and physical performance.

DOI - https://doi.org/10.18632/aging.206365

Corresponding author - David A. Hood - [email protected]

Abstract video - https://www.youtube.com/watch?v=u2OeppqIPN4

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Keywords - aging, skeletal muscle, ATF5, mitochondria, stress response

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