ROCHESTER, Minn. — Researchers have uncovered a previously unknown mechanism that helps aging cells drive the chronic inflammation linked to many age-related diseases. The findings reveal how dysfunctional mitochondria — the cell’s energy-producing structures — work with the cell’s epigenetic machinery to switch on inflammatory genes, opening the door to a new therapeutic approach for promoting healthier aging.

The study, published in Nature, builds upon years of research showing that senescent, or “zombie,” cells accumulate with age. While these cells no longer divide, they remain metabolically active and release a cocktail of inflammatory molecules known as the senescence-associated secretory phenotype, or SASP.

This persistent inflammation is thought to contribute to frailty, cardiovascular disease, cancer, neurodegeneration and other disorders of aging.

“For years, the field has focused on getting rid of senescent cells,” says João Passos, Ph.D., a Mayo Clinic researcher and senior author of the study conducted in collaboration with Sanford Burnham Prebys Medical Discovery Institute. “Our strategy has been different. Instead of killing the cells, we asked whether we could switch off the inflammation that makes them harmful.”

Previous work from the Passos laboratory demonstrated that damaged mitochondria leak mitochondrial DNA and RNA into the cell, activating immune pathways that trigger inflammation. The new study identifies a second, independent pathway that is equally essential.

“We found that inflammatory signaling alone isn’t enough,” says Helene Martini, Pharm.D., Ph.D., a Mayo Clinic researcher and first author of the study. “The cells also need a metabolic signal from mitochondria that changes how inflammatory genes are turned on.”

The researchers discovered that senescent cells increase production of acetyl-CoA, a molecule generated through mitochondrial metabolism. Acetyl-CoA enables epigenetic modifications — chemical changes that regulate whether genes are switched on or off without altering the DNA sequence itself. These modifications make inflammatory genes more accessible, allowing them to be robustly expressed.

In other words, mitochondrial DNA and RNA provide the inflammatory alarm, while mitochondrial metabolism grants the molecular “permission” needed to fully activate inflammatory genes.

“This is a completely new pathway,” says Dr. Martini. “We found that dysfunctional mitochondria can promote inflammation by controlling epigenetic switches that turn inflammatory genes on.”

The team also identified a promising therapeutic target: a mitochondrial citrate transporter known as SLC25A1. Blocking this transporter reduced the supply of acetyl-CoA, limiting activation of inflammatory genes even though the initial immune signals remained present. Together, these findings reveal a previously unrecognized control point that could be exploited to promote healthier aging.

The research is part of a larger effort at Mayo Clinic called the Precure Research initiative, which is focused on developing tools that empower clinicians to predict and intercept biological processes before they evolve into disease or progress into complex, hard-to-treat conditions.

Review the study for a complete list of authors, disclosures and funding.

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Mitochondria, often celebrated as the cell’s “powerhouses,” are responsible for producing the energy required to sustain virtually every biological process. However, mitochondria are also vulnerable to damage caused by oxidative stress and metabolic imbalances, leading to the accumulation of dysfunctional organelles that exacerbate cellular decline. Findings by Shan, Liu, Tang, and colleagues highlight that the selective degradation of impaired mitochondria—mitophagy—not only preserves cellular health but may actively delay cellular senescence and tissue degeneration.

The study delves into the molecular intricacies that regulate mitophagy, spotlighting key proteins and signaling pathways that could be manipulated to enhance this process. Among these, PINK1 and Parkin, proteins that tag defective mitochondria for destruction, emerge as pivotal players. By boosting the effectiveness of these molecular markers, cells can maintain mitochondrial integrity longer, thus stalling the biochemical cascades that typically precipitate aging.

Crucially, the researchers employed advanced imaging techniques and biochemical assays to quantify mitophagy activity in both cultured cells and animal models. Their data convincingly demonstrate that interventions targeting mitophagy pathways can restore mitochondrial function and improve cellular resilience against age-associated stressors. Such enhancement delays phenotypes linked to aging, including inflammation, apoptosis, and metabolic dysfunction, offering a compelling therapeutic window.

The ramifications of this research extend beyond simple lifespan extension. By improving mitochondrial quality control mechanisms, it becomes possible to mitigate the effects of neurodegenerative diseases such as Parkinson’s and Alzheimer’s, which have been intricately connected to mitochondrial decay. This fusion of aging biology with neurodegeneration provides a much-needed bridge to translate cellular insights into clinical outcomes, positing mitophagy modulation as a versatile intervention.

Additionally, the study confronts long-standing challenges in the field, such as the difficulty in selectively activating mitophagy without triggering excessive cellular stress or unintended side effects. The authors propose targeted drug delivery systems and small molecule modulators that offer high specificity, mitigating potential risks and maximizing therapeutic benefits. This nuanced approach represents a major step forward in translating bench-side discoveries to bedside applications.

By elucidating the role of mitochondrial turnover in maintaining cellular homeostasis, this work reshapes our understanding of how intrinsic cellular housekeeping impacts organismal aging. The notion that promoting the clearance of faulty mitochondria can rejuvenate tissues adds a new dimension to the anti-aging toolkit, one that complements genetic, metabolic, and environmental strategies already in vogue.

Furthermore, Shan and colleagues provide evidence that mitophagy is intimately linked with systemic metabolic health. Their experiments indicate that manipulating mitochondrial clearance in key tissues like skeletal muscle and liver enhances metabolic efficiency, improving glucose homeostasis and reducing age-related insulin resistance. This intersection of mitophagy with metabolic regulation highlights its potential to combat chronic conditions associated with aging.

As with any emerging field, many questions remain unanswered. The complexity of the mitophagy network and its crosstalk with other cellular processes demand further inquiry. The authors call for extensive longitudinal studies to examine the long-term effects of mitophagy enhancement on whole-organism aging, which could clarify optimal intervention windows and dosages in humans.

The researchers also underscore the importance of personalized approaches in anti-aging therapies. Since mitochondrial quality and dynamics vary among individuals due to genetics, lifestyle, and environmental exposures, tailoring mitophagy-targeted treatments could enhance efficacy and reduce adverse outcomes. Precision medicine strategies anchored in mitophagy biomarkers may thus hold the key to maximizing lifespan and healthspan simultaneously.

In the broader context of aging research, this paper helps to consolidate mitophagy as a prime target alongside other established anti-aging interventions such as caloric restriction, senolytics, and telomerase activation. Its insights invigorate the scientific community’s enthusiasm for mitochondrial maintenance and invite collaborative efforts across disciplines to harness the full potential of cellular renewal.

Public and scientific interest in cellular rejuvenation and longevity is higher than ever, driven by demographic shifts and the increasing burden of age-related diseases. By offering a mechanistic foundation for therapies that clear damaged mitochondria, Shan et al. contribute to a transformative narrative in biomedicine—where aging itself can become manageable, rather than inevitable.

In conclusion, this pioneering work not only elucidates the fundamental biology of mitochondrial autophagy but also lights the path toward interventions that could profoundly alter the trajectory of human aging. As the field progresses, we move closer to a future where enhancing cellular waste disposal and energy production may unlock unprecedented health benefits and redefine the limits of lifespan.

Subject of Research: Mitochondrial autophagy (mitophagy) as a target for combating aging and age-related cellular decline.

Article Title: Targeting mitochondrial autophagy for anti-aging.

Article References: Shan, W., Liu, Y., Tang, R. et al. Targeting mitochondrial autophagy for anti-aging. Cell Death Discov. (2025). https://doi.org/10.1038/s41420-025-02913-y

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41420-025-02913-y

Cellular senescence, the complex process through which cells irreversibly cease to divide while remaining metabolically active, has gained immense attention for its dual role in physiology and pathology. The senescent phenotype exhibits profound changes, notably the senescence-associated secretory phenotype (SASP), which involves the secretion of pro-inflammatory cytokines, growth factors, and proteases that can alter the tissue microenvironment. This feature, extensively characterized in Campisi’s research, contributes both to tumor suppression and, paradoxically, tissue dysfunction linked to aging and chronic diseases.

This special collection seeks to gather cutting-edge studies elucidating the fundamental molecular triggers that induce senescence, including DNA damage responses, telomere attrition, oxidative stress, and oncogene activation. Further, it emphasizes mechanistic insights into how senescent cells maintain their arrest and modulate their secretory profile in various physiological contexts. These scientific inquiries delve into the signaling pathways such as p53/p21 and p16INK4a/Rb, which orchestrate the senescence program and determine cell fate decisions influential in organismal aging.

Beyond mechanistic studies, the scope extends to the physiological roles of senescent cells, revealing their context-dependent effects. Researchers are invited to submit findings that explore the beneficial roles of senescence in embryonic development, wound healing, and regeneration, juxtaposed with detrimental consequences in chronic inflammation, fibrosis, and tumor microenvironment modulation. This nuanced perspective underscores the intricacy of senescence as a biological phenomenon, pivotal to both healthspan and disease progression.

An additional focal point of the collection is the advancement of biomarkers and innovative tools for the detection and quantification of senescent cells. Accurate identification remains a challenge due to the heterogeneous and dynamic nature of the senescent phenotype. Contributions that present novel imaging techniques, single-cell analyses, and molecular signatures provide critical resources for both basic research and translational applications, facilitating precision medicine approaches in aging-related conditions.

Therapeutic interventions targeting senescent cells represent a rapidly expanding frontier directly inspired by foundational research in this domain. The collection invites submissions on the development and evaluation of senolytics—agents that selectively eliminate senescent cells—and senomorphics, compounds that modulate the SASP without cell death. This line of investigation aims to mitigate the deleterious effects of senescent cells in vivo and translate these findings into clinical therapies for age-related diseases such as osteoarthritis, atherosclerosis, and neurodegeneration.

Importantly, the special issue is guest edited by Han Li and Irina Conboy, internationally recognized leaders in the study of senescence and aging. Their combined expertise spans molecular biology, regenerative medicine, and systemic aging, positioning them perfectly to curate a collection that integrates multidisciplinary perspectives on cellular senescence. Their leadership recommits the field to rigorous, innovative, and impactful research trajectories in honor of Professor Campisi’s enduring legacy.

The submission deadline is set for January 15, 2026. Authors are encouraged to adhere strictly to Aging’s manuscript guidelines outlining formatting, ethical considerations, and original research standards. Each submission will undergo a thorough and rigorous peer-review process ensuring the highest scientific quality and relevance. Researchers worldwide are encouraged to contribute original research, comprehensive reviews, and thought-provoking perspectives that collectively advance the field.

This commemorative call for papers not only serves as a tribute to an extraordinary scientist but also catalyzes a renewed collective effort to decode the complex biology underpinning senescence and its vast implications. It invites the scientific community to push the boundaries of knowledge surrounding the molecular and cellular underpinnings of aging and age-related diseases, potentially unlocking novel paths to enhance human healthspan and longevity.

This initiative also reflects a growing recognition that interventions targeting senescent cells hold promise to redefine aging research from a descriptive to a therapeutic discipline. The research curated under this collection will contribute to a more profound understanding of age-associated pathologies, offering hope for innovative clinical solutions and improved quality of life for aging populations globally.

For more detailed information regarding manuscript submission, interested researchers are directed to the official Aging journal website. The platform also offers extensive resources relating to editorial policies and open-access publishing, enabling a broad dissemination of knowledge. The Aging journal remains committed to fostering open scientific communication and public engagement, with active outreach on multiple social media platforms.

In closing, this commemorative special collection provides a unique opportunity for scientists to honor the memory of Professor Judith Campisi by contributing to a growing body of knowledge that she inspired. It resonates as a call to action for the global aging research community to continue unraveling the complexities of cellular senescence and its manifold effects on health and disease.

Subject of Research: Cellular senescence and its role in aging, cancer, and tissue homeostasis.

Article Title: Call for Papers: Commemorative Collection Honoring Dr. Judith Campisi on Cellular Senescence

News Publication Date: May 1, 2025

Web References:
https://www.aging-us.com/judith-campisi-commemorative-call-for-papers
http://www.aging-us.com/

Image Credits: © 2025 Rapamycin Press LLC dba Impact Journals

Keywords: Cellular senescence, SASP, aging, cancer, tissue homeostasis, senolytics, senomorphics, biomarkers, regenerative medicine, peer review, open access, scientific publishing