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.

###

About Mayo Clinic
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.

Inflammaging is not a monolithic process; rather, it emerges from a unique interplay of life-long exposures to various inflammatory stimuli. These exposures are intricately modulated by an individual’s genetic makeup, lifestyle choices, socioeconomic environment, and external factors such as infections and environmental pollution. This multilayered perspective challenges earlier conceptions of inflammaging as simply a consequence of aging, positioning it instead as a dynamic, individualized landscape shaped by a life course of inflammatory insults and bodily responses.

Central to understanding inflammaging is recognizing the diverse biological mechanisms that converge to sustain chronic inflammation. Among them, immunosenescence—the gradual decline of immune function with age— plays a pivotal role, compromising the ability to resolve inflammation efficiently. Simultaneously, cellular senescence contributes to inflammaging through the secretion of pro-inflammatory factors collectively termed the senescence-associated secretory phenotype (SASP). Moreover, mitochondrial dysfunction and altered metabolic states further fuel inflammatory pathways, creating a feedback loop that exacerbates tissue damage and accelerates the onset of ARDs.

A significant hurdle in inflammaging research has been the challenge of quantifying this complex state. Traditional biomarkers of inflammation, such as C-reactive protein (CRP) or interleukin-6 (IL-6), provide snapshots but fail to capture the longitudinal, systemic nature of inflammaging. To overcome this, researchers have developed innovative “inflammatory clocks” — computational tools that analyze patterns of inflammatory markers to quantify an individual’s “inflammatory age.” Intriguingly, these clocks not only correlate with chronological age but also strongly predict the incidence and progression of ARDs, offering a powerful metric to gauge biological aging from an inflammatory perspective.

Beyond inflammatory clocks, other aging clocks based on epigenetic, proteomic, and metabolic signatures demonstrate significant intersections with inflammaging, highlighting its central role within the broader aging spectrum. For example, epigenetic clocks that measure DNA methylation patterns show alterations linked to systemic inflammation, while proteomic profiles often reflect changes in inflammatory mediators. These multi-modal approaches provide a more holistic view of aging and enable researchers to dissect the distinct contributions of inflammation to biological aging trajectories.

Recognizing inflammaging’s heterogeneous origins and manifestations has urged the scientific community to rethink intervention strategies. Historically, anti-inflammatory drugs targeted at specific cytokines or pathways offered limited success, partly due to the systemic and multifactorial nature of inflammaging. Moving forward, precision interventions tailored to an individual’s unique inflammatory profile show promise. This paradigm shift leverages advances in genomics, exposomics, and bioinformatics to tailor prevention and treatment approaches that align with personal risk factors and biological states.

Among the most accessible yet effective interventions against inflammaging are lifestyle modifications. Nutritional strategies that emphasize anti-inflammatory diets rich in polyphenols, omega-3 fatty acids, and antioxidants play a crucial role in modulating inflammatory pathways. Simultaneously, regular physical activity exerts systemic anti-inflammatory effects by improving immune function, reducing visceral fat, and modulating metabolic health. These interventions, while broadly beneficial, can be optimized based on individual inflammatory profiles to maximize efficacy and reduce ARD risk.

Beyond these foundational approaches, the emerging field of gerotherapies introduces novel possibilities to counteract inflammaging at the molecular and cellular level. Senolytics, drugs that selectively eliminate senescent cells, have demonstrated the ability to reduce SASP-induced inflammation and improve tissue function in preclinical models. Additionally, interventions targeting mitochondrial health, autophagy, and immune rejuvenation are being explored to break the vicious cycles fueling chronic inflammation.

However, the path toward clinical translation of inflamaging-targeted therapies is fraught with challenges. The heterogeneity of inflammaging across populations necessitates robust biomarkers and standardized metrics to stratify patients effectively and monitor treatment responses. Advances in machine learning and artificial intelligence are accelerating the development of personalized predictive models that integrate multi-omic data, clinical indicators, and environmental exposures, thereby enabling more precise intervention designs.

The implications of inflammaging research extend beyond individual health, touching upon socioeconomic and public health arenas. Chronic low-grade inflammation disproportionately affects populations exposed to adverse environmental conditions, including pollution and persistent infections, as well as those burdened by social inequities. Addressing inflamaging in a societal context requires integrating personalized medical approaches with public health policies that mitigate these external inflammatory risk factors.

Importantly, inflammaging embodies a convergence point not only of biological aging but also of numerous age-related pathologies including cardiovascular diseases, neurodegeneration, type 2 diabetes, and cancer. Understanding its central role can potentially unify disparate fields within aging research, creating synergies for developing multi-target therapeutics that address the root causes shared among these conditions.

Future research must continue to unravel the mechanistic underpinnings of inflammaging’s heterogeneity. Longitudinal cohort studies incorporating detailed immunological, genetic, and environmental data are essential to map individual aging trajectories accurately. Equally critical is elucidating how inflammaging interfaces with other hallmarks of aging, such as telomere attrition, proteostasis decline, and stem cell exhaustion, to build comprehensive models of aging biology.

In the clinical domain, integrating inflammaging metrics into healthcare practice could revolutionize how aging and ARD risk are assessed and managed. Personalized inflammatory profiles could inform screening protocols, lifestyle recommendations, and therapeutic choices, advancing the vision of precision geroscience. Furthermore, routine use of inflammatory clocks alongside traditional biomarkers could enhance early disease detection and intervention timing, ultimately improving healthspan and quality of life.

As the scientific community moves swiftly toward this new era, interdisciplinary collaboration becomes indispensable. Bridging immunology, molecular biology, computational sciences, and clinical medicine will be paramount to translate the biological insights of inflammaging into tangible health outcomes. Moreover, educating healthcare providers and the public about the significance of inflammaging and its modifiable nature can foster proactive engagement in health maintenance.

In sum, inflammaging represents a paradigm shift in aging research—a recognition that aging and disease susceptibility emerge from complex, individualized inflammatory landscapes sculpted by genetics, lifestyle, and environment. By advancing precise metrics and personalized interventions targeting this state, we stand on the cusp of transforming aging from an inevitable decline into a manageable, modifiable process, extending healthspan and mitigating the burden of age-related diseases for future generations.

Subject of Research: The heterogeneous nature of inflammaging and its implications for precision measurement and personalized interventions targeting age-related diseases.

Article Title: Toward precision interventions and metrics of inflammaging.

Article References:
Franceschi, C., Olivieri, F., Moskalev, A. et al. Toward precision interventions and metrics of inflammaging. Nat Aging 5, 1441–1454 (2025). https://doi.org/10.1038/s43587-025-00938-7

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s43587-025-00938-7