The Sixth Annual Symposium of the Midwest Aging Consortium

Abstract

Geroscience research benefits from interdisciplinary approaches, team science, and collaborations, which collectively facilitate the discovery of aging mechanisms and their translation into tangible, clinical interventions. Since its inception in 2019, the Midwest Aging Consortium (MAC) has provided an engaging platform for aging researchers in the United States’ Midwest to connect, collaborate, and exchange ideas. The Sixth Annual Research Symposium of the MAC held at the Mayo Clinic in Rochester, Minnesota in April 2025 highlighted the continued impact of the MAC in bringing together aging researchers, including many trainees and early career investigators, into a collaborative environment. This record-setting event featured interdisciplinary research on key aging mechanisms, including lipid metabolism, mitochondrial dysfunction, stress response, cellular senescence, and immune adaptations across organ systems. New therapeutic concepts and clinical trial approaches were presented. Cutting-edge methodologies including single-cell and spatial transcriptomics, metabolomics, and organoid cultures, to dissect aging process in tissue-specific and systemic contexts also were presented. Overall, the MAC symposium underscored the translational potential of geroscience and reinforced the MAC’s mission to accelerate aging research through regional collaborations and innovation.

Biomedical research on aging has advanced rapidly over the last few decades (1). New model systems and technological innovations are revolutionizing our ability to conduct and translate geroscience research. Federal funding bodies, including the National Institutes on Aging (NIA), which celebrated their 50^th anniversary last year, as well as foundation and private funding sources (e.g. American Federation for Aging Research AFAR, Glenn Foundation for Medical Research, and Hevolution) have been instrumental in facilitating the discovery of major drivers of aging and the development of therapeutic interventions aimed at ameliorating age-related pathologies.

Geroscience posits that aging is the major risk factor for most chronic diseases and, thus, targeting aging mechanisms will be an effective approach to reduce the incidence and severity of disease. Considering the complex, multifactorial causes and consequences of aging, geroscience research highly benefits from team science, collaborations, and interdisciplinary research approaches. Furthermore, training the next generations of geroscience researchers remains a cornerstone of our profession. The Midwest Aging Consortium (MAC) was established in 2019 to connect a network of aging researchers among institutions in the Midwest of the United States with a specific goal of fostering collaborations, new ideas, training, and career development opportunities. The MAC currently spans institutions in 9 states: Illinois (Northwestern University, University of Illinois Chicago, University of Illinois Urbana-Champaign, Southern Illinois University), Indiana (Indiana University-Bloomington), Iowa (Iowa State University, University of Iowa,), Michigan (University of Michigan, Wayne State University), Minnesota (Mayo Clinic, University of Minnesota), North Dakota (University of North Dakota), Ohio (The Ohio State University, Xavier University), Kansas (Kansas State University), and Wisconsin (University of Wisconsin-Madison).

The Sixth Annual Research Symposium of the MAC was held at the Mayo Clinic in Rochester Minnesota on April 23^rd to 25^th, 2025. The meeting was jointly organized by Drs. Marissa J. Schafer, Nathan K. LeBrasseur, Ines Sturmlechner, Hélène Martini, Luis I. Prieto, Niels C. Asmussen, and Ms. Shelly K. McCrady-Spitzer from the Mayo Clinic, Drs. Maria M. Mihaylova, Ana L. Mora, and Mauricio Rojas of The Ohio State University, Drs. G. R. Scott Budinger, Luisa C. Morales-Nebreda, and Deborah R. Winter from the Northwestern University, and Dr. Rozalyn M. Anderson from the University of Wisconsin-Madison.

The symposium attracted 186 attendees across 19 institutions - a record attendance highlighting the continuous growth trajectory of the MAC community over the last years (2–5) that goes well beyond the core MAC partner institutions (Figure 1). This year’s attendees represented the following institutions: Indiana University Bloomington, Iowa State University, Kansas State University, Mayo Clinic Arizona, Mayo Clinic Florida, Mayo Clinic Minnesota, New York Genome Center & Columbia University, Northwestern University, The Ohio State University, Southern Illinois University, University of Kansas, University of Louisville, University of Michigan, University of Minnesota, University of North Dakota, University of Wisconsin-Madison, Wake Forest University, Wayne State University, and the biotechnology start-up Dragonase.

Figure 1: Growth of the Midwest Aging Consortium’s Annual Research Symposium.

The MAC symposia in 2021 and 2022 were virtual conferences (*), while symposia in 2023 and thereafter were held in person. The number of represented institutions for the 2021 Second Annual MAC symposium was not available (x). The number of abstracts for the 2021 Second Annual MAC symposium reflects 9 invited presentations selected by institutional representatives. Abstracts for the 2022 MAC symposium include 10 invited presentations selected by institutional representatives and 24 additional virtual posters. Not depicted is the First MAC Research Symposium in 2019, which was organized in conjunction with the University of Minnesota’s Institute on the Biology of Aging Metabolism symposium.

Drs. Marissa J. Schafer and Nathan K. LeBrasseur at Mayo Clinic developed the scientific program of the Sixth Annual MAC symposium, which included 2 keynote lectures and 7 invited talks, as well as 17 short talks and 10 poster teaser talks selected from the 104 submitted abstracts. Students, postdoctoral fellows, and other early-career researchers were prioritized in the selected talks. The record number of abstract submissions exceeded those of previous years by over 30% (Figure 1). The poster session featured 101 posters and encouraged lively engagement and discussions among trainees, staff, and faculty attendees. Excellent abstract submissions received travel awards, and outstanding poster presentations received poster awards.

This report summarizes the research talks presented at the Sixth Annual MAC Research Symposium, highlighting new scientific discoveries, methodologies, and translation research approaches by Midwestern researchers in the aging and geroscience field.

Critical new areas of development – interdisciplinary geroscience at spatial resolution

The keynote lectures by Dr. Douglas G. Mashek and Dr. Hemali Phatnani emphasized the importance of interdisciplinary, basic-translational geroscience. They demonstrated how the integration of molecular geroscience pathways with tissue architecture can drive avenues for both mechanistic discovery and translational innovation.

Dr. Douglas G. Mashek, a professor at the University of Minnesota and co-director of the Masonic Institute on the Biology of Aging and Metabolism, set the stage of the symposium and underscored the power of interdisciplinary research in making innovative, clinically relevant scientific discoveries. Dr. Mashek combined multiple themes of the symposium, including metabolism, stress response, and cellular senescence. He discussed the role of lipid droplets (LDs) which accumulate in non-adipose tissues and in senescent cells with aging. Dr. Mashek described that LDs accumulate quickly following DNA damage in cultured cells before the onset of cellular senescence. Inhibiting diacylglycerol acyltransferase (DGAT), an enzyme necessary for the formation of LDs, ablated LDs and worsened DNA damage. To probe the underlying mechanism, Dr. Mashek and his team interrogated adipose triglyceride lipase (ATGL), which regulates lipolysis and lipid droplet turnover in most cell types (6). Intriguingly, ATGL-mediated lipolysis promoted DNA repair in vitro, indicating that lipid catabolism may enhance DNA repair. Given that lipolysis promotes DNA repair in vitro, the Mashek laboratory induced DNA damage in ATGL-overexpressing mice by irradiation and collected tissues within 4 hours. Results confirmed that ATGL also enhanced DNA repair in vivo and attenuated replicative senescence in mouse embryonic fibroblasts. Inhibiting lipolysis before DNA damage appeared to be crucial, as it enhanced the DNA damage repair capacity. However, induction of ATGL expression after DNA damage did not prevent DNA damage and may even worsen it. Dr. Mashek and his team examined the mechanism by which ATGL reduces DNA damage and found that ATGL activation promoted non-homologous end joining facilitating the repair of DNA double-stranded breaks. ATGL both promoted homologous recombination via RAD51 and increased 53BP1 on chromatin at baseline, even in the absence of DNA damage. Interestingly, ATGL promoted the acetylation of both proteins while histone acetyltransferase inhibitor P300 impeded the benefits of ATGL. Lastly, Dr. Mashek showed that ATGL-overexpressing mice administered a chemotherapeutic drug had reduced chemotherapy-related toxicity, further cementing ATGL and lipolysis as potential therapeutic targets to ameliorate cellular senescence and aging.

Dr. Hemali Phatnani is an assistant professor at the Columbia University and a core faculty member and director of the Center for Genomics of Neurodegenerative Disease, New York Genome Center. She presented the NIH Cellular Senescence Network (SenNet) Consortium Columbia University Senescence Tissue Mapping Center (CUSTMAP) efforts to generate a comprehensive 3-dimensional atlas of the human brain and spinal cord across the lifespan. Dr. Phatnani and her team deeply profiled tissues obtained from the Edinburgh Sudden Death Brain and Tissue Bank, including the hippocampus, dorsolateral prefrontal cortex, and spinal cord (7). These samples were analyzed using spatial transcriptomics, single-nucleus RNA sequencing (snRNA-seq), and multiplex immunostaining. This enabled high-throughput molecular profiling at single-cell resolution with spatial context within anatomically complex tissues. By integrating snRNA-seq, spatial transcriptomic mapping, and manual anatomical annotation, Dr. Phatnani used computational deconvolution methods to resolve the spatiotemporal dynamics of cell-type-specific gene expression within the tissue microenvironment. Further, Dr. Phatnani incorporated proteomics to complement transcriptomic data and validated key findings at the protein level, providing a more complete understanding of the cellular changes which occur with age. Her work is advancing our ability to detect and characterize senescent cells and uncover pathological gene expression signatures associated with aging and neurodegeneration. Dr. Phatnani’s work is providing critical insights into how aging and cellular senescence contribute to the onset and progression of neurodegenerative diseases (8).

Senescent cells – local and systemic disruptors of tissue homeostasis

Cellular senescence has emerged as a cell fate with broad yet context-dependent implications in aging and many diseases, making it a key hallmark of aging. Although these cells are usually rare in tissues, they can disrupt tissue microenvironments and systemic homeostasis at least in part through their potent secretome, the Senescence-Associated Secretory Phenotype (SASP). Senescent cells that persist for prolonged periods of time may therefore promote inflammaging, tissue dysfunction, and chronic diseases. How senescent cells and their SASP confer these detrimental consequences on their surrounding tissues is incompletely understood and requires further in-depth discovery, as presented by researchers at the Sixth Annual MAC Research Symposium.

Dr. João F. Passos, a professor at the Mayo Clinic Minnesota, investigates mitochondrial dysfunction, a hallmark of aging that is linked to senescence, and its central role in the development of the SASP (9). Recent findings by Dr. Passos and his laboratory showed that leakage of mitochondrial DNA (mtDNA) into the cytosol promoted the SASP (10) and activated pro-inflammatory pathways like cGAS-STING or NF-kB. Leakage occurs through pores in the mitochondrial membrane mediated by the pro-apoptotic proteins BAX and BAK. Genetic deletion of BAX and BAK in senescent cells prevented mtDNA leakage and the SASP without interfering with the durable cell cycle arrest characteristic of senescence. In mouse models in which senescent cells accumulated due to natural aging, irradiation, or a Western diet, BAX/BAK deletion reduced inflammation. Pharmacological inhibition of BAX also improved healthspan and reduces senescence markers across multiple organs. In addition to mtDNA, senescent cells also leak double-stranded RNA of mitochondrial origin into the cytosol that activate the innate immune sensors, MDA5 and RIG-I, which in turn promote MAVS aggregation and NF-κB activation to further amplify the SASP. Deleting BAX and BAK also reduced mitochondrial RNA leakage and diminished the activation of MDA5 and RIG-I, and knockout of MAVS also suppressed the SASP (11). Taken together, the studies presented by Dr. Passos strengthen mitochondria as central and versatile regulators of the SASP, both in vitro and in vivo.

Dr. Hélène Martini, a research associate in Dr. João Passos’ laboratory at the Mayo Clinic, further demonstrated the relevance of mitochondria in senescence by presenting her work on the interplay between mitochondrial metabolism and epigenetic mechanisms. While epigenetic modulation and histone modifications are established contributors of the SASP (12), their regulation and coupling to other features of senescence are poorly understood. Dr. Martini demonstrated that mitochondrial metabolites are critical regulators of the epigenetic program that allows for SASP expression (13). Upon clearing the mitochondria in human fibroblasts via parkin-mediated mitophagy, transcriptionally permissive histone H3K27 acetylation was reduced at key SASP gene promoters. Inhibition of the mitochondrial citrate transporter SLC25A1 in senescent cells also reduced histone acetylation at SASP loci and the expression of SASP factors without affecting the senescent cell cycle arrest. This suggests a critical role of the citrate/ACLY/histone acetylation pathway to SASP expression. Importantly, pharmacological inhibition of SLC25A1 in aged mice reduced systemic inflammation and frailty and improved muscle and heart physiology. Overall, these studies demonstrate the functionally relevant interplay of mitochondria and histone acetylation in senescent cells, and highlights SLC25A1 as a potential therapeutic target to mitigate age-related inflammation.

Jhonny Rodriguez Lopez, a bioinformatician in the laboratory of Drs. Ana L. Mora and Mauricio Rojas at The Ohio State University, presented his work focused on elucidating the anatomical location of senescent cells in healthy aging lung as well as during idiopathic pulmonary fibrosis (IPF). Determining the location of senescent cells is critical as it can provide meaningful insights into their impact on tissue function (14). He introduced a new framework that utilizes spatial transcriptomic patterns to identify senescent cell niches within three distinct lung anatomical regions: the parenchyma, peri-bronchial, and subpleural areas. By combining deep learning and Bayesian modeling to integrate multiple samples, Rodriguez Lopez performed deconvolution analysis and paired single-cell RNA sequencing profiles with each sample. This approach enabled him to identify regions with elevated expression of genes that correlated with pathological cell types in the IPF lung, including CTHRC1⁺ fibroblasts and aberrant basaloid KRT17⁺/KRT5⁻ epithelial cells. Notably, senescent cell-associated genes are enriched in specific regions in both healthy and IPF samples. In healthy-aged lung specimens, senescence-associated genes, such as Cdkn1a, are abundant in peri-bronchial regions, whereas in IPF lungs, these genes are highly expressed in the upper lung lobes. As such, Mr. Rodriguez Lopez’s findings suggest that employing an unbiased spatial transcriptomics approach is a viable tool to identify and map the accumulation of senescent cells in healthy aging and disease.

Dr. Blake Monroe, a postdoctoral fellow mentored by Drs. Paul Robbins and David Bernlohr at the University of Minnesota, presented his work on how lipid-derived electrophiles, especially 4-hydroxynonenal (4-HNE), drive aging and metabolic disease by promoting cellular senescence in fat tissue. 4-HNE is generated when polyunsaturated fatty acids undergo oxidative damage. In murine models of obesity and aging, 4-HNE accumulates in the visceral fat depots of aged or obese mice to levels that can exert toxic effects through modification of enzymes and DNA. Dr. Monroe described a novel senescence type, termed Biogenic Lipid-Induced Senescence (BLIS), associated with 4-HNE and related reactive compounds. BLIS occurs when cells are chronically exposed to 4-HNE, which damages DNA and mitochondria and activates key pathways like p53/p21. Sirtuins (SIRT1 and SIRT3), which help protect against aging and support mitochondrial health, showed impaired function upon modification by 4-HNE. In turn, loss of sirtuin activity led to downregulation of DNA damage repair and antioxidant responses. The resultant elevated senescent cell burden from BLIS in adipose tissues facilitated chronic inflammation, loss of adipocyte function, and metabolic dysfunction. Importantly, the sequestration of 4-HNE by the carbonyl scavenger L-carnosine showed promising, beneficial results in mouse models of diet-induced obesity. Oral L-carnosine treatment reduced 4-HNE levels, blunted senescence markers p21^Cip1, PLAUR, and BCL2L1, and improved glucose tolerance in obese mice. Altogether, Dr. Monroe’s work suggests that scavenging lipid electrophiles may be a promising therapeutic strategy to ameliorate adipose senescence and improve metabolic function in obesity and aging.

Metabolic health and dysfunction with aging

The central role of metabolism to aging and lifespan was underscored by the discovery in 1935 that caloric restriction (CR) prolongs lifespan (1, 15). The profound effects of CR on healthspan and lifespan in model organisms resulted in the extensive investigation of its mechanistic impacts on aging. It also prompted research into the diverse diets, nutrient compounds, metabolites, and their respective cellular and molecular pathways associated with healthspan and lifespan extension. New advances in the field of metabolic health and dysfunction with aging were presented by MAC researchers employing well-established and innovative models and techniques, ranging from organoid cultures to long-lived murine models, metabolomics and more.

Dr. Maria M. Mihaylova, an assistant professor at The Ohio State University, presented her previous and ongoing work on the impact of aging and dietary factors on intestinal stem cell (ISC) function (16). Her research focuses on LGR5⁺ ISCs, a population of actively dividing stem cells essential for maintaining intestinal homeostasis. Previously, she and colleagues had shown that the regenerative capacity of LGR5⁺ ISCs diminishes with age, resulting in impaired intestinal stem cell function (17). They also had shown that dietary interventions in mice, such as 24-hour fasting, improved intestinal regeneration through activation of fatty acid oxidation. Using intestinal organoid cultures, RNA sequencing, and metabolomics, they showed that the beneficial effects of fasting depended in part on Carnitine Palmitoyltransferase 1A (CPT1α), the rate-limiting enzyme in mitochondrial fatty acid oxidation. Dr. Mihaylova presented additional, unpublished findings from her group on age-dependent alterations in the colon, utilizing single-cell RNA sequencing and spatial approaches. Her lab, in collaboration with others, has recently developed methods for Mass Spectrometry Imaging in organoids and tissues (18), which they are now applying to investigate the metabolic alterations associated with aging and pathologies. Collectively, this work highlights the importance of metabolic regulation of adult stem cells and tissue homeostasis and suggests that dietary modulation may be a powerful strategy to enhance intestinal regeneration in aging.

Bailey Knopf, a graduate student in Dr. Dudley W. Lamming’s laboratory at the University of Wisconsin-Madison, presented her work on dietary protein restriction and its sex-specific effects in promoting healthy aging in mice. An alternative geroprotective dietary intervention in rodents and humans is protein restriction, where macronutrient protein composition is decreased but overall calories consumed is unchanged (19–21). Protein restricted diets can improve metabolic health, reduce frailty, and extend the lifespan in rodents (22, 23). Sex-specific metabolic changes are evident across the lifespan and are known to effect longevity in both mice and humans, with male mice benefiting more from protein restriction than females (24–26). Using standard (21% protein) and low (7%) protein diets and a gonadectomy-based approach in mice, Ms. Knopf identified ovaries as being responsible for the sex-specific metabolic effects of protein restriction in young mice. Male mice on protein restriction exhibit significantly blunted body weight gain and improved glucose homeostasis. Interestingly, these benefits in males were independent of whether male sex organs were intact or removed via castration. Conversely, female mice were less responsive to protein restriction; however, ovariectomy facilitated beneficial effects of protein restriction, including decreased body weight and improved glycemic control with improved glucose tolerance and insulin sensitivity. The increased responsiveness of ovariectomized mice to protein restriction was potentially linked to reduced mTORC1 signaling in muscle tissue and increased carbohydrate metabolism. This work demonstrates that the sex-specific sensitivities to dietary protein restriction with ovarian-dependent mTORC1 regulation are an important mediator of the benefits of protein restriction in females.

Matthew J. Johnston, a graduate student in Dr. Holly M. Brown-Borg’s laboratory at the University of North Dakota, presented his work on skeletal muscle function in growth hormone-deficient Ames dwarf mice. Mr. Johnston assessed how skeletal muscle function was maintained in Ames dwarf animals across their lifespan. Using young, middle, and aged cohorts, he found that Ames dwarf mice outperformed age-matched wild-type control animals in grip strength and rotarod tests. Twenty-one-month-old Ames dwarf mice exhibited striking endurance running capacity compared to control mice, despite smaller running strides. Extensive histological assessments revealed that Ames dwarf mice had expectedly smaller myofibers but, strikingly, they had overall more myofibers per muscle than control animals. These results highlight that long-living Ames dwarf animals resist sarcopenia and maintain muscle health across the lifespan, providing novel insights on the mechanisms by which skeletal muscle maintenance could support healthy aging.

Spencer A. Tye, a graduate student at University of Wisconsin-Madison in Dr. Timothy Rhoads’ laboratory, presented his graduate research on how CR improves brain health with age. Lipid profiles change significantly with age and alterations in lipidome fatty acid profiles have been linked to age-related diseases such as Alzheimer’s disease (AD) (27) and Parkinson’s disease (28). However, it remains unclear how lipid synthesis pathways are altered by CR in the brain. Mr. Tye employed transcriptomic and lipidomic approaches on the brains of 10- to 30-month-old mice and discovered that CR broadly alters gene expression and RNA splicing variations, which he hypothesized to modify lipid synthesis. Lipidomic profiling by liquid chromatography and mass spectrometry revealed that age and CR increased the abundance of unsaturated lipids while disproportionately decreasing saturated lipids. This CR-mediated lipid shift increased the number fatty acid chain chemical bonds, introducing structural bends in the chains and preventing tight packing of lipids. These changes can alter the ability of lipids to interact with other proteins and may highlight a novel functional consequence of CR in the brain.

Combating age-related diseases of the brain, lungs, liver and vessels

Aging manifests differently across organs yet converges on shared mechanisms involving the breakdown of cellular quality control and metabolic imbalance leading to maladaptive tissue remodeling and functional decline. In the lung, impaired mitochondrial turnover and fatty acid oxidation disrupt epithelial repair, paralleling how dysfunctional microglia in the brain alter immune responses to accelerate neurodegeneration. Similar processes underlie vascular aging, where senescent cells weaken plaque stability, and in metabolic tissues, where shifts in lipid synthesis between liver and adipose depots determine resilience versus vulnerability. Together, these studies reveal how multiple mechanisms of aging such as mitochondrial dysfunction, lipid metabolism, and senescence intersect across tissues to shape systemic aging. By mapping shared aging mechanisms, MAC researchers are uncovering therapeutic strategies that could simultaneously target age-related diseases of the brain, lungs, liver, and vessels.

Dr. Ana L. Mora, a professor at The Ohio State University, presented her work on the importance of mitochondrial dysfunction and cellular senescence during lung aging and IPF. In the lung, alveolar type 2 cells (AT2) exhibit high mitochondrial content and metabolic demand. However, during aging and IPF, mitochondria become dysfunctional and show impaired turnover, due to reduced PINK1-mediated mitophagy. Interestingly, Pink1-deficient mice develop lung fibrosis, demonstrating that mitochondrial dysfunction is a key player in lung fibrosis with aging and IPF (29). Employing single-cell RNA sequencing, Dr. Mora and her team found that IPF lungs display significantly reduced expression of fatty acid oxidation genes, particularly CPT1α. Loss of Ctp1a caused mitochondrial dysfunction and enhanced lung fibrosis in mice. During lung injury repair, a subset of AT2 cells typically act as a progenitor reservoir and replenishes both AT2 cells and alveolar type 1 (AT1) cells. In IPF, however, a distinct transitional epithelial cell population emerged, characterized by the co-expression of basaloid markers (KRT17, KRT8) and airway secretory markers. These cells exhibited markers of cellular senescence and TGFβ signaling. Interestingly, this transitional cell population was also found in Ctp1a-deficient mice. Mechanistically, Dr. Mora’s team found that CPT1α deficiency reduced acetyl-CoA production and decreased SMAD7 acetylation, thereby amplifying TGFβ signaling and fibrosis (30). Finally, Dr. Mora investigated alterations in lipid metabolism in IPF lungs, demonstrating the accumulation of gangliosides in the lower lung lobes of IPF patients. Gangliosides are also induced in the AT2 transitional cell population of IPF patients and of Ctp1a-deficient mice, as well as in multiple other senescence models. These findings highlight the central role of mitochondrial dysfunction and lipid metabolism, particularly fatty acid oxidation, in lung repair and in the pathogenesis of pulmonary fibrosis.

Dr. David M. Gate, an assistant professor at the Northwestern University Feinberg School of Medicine, presented his work on microglial mechanisms underlying amyloid β (Aβ) clearance in brains of immunized AD patients. A major therapeutic strategy to reverse or prevent AD progression includes targeting cerebral Aβ accumulation through active or passive immunization against Aβ. One approach, termed AN1792, actively immunizes against a synthetic Aβ_1–42 peptide. While AN1792 has successfully reduced amyloid burden in clinical trials, it is associated with the risk of developing aseptic meningoencephalitis (31, 32). Passive immunization with lecanemab, an antibody binding soluble Aβ fibrils, has emerged as a safer alternative, reducing amyloid burden and cognitive decline in early-stage AD (33). The precise mechanisms of Aβ clearance in immunized patient brains remain poorly understood. Using spatial transcriptomics, spatial proteogenomics, and single-cell RNA sequencing, Dr. Gate and his team profiled the neuroimmune response in frontal cortex tissues of patients with AN1792-immunized AD, non-immunized AD, and non-neurologic disease, as well as one AD patient treated with lecanemab. His findings suggest that AN1792 immunization induced TREM2 and APOE in microglia to promote Aβ removal. Strong inflammatory microglial profiles were identified in patient brains with limited cerebral Aβ clearance, while microglia in samples with extensive Aβ clearance downregulated genes encoding heat shock proteins and upregulated neuroprotective genes such as FGFR3. In the lecanemab-immunized brain, microglia were spatially associated with Aβ plaques and upregulated genes involved in complement signaling pathways (34). Dr. Gate’s findings illustrate the transcriptional mechanisms associated with Aβ removal by microglia while also discovering molecular targets that could advance Aβ immunization and clearance strategies.

Dr. Bennett G. Childs, a research associate and assistant professor working with Dr. Darren J. Baker at the Mayo Clinic Minnesota, presented his work on atherosclerotic plaque stabilization to prevent plaque rupture, one of the leading causes of myocardial infarction and stroke. Senescent cells within the atherosclerotic plaque promote fibrous cap thinning and instability (35). Dr. Childs’ work presented the use of antibodies to deliver growth factors, including IGF-1, which can increase plaque stability by re-invigorating vascular smooth muscle cell functionality (35), to atherosclerotic plaques (36). His antibody strategy combined oxidized low-density lipoprotein targeting with delivery of LR3 IGF-1, a synthetic IGF-1 mimic with an increased half-life. Dr. Childs administered this agent to atherosclerosis-predisposed Ldlr-knockout mice on high fat diet and demonstrated that LR3 IGF-1 was stable in plasma and localized preferentially to aortic arch plaque tissue. Importantly, delivery of the αOxLDL/LR3 IGF-1 antibody four times over two weeks resulted in thickening of aortic arch fibrous plaque caps, demonstrating successful targeting and stabilization of the atherosclerotic plaques. Transcriptional profiling on plaque compartments was used to identify alternative, more potent cap-specific growth factors. TGFβ2 emerged as a candidate gene, and in vitro tests suggested that TGFβ2 indeed produced a more ‘fibrous cap-like phenotype’. Replacing the antibody-mediated delivery of IGF-1 with TGFβ2 and testing for in vivo plaque stabilizing effects is currently being tested. In conclusion, Dr. Childs’ work demonstrates a novel approach to target and stabilize atherosclerotic plaques.

Dr. Xinna Li is an associate research scientist working with Dr. Richard A. Miller at the University of Michigan on the role of de novo lipogenesis (DNL) in longevity. DNL is the metabolic conversion of carbohydrates into fatty acids, which can be utilized for immediate energy or stored as triglycerides. Elevated DNL activity in brown adipose tissue (BAT) is an indicator of metabolic health, enhanced metabolic function, and reduced inflammation. In contrast, when DNL is induced in the liver, it is associated with impaired metabolic function, reduced insulin sensitivity, and disorders such as hepatic steatosis. Long-lived mouse models, including Snell dwarf, growth hormone receptor Ghr knockout, Pappa knockout, and PTEN overexpression, are characterized by enhanced insulin sensitivity. In this study, protein samples from adipose tissues and livers of all four models and respective controls were examined for adaptations in DNL. Key DNL enzymes, acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN), as well as their key transcription factor ChREBP were measured. Results demonstrated a significant downregulation of DNL as indicated by reduced ACC1 and FASN in the liver of long-lived mice, in both males and females. Conversely, these lipogenic markers were upregulated in various adipose depots, including inguinal white adipose tissue and BAT. Similarly, ChREBP levels were decreased in the liver but increased in adipose tissues of the same mice. Western blot analysis confirmed these tissue-specific patterns. Dr. Li’s findings suggest that a redistribution of DNL activity, from the liver to adipose tissue, may underly improved metabolic health and insulin sensitivity in long-lived mouse models. Future studies will explore whether similar effects can be induced through pharmacological interventions such as rapamycin.

Immune aging – clinically relevant and therapeutically actionable

Changes in the immune system with aging are highly clinically relevant considering the disproportionate vulnerability of older adults to infections and infectious diseases. Virtually all immune cell types are affected by aging, but given the immune system’s complexity and heterogeneity, the underlying causes and functional consequences are challenging to pinpoint. Research on immune aging presented at the Sixth Annual MAC symposium leveraged high-throughput omics and spatial technologies in murine models and human specimens to uncover new mechanisms by which the aging immune system affects age-related pathologies in relevant tissue contexts of the lung, adipose tissue, or systemically.

Dr. Luisa C. Morales-Nebreda, an assistant professor and critical care physician-scientist at the Northwestern University Feinberg School of Medicine, investigates the age-related pathophysiology of lung injury and repair with particular focus on the interactions between immune cells and lung epithelial cells (37). Dr. Morales-Nebreda presented on age-related pathological lung niches during recovery from viral pneumonia. Using spatial transcriptomic technologies and NicheCompass, Dr. Morales-Nebreda and her team discovered that tertiary lymphoid structures (TLS) disproportionately expand in old mice compared to young adult mice during recovery from Influenza A virus (IAV) pneumonia. Niche analysis revealed that activated T cells are spatially localized to TLS and establish a self-reinforcing signaling circuit with a subset of lung epithelial cells characterized by Ccl20 expression and a shared gene program with Microfold (M) cells. This epithelial-immune cell circuit induces an inflammatory signature on fibroblasts, pericytes, endothelial and smooth muscle cells localized adjacent to TLS, driving tissue remodeling and precluding recovery from IAV pneumonia in old mice.

In Hwa Jang, a graduate student in Dr. Christina D. Camell’s laboratory at the University of Minnesota, presented her research on the age-related susceptibility to sepsis and endotoxemia, with a focus on GDF3 as a key mediator of macrophage-driven inflammation in aging (38). Using a murine model of endotoxemia, in which young and aged mice were challenged with lipopolysaccharide, Ms. Jang observed a significant accumulation of CD11c⁺ inflammatory macrophages in the adipose tissue of aged mice. She identified GDF3, a TGFβ superfamily cytokine, as a candidate mediator in this process, since GDF3 was upregulated during both aging and NLRP3 inflammasome activation and predominantly secreted by CD11c⁺ inflammatory macrophages in adipose tissue. Genetic deletion of Gdf3 in mice, either systemically or specifically in myeloid cells, decreased CD11c⁺ inflammatory macrophages in the adipose tissue and protected aged mice from endotoxemia-induced inflammation. Mechanistically, GDF3 induction in adipose macrophages during aging prompted SMAD2/3 phosphorylation, activation, and nuclear translocation. ATAC-seq analysis of Gdf3-deficient and wild-type adipose tissue macrophages showed that the GDF3–SMAD2/3 axis enhances chromatin accessibility at pro-inflammatory gene loci, a pattern attenuated in Gdf3 knockout mice. Pharmacological SMAD3 inhibition was sufficient to mimic the protective effect of Gdf3 deletion in aged mice, suggesting that targeting this pathway could offer a novel therapeutic strategy to mitigate age-associated susceptibility to endotoxemia. Overall, Ms. Jang’s work highlights the role of the GDF3–SMAD2/3 signaling axis in promoting endotoxemia-induced inflammation during aging.

Ethan A. Leitschuh, a research technologist in Dr. Marissa J. Schafer’s laboratory at the Mayo Clinic Minnesota, examines the potential of circulating proteins secreted from senescent cells to serve as plasma biomarkers of aging. Screening the plasma of aged versus young mice revealed elevated IL-23R in older, male and female mice (39). Using an irradiated mouse embryonic fibroblast in vitro model, they demonstrated that senescent cells upregulate expression of Il-23r, and similarly, they detected greater IL-23R protein in senescent cell media. Il-23r gene expression increased with age in various tissues, including kidney and liver in older males and females. Next, they discussed the comparative impacts of senotherapeutic strategies in vivo. Pharmacogenetic elimination of senescent cells using the AP20187-induced p16-INK-ATTAC model was compared to treatment with the senolytics Venetoclax, Navitoclax, Fisetin, or Luteolin treatment. Venetoclax reduced circulating plasma IL-23R in males and females. Gene expression analysis revealed the aged kidney as responsive to the senotherapeutics. Venetoclax, Fisetin, and Luteolin, and AP20187 reduced Il-23r in aged female mice while Fisetin reduced Il-23r expression in aged male mice. This implicates the kidney as a likely source of age-increased circulating IL-23R. To examine the translational potential, ELISA was used to quantify human IL-23R in plasma of Mayo Clinic Biobank participants aged 20 to 82 years old, which revealed that IL-23R increased with age in both males and females. In conclusion, this work identifies IL-23R as circulating biomarker of aging and senescence, which can be modulated by senotherapeutic interventions.

Zachary Miller, a graduate student in the laboratory of Drs. Ana L. Mora and Mauricio Rojas at The Ohio State University, investigates mechanisms by which natural killer (NK) cell dysfunction influences IPF. Mr. Miller found that in bleomycin-mediated lung injury the depletion of NK cells led to the accumulation of senescent cells and increased fibrosis in mice. To define alterations in NK cell activation, he examined NK cells from the lungs of IPF patients and healthy aged donors using single-cell RNA sequencing. He discovered gene expression changes in IPF NK cells, characterized by reduced expression of cytotoxicity genes and increased levels of genes associated with innate lymphoid cells group 1 (ILC1), including inflammatory cytokines and immunoregulatory genes such as PD-1. These findings were corroborated by flow cytometry in lungs and lung lymph nodes of IPF and healthy donor tissues. ILC1-like NK cells were present at a higher frequency in both IPF lymph nodes and lungs, and these cells highly expressed PD-1. Interestingly, the corresponding ligand, PD-L1, was highly expressed in IPF lung fibroblasts expressing senescence features. To test the potential role of senescent fibroblasts in influencing NK-ILC1 conversion, Mr. Miller cultured NK cells with conditioned media from IPF lung fibroblast. This conditioned medium was more effective in skewing NK cells to ILC1 phenotype than control conditioned medium from young or aged healthy donors. Altogether, Zachary Miller’s findings suggest that systemic and local IPF factors shape the phenotype and function of NK cells, which may contribute to impaired senescent cell surveillance.

Pharmacological and therapeutic developments for aging

Due to the exciting advances in the basic mechanisms of aging, including discoveries by Midwesterner aging researchers, targeted aging interventions are advancing from preclinical exploration to testing in humans. Pharmacological strategies to ameliorate specific age-related conditions are underway, and those presented at the Sixth Annual MAC Research symposium include rapamycin and its analogs, and senomorphic strategies to target the detrimental effects of senescent cells in settings such as transplantation, IPF, and cancer.

Dr. Adam R. Konopka, an assistant professor at the University of Wisconsin-Madison, investigates whether mTOR inhibition via rapamycin can improve indices of human healthspan (40). Pre-clinical studies across multiple model systems demonstrated that rapamycin extends lifespan and mitigates various age-related pathologies (40, 41). However, therapeutic rapamycin use in humans is limited by adverse effects such as immunosuppression, hyperglycemia, or new onset of diabetes. Dr. Konopka discussed opposing and time-dependent effects of mTORC1 and mTORC2 inhibition on healthspan (40). Pre-clinical data support the premise that rapamycin effectively inhibits mTORC1 which is linked to longer lifespan. However, when given at high doses and over prolonged time, rapamycin can also inhibit mTORC2 and cause disruptions to metabolic and immune function. This highlights the critical need for tailoring dosing strategies to selectively inhibit mTORC1 while avoiding mTORC2. Dr. Konopka’s current clinical trials were designed to address these knowledge gaps. In a phase I trial, a Bayesian optimal interval design is being used to identify safe and effective intermittent (1x/week) dosing strategies for rapamycin (sirolimus) and a rapamycin analog (everolimus). In another ongoing double-blinded randomized trial, the primary outcome is changes in insulin sensitivity, and secondary outcomes include cardiac, physical, and cognitive function. Blood, urine, and saliva samples are also collected to explore mechanistic basis of mTORC1 inhibition on the fundamental biology and proposed biomarkers of aging. Dr. Konopka emphasized that this multi-dimensional approach would yield valuable insights into safe dosing regimens and identify whether mTORC1 inhibition by rapamycin can modulate the biology of aging and clinically relevant functional outcomes in humans.

Dr. Andrew J. Haak, an assistant professor at the Mayo Clinic Minnesota, presented his work on Pim-1 kinase inhibitors as a potential therapeutic target for the SASP and IPF. Pim-1 kinase increases NF-κB activity, a SASP regulator, which can result in increased production of cytokines, leading to inflammation and fibrosis (42). His team also explored the hypothesis that Pim-1 kinase is a critical regulator of senescence propagation through a positive feedback loop between Pim-1, IL-6, JAK, and STAT. Previous work demonstrated that inhibition of Pim-1 and corresponding signaling pathways reduced extracellular matrix remodeling in vitro and reduced fibrosis in bleomycin-induced lung fibrosis mouse models (43, 44). In ongoing studies, Dr. Haak compared two small molecule drug candidates for Pim kinase inhibition, LGH447 and TP-3654, on senescent lung fibroblasts and precision-cut lung slices derived from aged (22-months) mice. Additionally, Dr. Haak’s team conducted an in vivo pilot study in which LGH447 or vehicle was administered to young (2-months) or aged (22-months) mice. At the completion of the study, whole organ RNA was analyzed for markers of inflammation and changes in expression of Pim kinase genes. These studies will define the role that Pim kinase plays in organ-specific, age-associated inflammation and explore the pharmacological potential of Pim kinase inhibitors to prevent and treat chronic disease associated with these processes.

Dr. Natalia Vanegas-Avendano, a postdoctoral fellow in the laboratory of Drs. Mauricio Rojas and Ana L. Mora at The Ohio State University presented on behalf of her colleague Ramya N. Akula. Their study investigated the contribution of cellular senescence to obliterative bronchiolitis (OB), a major cause of chronic lung allograft dysfunction. They leveraged single-cell RNA sequencing to assess the heterogeneity of senescence and apoptosis profiles and identify cellular “hotspots” exhibiting higher levels of senescence and apoptotic gene expression. Human lung samples were collected from a variety of conditions, including brain death (BD), cardiac death (CD), or re-transplant (RxTx) cases. By profiling cell types across each group, they identified differential shifts in senescence and apoptotic markers in endothelial, epithelial, and mesenchymal lung cells. While BD donor lungs showed the lowest senescence and apoptosis markers and only moderate changes with donor age, CD lungs exhibited a strong increase in senescence markers across all lung compartments. However, RxTx donor lungs showed the strongest senescence gene expression profiles in mesenchymal and endothelial populations. These results demonstrate that senescence profiles differ in BD, CD, and RxTx lungs and highlight the potential of senescence-targeting therapeutics to improve lung transplantation outcomes, especially in patients receiving donor lungs from RxTx and CD cases.

Ajinkya R. Limkar, an M.D. Ph.D. student in the laboratory of Dr. William A. Ricke at the University of Wisconsin-Madison, presented on the adverse role of cellular senescence in benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) in Medical Therapy of Prostatic Symptoms (MTOPS) study participants. Previous research demonstrated a correlation between fibrosis in the prostate transition zones and accelerated clinical progression of benign prostatic hyperplasia, particularly in patients who received a combination therapy regimen that included an α1-adrenergic receptor antagonist (doxazosin) and a 5α-reductase inhibitor (finasteride) (45). However, the underlying mechanisms remained elusive. Utilizing transition zone biopsies from MTOPS patients, Mr. Limkar identified that p16-expressing cells accumulated in patients who clinically progressed compared to those who did not. Conversely, the expression of Lamin B1, which is typically lost in senescent cells, was higher in control (non-progression) patient samples. Interestingly, patients who clinically progressed while receiving doxazosin or combination doxazosin plus finasteride had a greater burden of p16-expressing cells compared to those who did not progress. These findings suggest that senescent cells accumulate in prostate transition zones and may contribute to BPH progression and resistance to standard therapies. Future research directions involve elucidating whether senescent cells promote fibrosis and disease progression through their SASP and the utility of senescence-targeting therapeutic strategies for the prevention or management of BPH/LUTS.

Stress response and aging - leveraging resilience and beneficial stresses

One conceptualization of the aging process focuses on the (im)balance of damage accumulation due to a variety of stressors and the loss of resilience capacities resulting in impaired recovery from damage or challenges (30). Maintaining and leveraging effective stress response and resilience mechanisms, on physiological, behavioral, cellular, and molecular levels, is central to supporting healthy aging. Presentations at the Sixth Annual MAC symposium highlighted innovative approaches for uncovering tissue- and cell-specific resilience pathways and leveraging beneficial (mild or intermittent) stress across a range of model organisms to support healthy aging.

Dr. Scott F. Leiser, an associate professor at the University of Michigan, and his team investigate how different interventions, including induction of longevity-associated genes like fmo-2 in Caenorhabditis elegans, promote cellular resilience and extend lifespan (46). Interestingly, mild or intermittent stress through exercise, cold exposure, or dietary restriction have been shown to be physiologically beneficial. Dr. Leiser’s research revealed that even the perception of stress or a stressful environment can be as impactful as the stressor itself. He demonstrated that organisms perceiving an abundance of resources, even in the absence of access, such as smelling of unreachable food, exhibit benefits of mild stress responses such as those triggered by food restriction. Sensory perception, particularly smell and touch, played a vital role in modulating these responses through neurochemicals like serotonin and dopamine (47). Disrupting these sensory cues altered metabolism, behavior, and lifespan. For instance, blocking serotonin increased lifespan in flies and worms, and impairing the sense of smell in mice improved glucose tolerance and insulin sensitivity. Experimental drugs that target these pathways are under investigation for their potential to extend lifespan. In addition, interventions like dietary restriction can affect brain function increasing aggression and anxiety while reducing exploratory behavior. The Leiser laboratory found that these changes in behavior were linked to FMO-2 activity, which metabolizes tryptophan and affects kynurenine pathway neuro-signaling molecules. This finding suggests that longevity-promoting interventions often involve behavioral trade-offs, such as reduced movement or exploration. The interplay between perception, genetics, sensory input, and behavior highlights the critical roles of the external environment and internal interpretation in shaping health and longevity.

Jacinta Correia, a graduate student in Dr. Hua Bai’s laboratory at Iowa State University, presented her research on the interplay between peroxisomal dysfunction and mitochondrial homeostasis in cellular senescence. Dr. Bai’s team previously demonstrated that aging impairs peroxisomal function, particularly the import of matrix proteins, which contribute to inflammation and age-associated diseases (48). Ms. Correia identified SCAF1 (Serine Arginine-Related CTD Associated Factor 1) as a key regulator in the peroxisomal stress response in HEK293 cells. Under peroxisome stress, SCAF1 expression was induced and translocated to mitochondria. Using immunoprecipitation followed by mass spectrometry, SCAF1 was found to interact with mitochondrial proteins. Interestingly, SCAF1 upregulation selectively decreased the expression of mitochondrially encoded proteins without affecting nuclear-encoded mitochondrial proteins, indicating a specific impairment of mitochondrial translation. Moreover, impairing peroxisomal import by PEX5 deletion or overexpressing SCAF1 in fibroblasts induced cellular senescence. Collectively, this work provides new insights into peroxisomal-mitochondrial communication and how peroxisomal stress impacts mitochondria homeostasis to promote cellular senescence.

Szczepan Olszewski, a graduate student in Dr. Adam R. Konopka’s laboratory at the University of Wisconsin-Madison, presented his ongoing work to determine the effect of frequent versus intermittent rapamycin treatment on skeletal muscle growth during exercise in aged mice (49). Old female C57/BL6 mice (22-month) were administered rapamycin (2 mg/kg) intermittently (once a week) or frequently (five times a week) and were subjected to progressive weighted wheel running (PoWeR) for 8 weeks. While PoWeR increased muscle mass in all three measured skeletal muscles (soleus, plantaris, flexor digitorum longus/FDL), the specific impact of rapamycin on these different muscle groups differed. In the soleus, frequent rapamycin attenuated the increase in muscle mass after PoWeR, however, only PoWeR-trained mice treated with frequent rapamycin increased type IIA myofiber cross-sectional area (CSA). In the plantaris, frequent rapamycin also attenuated muscle mass increase after PoWeR, while Type IIA myofiber was greater in PoWeR trained mice treated with vehicle or frequent rapamycin. In the FDL, frequent and intermittent rapamycin did not impact the increase in muscle mass after PoWeR. Intriguingly, there was no increase in FDL myofiber Type IIA CSA in any group. Overall, Mr. Olszewski’s results identify a discrepancy between muscle mass and myofiber CSA and indicate that, contrary to the current dogma, rapamycin does not attenuate the increase in myofiber size after a translational model of exercise training. These findings suggest that the impact of rapamycin on muscle is dose-dependent and muscle-specific and that muscle mass changes after PoWeR may be related to other exercise adaptations beyond myofiber size, including but not limited to accumulation of lipids, glycogen, extracellular matrix, or protein aggregates.

Dr. Kenneth L. Seldeen, an associate professor at the University of Kansas, presented his work on the age-associated decline in physiological stress resilience that contributes to frailty and functional decline in older adults. Dr. Seldeen examined differences in resilience between young and old C57BL6 mice in response to various stressors: anesthesia, thermal stress (heat and cold), chemical stimulus (capsaicin), and exercise-induced muscle injury (downhill treadmill running). Loss of consciousness time following anesthesia was similar across ages, but older mice demonstrated a significantly delayed recovery. Aged mice showed decreased tolerance to heat stress compared to young controls, whereas cold exposure revealed no significant differences between age groups. Capsaicin-induced reduction in activity was similar across age groups; however, older mice exhibited a bimodal response with a subset displaying high resilience and others displaying markedly reduced responsiveness. No differences were detected between age groups in the downhill treadmill running test. Using the test outcomes, Dr. Seldeen’s team developed a composite resilience index that showed significantly lower scores in aged mice. This resilience index positively correlated with cardiovascular function as measured by VO₂ max. Notably, young and older mice with higher stress resilience showed higher levels of mitochondrial complexes I and V in skeletal muscle tissue. These findings indicate that older mice have reduced physical resilience to selective stressors such as heat and anesthesia, likely due to alterations in mitochondrial complexes.

Poster teaser talks

Ten researchers presented a snapshot of their research and invited further discussions during their poster presentations. Their research spanned the entire spectrum of topics discussed in this report and included cutting-edge technologies, discovery science approaches, and translational research.

Dr. Anthony B. Lagnado, an assistant professor and research scientist in Dr. João F. Passos’ laboratory at the Mayo Clinic Minnesota, presented Senoquant, an Artificial Intelligence-powered tool that he developed to facilitate the detection and quantification of senescence markers in images of a variety of sample types.

Dr. Lorena Rosas, a postdoctoral scholar in the laboratory of Drs. Ana L. Mora and Mauricio Rojas at The Ohio State University, demonstrated the utility of spatial mapping of proteomic changes in IPF.

Michael E. Todhunter, co-founder and Chief Scientific Officer of the biotechnology start-up Dragonase, presented on a new technology to rejuvenated hematopoietic stem cells.

Dr. Niels C. Asmussen, a postdoctoral fellow in the laboratory of Dr. Marissa J. Schafer at the Mayo Clinic Minnesota, presented on novel plasma biomarkers of cognitive decline in AD and mild cognitive impairment.

Maria Ford, a graduate student in the laboratory of Dr. Rodney D. Britt Jr. at The Ohio State University, presented on airway hyperresponsiveness in chronically allergen challenged mice.

Dr. Ana Catarina Franco, a postdoctoral fellow in Dr. Joao F. Passos’ laboratory at the Mayo Clinic Minnesota, demonstrated that transplanting senescent fibroblasts into the skin of young mice induced systemic aging phenotypes.

Mahima Devarajan, a graduate student in Dr. Douglas G. Mashek’s laboratory at the University of Minnesota, highlighted the potential therapeutic role of ATGL-induced lipolysis to DNA repair and genomic stability.

Dr. Seung-Hwa Woo, a postdoctoral fellow in the laboratory of Dr. João F. Passos at the Mayo Clinic Minnesota, presented a novel mouse model to induce telomere-specific DNA damage that causes systemic aging and age-related pathologies.

Dr. Matthew D. Bruss, a scientist in the laboratory of Dr. Adam R. Konopka at the University of Wisconsin-Madison, presented on the mitochondrial effects of metformin on skeletal muscle metabolism and exercise adaptation in mice (50).

Dr. Chase M. Carver, an assistant professor and principal research technologist in Dr. Marissa J. Schafer’s laboratory at the Mayo Clinic Minnesota, outlined how spatial transcript- and proteomic methods can be leveraged to identify age-sensitive, functionally relevant cell types in the murine brain.

CONCLUSION

The Sixth Annual MAC Research Symposium brought together a vibrant and growing network of researchers to share and discuss advances in the biology of aging, geroscience, and age-related diseases. The record number of attendees and abstract submissions reflect the expanding impact of the MAC in the Midwest and beyond. As in previous years, the meeting provided an engaging and supportive platform for trainees and early career investigators to share their research and build important connections across institutions invested in aging research. The symposium emphasized the importance of interdisciplinary collaboration and technological innovation to advance basic and translational aging research. Researchers introduced new concepts, as well as advancements in established approaches in the therapeutic development for age-related pathologies, including dietary interventions, small molecule drugs, and biologics. The integration of high-dimensional datasets such as spatial transcriptomics, proteomics, and multi-omics illustrated the field’s growing emphasis on cellular context, tissue microenvironments, and precision targeting of aging mechanisms. Collectively, the gathering emphasized the critical importance of integrating basic and translational research to discover aging mechanisms and develop safe and effective therapeutics to support health and function across the lifespan.