Childs, Bennett G.

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.

ABSTRACT His domain protein tyrosine phosphatase (HD-PTP; also known as PTPN23) facilitates function of the endosomal sorting complexes required for transport (ESCRTs) during multivesicular body (MVB) formation. To uncover its role in physiological homeostasis, embryonic lethality caused by a complete lack of HD-PTP was bypassed through generation of hypomorphic mice expressing reduced protein, resulting in animals that are viable into adulthood. These mice exhibited marked lipodystrophy and decreased receptor-mediated signaling within white adipose tissue (WAT), involving multiple prominent pathways including RAS/MAPK, phosphoinositide 3-kinase (PI3K)/AKT and receptor tyrosine kinases (RTKs), such as EGFR. EGFR signaling was dissected in vitro to assess the nature of defective signaling, revealing decreased trans-autophosphorylation and downstream effector activation, despite normal EGF binding. This corresponds to decreased plasma membrane cholesterol and increased lysosomal cholesterol, likely resulting from defective endosomal maturation necessary for cholesterol trafficking and homeostasis. The ESCRT components Vps4 and Hrs have previously been implicated in cholesterol homeostasis; thus, these findings expand knowledge on which ESCRT subunits are involved in cholesterol homeostasis and highlight a non-canonical role for HD-PTP in signal regulation and adipose tissue homeostasis.

The accumulation of senescent cells, a hallmark phenotype of aging tissues, elevates the risk of cardiovascular disease with age. Our prior studies have illustrated a crucial role played by senescent cells in promoting coagulation during murine atherosclerosis through the senescence-associated secretory phenotype (SASP). To explore the heterogeneity of senescent vascular cells in thrombotic vascular diseases and identify potential druggable pathways to counter senescence, we utilized the senescence reporter mouse p16TdTomato+/-, which was injected with an adeno-associated virus expressing Proprotein Convertase Subtilisin/Kexin type 9 to induce atherosclerosis when subjected to a high-fat diet (HFD). In a subset of HFD mice, some were left untreated, while others were treated with senolytic drug ABT-737 to selectively eliminate senescent cells. Aortas from ABT-737-treated mice exhibited increased collagen deposition and reduced arterial stiffness. Paired with pseudo-bulk RNA-sequencing analysis, we observed that HFD-induced extracellular matrix (ECM) remodeling genes were diminished by ABT-737, suggesting that ECM-platelet interactions may be influenced by senescence. Single-cell RNA-sequencing analysis from aortas identified 28 distinct cell clusters. Utilizing Gene Set Enrichment Analysis with the SenMayo and CellAge panels, we identified four cell clusters exhibiting increased senescent features that were mitigated by ABT-737. These included two VSMC clusters, fibroblasts, and neutrophil-like cells. Unbiased subclustering of potentially senescent clusters revealed a small population of cells enriched with HFD and reduced by ABT-737, confirming their senescent nature. In the most abundant cluster, Spp1 and Serpine2 strongly represented the senescent VSMC subpopulation, enriched for TGFβ signaling, ECM remodeling, and coagulation cascade genes. Further, we validated these findings through spatial transcriptomics and single-molecule FISH of brachiocephalic arteries from atherosclerotic mice and atherosclerotic mice depleted of senescent cells. Our results reveal a novel transcriptomic signature for senescent vascular cells that holds potential for therapeutic targeting in age-related vascular diseases.

Abstract Studying cardiovascular senescence is crucial for understanding disease-related changes in the cardiovascular system and their impact on health and disease. To systematically investigate the heterogeneity of senescent vascular cells in atherosclerosis, we employed the senescence reporter mouse p16tdTomato+/-, overexpressed PCSK9 and fed a high-fat diet (HFD) to induce atherosclerosis, and treated them with the senolytic drug ABT-737. Whole-aorta, single-cell RNA-sequencing (scRNA-seq) and Gene Set Enrichment Analysis (GSEA) using the SenMayo panel uncovered 10 cell clusters displaying senescent features, although not ‘classical’ senescence markers, that were reduced by treatment with ABT-737. Unbiased subclustering revealed subsets of cells increasing by HFD and reduced by ABT-737 treatment that expressed unique transcripts Spp1, Ctsb, and Tnfrsf11b mRNAs. Spatial analysis of these RNAs identified senescent cells in the cap and core of brachiocephalic arteries from atherosclerotic mice. Our results uncover a vascular-specific transcriptomic signature that may be exploited for therapeutic targeting in age-related vascular diseases.

Significance Statement Renal artery stenosis (RAS) engenders stenotic-kidney ischemia, dysfunction, and injury, but whether these are mediated by cellular senescence has not been elucidated. INK-ATTAC transgenic mice, high-resolution imaging, and unbiased single-cell RNA sequencing of murine kidneys demonstrated cellular senescence as an important mechanism of progressive injury to epithelial/stromal cells within poststenotic kidneys. Both p16-specific and broad quercetin/dasatinib interventions to blunt senescence improved renal function and structure, underscoring the central role of senescence in the pathogenesis. Furthermore, this mechanism was conserved in human subjects with RAS. These observations reveal new mechanisms that contribute to the pathogenesis of chronic ischemic renal injury, and support the development of senolytic therapy to reduce senescent cell burden and delay renal injury. Background Peripheral vascular diseases may induce chronic ischemia and cellular injury distal to the arterial obstruction. Cellular senescence involves proliferation arrest in response to stress, which can damage neighboring cells. Renal artery stenosis (RAS) induces stenotic-kidney dysfunction and injury, but whether these arise from cellular senescenceand their temporal pattern remain unknown. Methods Chronic renal ischemia was induced in transgenic INK-ATTAC and wild type C57BL/6 mice by unilateral RAS, and kidney function ( in vivo micro-MRI) and tissue damage were assessed. Mouse healthy and stenotic kidneys were analyzed using unbiased single-cell RNA-sequencing. To demonstrate translational relevance, cellular senescence was studied in human stenotic kidneys. Results Using intraperitoneal AP20187 injections starting 1, 2, or 4 weeks after RAS, selective clearance of cells highly expressing p16 Ink4a attenuated cellular senescence and improved stenotic-kidney function; however, starting treatment immediately after RAS induction was unsuccessful. Broader clearance of senescent cells, using the oral senolytic combination dasatinib and quercetin, in C57BL/6 RAS mice was more effective in clearing cells positive for p21 ( Cdkn1a ) and alleviating renal dysfunction and damage. Unbiased, single-cell RNA sequencing in freshly dissociated cells from healthy and stenotic mouse kidneys identified stenotic-kidney epithelial cells undergoing both mesenchymal transition and senescence. As in mice, injured human stenotic kidneys exhibited cellular senescence, suggesting this process is conserved. Conclusions Maladaptive tubular cell senescence, involving upregulated p16 ( Cdkn2a ), p19 ( Cdkn2d ), and p21 ( Cdkn1a ) expression, is associated with renal dysfunction and injury in chronic ischemia. These findings support development of senolytic strategies to delay chronic ischemic renal injury.

Wreaking havoc while (growth-)arrested Cells enter a state of senescence in response to certain stresses. Studying mouse models, Childs et al. examined the role of senescent lipid-loaded macrophages (so-called “foam cells”) in the pathogenesis of atherosclerosis. At early stages of atherosclerosis, senescent foam cells promoted the expression of inflammatory cytokines. At later stages, they promoted the expression of matrix metalloproteases implicated in the rupture of atherosclerotic plaque, which can lead to blood clots. Experimental removal of the senescent cells had beneficial effects at both stages of the disease. Science , this issue p. 472

Pain in cancer therapy is a common condition and there is a need for new options in therapeutic management. While phytochemicals have been proposed as one pain management solution, knowledge of their utility is limited. The objective of this study was to perform a systematic review of the biomedical literature for the use of phytochemicals for management of cancer therapy pain in human subjects. Of an initial database search of 1,603 abstracts, 32 full-text articles were eligible for further assessment. Only 7 of these articles met all inclusion criteria for this systematic review. The average relative risk of phytochemical versus control was 1.03 [95% CI 0.59 to 2.06]. In other words (although not statistically significant), patients treated with phytochemicals were slightly more likely than patients treated with control to obtain successful management of pain in cancer therapy. We identified a lack of quality research literature on this subject and thus were unable to demonstrate a clear therapeutic benefit for either general or specific use of phytochemicals in the management of cancer pain. This lack of data is especially apparent for psychotropic phytochemicals, such as theCannabisplant (marijuana). Additional implications of our findings are also explored.