Citations

Abstract Cellular senescence has been implicated in the pathophysiology of radiotherapy-associated bone loss. Based on our previous work, clearance of senescent cells using genetic and pharmacological tools alleviates the anomalies associated with radiation-associated bone deterioration. The pro-inflammatory senescence associated secretome referred to as senescence associated secretory phenotype (SASP), is a hallmark of cellular senescence. The modulation of SASP by senomorphic drugs, potentially can suppress the pro-inflammatory secretome of senescent cells, irrespective of the underlying senescence mechanism. In this study we tested a senomorphic drug, ruxolitinib, a Janus kinase inhibitor (JAKi), during acute and chronic radiotherapy related effects on the bone. Our clinical data indicate an early increase in several pro-inflammatory SASP proteins following radiotherapy of spinal metastasis in prostate cancer patients. Longitudinal assessment of SASP-related genes confirmed this acute elevation in several SASP markers in systemic circulation following irradiation of male mouse femurs. In studies done in male mice, following three preclinical radiotherapy regimens of 30Gy (5 x 6Gy), 60Gy (5 x 12Gy) and a single dose of 24Gy, suppression of SASP by JAKi was efficacious in suppressing radiation-induced bone damage. In comparison and as shown before, the senolytic combination of D+Q was also able to alleviate radiation-associated bone loss. Early and intermittent suppression of SASP using JAK inhibitors in male mice alleviated chronic bone deterioration, diminished telomere dysfunction, lowered senescence and SASP marker expression and reduced bone-marrow adiposity. Overall, our study shows that early targeting of SASP proteins could be a potential therapeutic to prevent radiotherapy-related chronic bone loss and risk of fractures.

Importance and Objective: Aging is a complex biological process uniquely shaped in women by hormonal transitions, particularly across the menopause transition. While chronological age alone fails to capture individual health variability, emerging molecular biomarkers offer tools to quantify biological aging and understand mechanisms underlying age-related decline. This review synthesizes the current landscape of aging biomarkers, including senescence-associated secretory phenotype factors, epigenetic clocks, clonal hematopoiesis of indeterminate potential, and telomere length, with a particular emphasis on their relevance to menopause. Methods: This narrative review synthesizes human studies, translational research, and foundational basic science identified through PubMed searches through June 2025, examining aging biomarkers in general populations, among women in the menopause transition, and in relation to vasomotor symptoms and hormone therapy. Discussion and Conclusion: Evidence demonstrates that changes in biological aging biomarkers are observed across multiple molecular systems during midlife, including the menopause transition, reflecting broader age-related biological remodeling. Postmenopausal status, particularly following early or surgical menopause, has been associated with biological aging phenotypes, including elevated senescence-associated secretory phenotype factors, epigenetic age acceleration, clonal hematopoiesis, and shorter leukocyte telomere length, likely reflecting a combination of chronological aging, hormonal changes, and individual biological vulnerability. While severe vasomotor symptoms have been linked to higher epigenetic age, hormone therapy may favorably influence certain senescence markers and biological age discrepancy. Despite these advances, significant limitations constrain clinical translation, as current biomarkers capture overlapping biological processes and lack validated thresholds to define biological aging, especially in women. Future research requires large, longitudinal studies across diverse populations to establish clinically meaningful thresholds and sex-specific calibration. Advancing precision health strategies for women requires a better understanding of how reproductive and hormonal factors modify biomarker trajectories to improve risk prediction and to facilitate the development of targeted interventions for age-related diseases.

Abstract Frailty predicts adverse outcomes in multiple myeloma (MM), yet an objective frailty biomarker is lacking. Circulating senescence-associated secretory phenotype (SASP) factors correlate with frailty and adverse outcomes in chronic diseases, but their relevance in MM is unclear. In this study, we investigated the relationship between 36 plasma SASP factors, frailty, and clinical outcomes in: (1) a historical cohort using stored specimens from 59 patients with newly diagnosed MM, and (2) a prospective cohort of 36 patients initiating new MM treatment. Several SASP factors were significantly associated with frailty after adjusting for age, sex, and body mass index; GDF-15, TNF-RI, IL-6, and IL-8 showed positive correlations with both cumulative-deficit based and physical frailty indices. Additionally, significant age-adjusted associations were observed between SASP factors and treatment outcomes, including overall survival (OS), high-grade toxicity, and healthcare utilization. We developed a 5-factor SASP model that demonstrated superior predictive performance for OS compared to chronological age, R-ISS stage, and clinical frailty, and TNF-RI alone (5-year OS AUC: 0.90). These findings highlight the association between senescence biomarkers and frailty and OS, and support further investigation of SASP factors as objective frailty biomarkers in MM.

Abstract Cellular senescence has been implicated in the pathophysiology of radiotherapy-related bone loss. Based on our previous work, clearance of senescent cells using genetic and pharmacological tools alleviates the anomalies associated with radiation-associated bone deterioration. The pro-inflammatory senescence associated secretome referred to as senescence associated secretory phenotype (SASP), is a hallmark of cellular senescence. The modulation of SASP by senomorphic drugs, potentially can suppress the pro-inflammatory secretome of senescent cells, irrespective of the underlying senescence mechanism. In this study we tested a senomorphic drug, ruxolitinib, a Janus kinase inhibitor (JAKi), during acute and chronic radiotherapy related effects on the bone. Our clinical data indicate an early increase in several pro-inflammatory SASP proteins following radiotherapy of spinal metastasis in prostate cancer patients. Longitudinal assessment of SASP-related genes confirmed this acute elevation in several SASP markers in systemic circulation following irradiation of mouse femurs. In a proof-of-concept study, following two preclinical radiotherapy regimens of cumulative doses of 30Gy (5 x 6Gy) and 60Gy (5 x 12Gy), a senomorphic approach of JAKi treatment was more effective in alleviating radiation-related bone loss compared to the senolytic cocktail of D+Q. Early and intermittent suppression of SASP using JAK inhibitors alleviated chronic bone deterioration, diminished telomere dysfunction, lowered senescence and SASP marker expression, reduced bone-marrow adiposity, and mitigated radiation related lymphatic impairment. Overall, our study shows that early targeting of SASP proteins could be a potential therapeutic to prevent radiotherapy-related chronic bone loss and risk of fractures. Lay Summary Radiotherapy as part of cancer treatment is correlated with an acute increase in senescent cells. Here we show that the pro-inflammatory senescence associated secretory phenotype (SASP) becomes much more prominent soon after radiotherapy in both patients and mice. Suppression of the SASP using a Janus kinase inhibitor, ruxolitinib, reduced the overall senescent cell burden, improved bone architecture by promoting bone formation, reduced bone marrow adiposity, and mitigated radiation-induced lymphatic impairment. Overall, these findings suggest that early inhibition of the SASP may help mitigate several bone anomalies and prevent long-term bone loss and fractures after radiotherapy. Graphical Abstract

Abstract Multiple lines of evidence suggest that calorie restriction may slow biological processes related to aging and extend lifespan. To determine whether calorie restriction affects mitochondrial function, we treated fibroblasts from adult donors with serum samples obtained from participants of the CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) study. The CALERIE study enrolled healthy, non-obese middle-aged (average 38y.o) participants to examine the effects of long-term calorie restriction. We studied the serum samples of 177 participants (calorie restriction CR = 121, ad libitum AL = 56) who had specimens available at two timepoints (12 and 24 months). We assessed the basal and maximal mitochondrial respiration of fibroblasts treated with dilute serum for 24 hours. Our results show that the baseline basal and maximal mitochondrial respiration of fibroblasts is positively correlated with the adiposity of the serum donor (R = 0.112, P = 0.137; R = 0.183, P = 0.015, respectively). Interestingly, treatment of fibroblasts with serum collected after 12 months of calorie restriction causes a decrease in both basal and maximal mitochondrial respiration (P = 0.1854; P = 0.0623, respectively). Fibroblasts treated with serum collected after 24 months of calorie restriction exhibited a further reduction in both basal and maximal mitochondrial respiration (P = 0.0174; P = 0.0092, respectively). These findings suggest that the serum of individuals on long term calorie restriction diet comprises factors that can reduce oxidative phosphorylation. This reduction in bioenergetic capacity may align with the theory that calorie restriction leads to a cellular energy-conserving state, which could have implications for cellular aging and metabolism.

ABSTRACT Objective Aging alters mesenchymal stromal cell (MSC) function, leading to dysregulated adipogenesis across tissues through biased lineage commitment. Fat redistribution from adipose depots to skeletal muscle and bone marrow is common in aging, but the underlying mechanisms remain unclear. This study investigates how MSC senescence modulates adipogenesis. Methods Primary MSCs were isolated from mouse skeletal muscle (FAPs), adipose tissue (APCs), and bone marrow (BMSCs). Single‐cell RNA sequencing was performed to compare transcriptional profiles among these populations. In vitro adipogenic differentiation and DNA damage–induced senescence assays were conducted, and the effects of autologous conditioned media from senescent MSCs on adipogenesis were assessed. Results Transcriptional analyses revealed that FAPs and APCs share greater similarity with each other than with BMSCs. All MSC types exhibited adipogenic potential and developed a robust senescence‐associated secretory phenotype (SASP) upon senescence induction. Conditioned media from senescent MSCs enhanced adipogenesis in BMSCs but inhibited adipogenesis in FAPs and APCs, revealing tissue‐specific paracrine effects. Conclusions MSC senescence reprograms adipogenic bias in a tissue‐dependent, non–cell autonomous manner, contributing to age‐related fat redistribution among adipose tissue, skeletal muscle, and bone marrow. Understanding these mechanisms may provide new therapeutic approaches for improving tissue composition and function in the context of aging.

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 Cellular senescence is an irreversible form of cell‐cycle arrest caused by excessive stress or damage. While various biomarkers of cellular senescence have been proposed, there are currently no universal, stand‐alone indicators of this condition. The field largely relies on the combined detection of multiple biomarkers to differentiate senescent cells from non‐senescent cells. Here we introduce a new approach: unbiased cell culture selections to identify senescent cell‐specific folded DNA aptamers from vast libraries of trillions of random 80‐mer DNAs. Senescent mouse adult fibroblasts and their non‐senescent counterparts were employed for selection. We demonstrate aptamer specificity for senescent mouse cells in culture, identify a form of fibronectin as the molecular target of two selected aptamers, show increased aptamer staining in naturally aged mouse tissues, and demonstrate decreased aptamer staining when p16 expressing cells are removed in a transgenic INK‐ATTAC mouse model. This work demonstrates the value of unbiased cell‐based selections to identify new senescence‐specific DNA reagents.