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A central process contributing to the phenotype of aging is cellular senescence. We recently identified the FOXO4 – p53 axis as pivotal in maintaining the viability of senescent cells, and that senescent cells can be targeted selectively with the senolytic peptide FOXO4-DRI. Here, we solve the solution NMR structural models of the p53 transactivation domain in complex with the FOXO4 forkhead domain and in complex with FOXO4-DRI. Strikingly, we find that the disordered FOXO4-DRI binds to the disordered p53 TAD2 and forms a transiently folded complex. In this complex, both, the FOXO4-derived region and the cationic cell permeability peptide contribute to the interaction. Furthermore, we show that p53 phosphorylation enhances the affinity for both FOXO4 and FOXO4-DRI. Summarizing we provide a detailed characterization of the interaction of p53 with FOXO4 and FOXO4-DRI which is the basis for development of p53 inhibitors to treat diseases linked to cellular senescence such as cancers. Cellular senescence drives aging, with the p53–FOXO4 axis sustaining senescent cell viability. This study reveals structural insights into p53 binding to FOXO4/FOXO4-DRI, informing the development of p53-targeted senolytics for age related diseases.

Background Grip strength is a key functional marker of musculoskeletal aging, widely used to assess sarcopenia. In preclinical research, multiple measurement methods are often combined to enhance reliability, but standardization remains challenging. To improve measurement robustness, we previously developed a composite strength score (SS5) that integrates five different grip strength tests into a single variable. While SS5 provides a comprehensive evaluation, its implementation is time‐consuming, limiting feasibility in large‐scale studies. In this study, we also examine two simplified composite scores, SS2 and SS3, as potential streamlined alternatives. Additionally, although normalizing grip strength to body weight is widely used, its appropriateness in geriatric mouse models has never been formally validated. Methods Forelimb grip strength was assessed in a cohort of 160‐aged C57BL/6J mice using five methods: Weight Lift Tests (Deacon protocol with sponge weights and a modified version with metal wire weights), the Cage Lift Test and the Grip Strength Meter (trapeze bar and grid). Additionally, a cross‐sectional group of 173 mice was analysed to assess the correlation between grip strength and muscle size. Each method was evaluated for its correlation with age, ability to detect sex differences, variability and association with muscle size. Results All methods strongly correlated with age (−0.518 ≤ rs ≤ −0.306). The Grip Strength Meter (trapeze bar) and modified Deacon method were the most effective in detecting sex differences (p < 0.001). While all methods correlated with muscle size (0.153 ≤ rs ≤ 0.332), the modified Deacon method and Grip Strength Meter showed the strongest associations. The mean coefficient of variation (CV%) ranged from 7% to 17%, demonstrating good repeatability. Notably, despite being widely used, normalization of grip strength to body weight was found to introduce bias in geriatric mice, as age‐related weight loss distorts strength assessments. Absolute values proved to be a more reliable measure. To improve efficiency while maintaining reliability, we developed two new composite scores (SS2 and SS3) by integrating a subset of methods from SS5. These scores preserved the strong correlation with age observed in SS5 while reducing the number of required tests, enhancing feasibility. Conclusions Combining multiple grip strength assessments improves measurement reliability in aging studies. The newly proposed SS2 and SS3 scores provide a streamlined yet robust alternative to SS5, improving standardization and facilitating future comparisons in preclinical sarcopenia research. Our findings also challenge the routine normalization of grip strength to body weight in geriatric mice, emphasizing the importance of using absolute values to avoid bias.

The Forkhead box O (FOXO) class of transcription factors are involved in the regulation of several cellular responses including cell cycle progression and apoptosis. Furthermore, in model organisms FOXOs act as tumor suppressors and affect aging. Previously, we noted that FOXOs and p53 are remarkably similar within their spectrum of regulatory proteins. For example, the de-ubiquitinating enzyme USP7 removes ubiquitin from both FOXO and p53. However, Skp2 has been identified as E3 ligase for FOXO1, whereas Mdm2 is the prime E3 ligase for p53. Here we provide evidence that Mdm2 acts as an E3 ligase for FOXO as well. In vitro incubation of Mdm2 and FOXO results in ATP-dependent (multi)mono-ubiquitination of FOXO similar to p53. Furthermore, in vivo co-expression of Mdm2 and FOXO induces FOXO mono-ubiquitination and consistent with this result, siRNA-mediated depletion of Mdm2 inhibits mono-ubiquitination of FOXO induced by hydrogen peroxide. Regulation of FOXO ubiquitination by Mdm2 is likely to be direct since Mdm2 and FOXO co-immunoprecipitate. In addition, Mdm2-mediated ubiquitination regulates FOXO transcriptional activity. These data identify Mdm2 as a novel E3 ligase for FOXOs and extend the analogous mode of regulation between FOXO and p53.

Loss of proper T‐cell functioning is a feature of aging that increases the risk of developing chronic diseases. In aged individuals, highly differentiated T cells arise with a reduced expression of CD28 and CD27 and an increased expression of KLRG‐1 or CD57. These cells are often referred to as immunosenescent T cells but may still be highly active and contribute to autoimmunity. Another population of T cells known as exhausted T cells arises after chronic antigen stimulation and loses its effector functions, leading to a failure to combat malignancies and viral infections. A process called cellular senescence also increases during aging, and targeting this process has proven to be fruitful against a range of age‐related pathologies in animal models. Cellular senescence occurs in cells that are irreparably damaged, limiting their proliferation and typically leading to chronic secretion of pro‐inflammatory factors. To develop therapies against pathologies caused by defective T‐cell function, it is important to understand the differences and similarities between immunosenescence and cellular senescence. Here, we review the hallmarks of cellular senescence versus senescent and exhausted T cells and provide considerations for the development of specific therapies against age‐related diseases. This review delineates the molecular hallmarks of cellular senescence and examines whether they are evident in aging‐associated T cells referred to as immunosenescent T cells and exhausted T cells.

Cellular damage invoked by reactive oxygen species plays a key role in the pathobiology of cancer and aging. Forkhead box class O (FoxO) transcription factors are involved in various cellular processes including cell cycle regulation, apoptosis and resistance to reactive oxygen species, and studies in animal models have shown that these transcription factors are of vital importance in tumor suppression, stem cell maintenance and lifespan extension. Here we report that the activity of FoxO in human cells is directly regulated by the cellular redox state through a unique mechanism in signal transduction. We show that reactive oxygen species induce the formation of cysteine-thiol disulfide–dependent complexes of FoxO and the p300/CBP acetyltransferase, and that modulation of FoxO biological activity by p300/CBP-mediated acetylation is fully dependent on the formation of this redox-dependent complex. These findings directly link cellular redox status to the activity of the longevity protein FoxO.

Loss of cognitive function is a significant challenge in aging, and developing models to understand and target cognitive decline is crucial for the development of Geroscience‐based interventions. Aged mice offer a valuable model as they share features of cognitive decline with humans. Despite numerous studies, knowledge of longitudinal age‐related cognitive changes and cognitive frailty in naturally aging mice is limited, particularly in cohorts exceeding 30 months of age, where cognitive decline is more pronounced. Moreover, the impaired physical function of aged mice is known to affect latency‐based strategies to measure cognitive performances. Here, we show a comprehensive longitudinal assessment using the Barnes Maze test in a large cohort of 424 aged (≥ 21 months) C57BL/6J mice. We introduced a new metric, the Cognitive Frailty Index (CoFI), which summarizes different age‐associated Barnes Maze parameters into a unique function. CoFI strongly associates with advancing age and mortality, offering a reliable ability to discriminate long‐ and short‐lived mice. We also established a CoFI cut‐off and a physically adjusted CoFI, both of which can distinguish between physical and cognitive frailty. This is further supported by the enhanced predictive power when physical and cognitive frailty are combined to assess short‐term mortality. Moreover, the computation method for CoFI is adaptable to various cognitive assessment tests, leveraging procedures akin to those used for calculating other frailty indices. In conclusion, through robust longitudinal tracking, CoFI has the potential to become an important ally in assessing the effectiveness of Geroscience‐based interventions to counteract age‐related cognitive impairment. Our study presents a groundbreaking longitudinal assessment of age‐related cognitive decline in a large cohort of aged mice. Through the development of the Cognitive Frailty Index (CoFI), we introduce a robust metric that correlates strongly with advancing age and mortality. Importantly, CoFI and physical frailty are distinct entities, with CoFI offering a new tool to assess cognitive impairment independently from physical decline. This adaptable tool will be valuable for testing the efficacy of innovative interventions in the field of Geroscience.

Senescence, the irreversible cell cycle arrest of damaged cells, is accompanied by a deleterious pro-inflammatory senescence-associated secretory phenotype (SASP). Senescence and the SASP are major factors in aging, cancer, and degenerative diseases, and interfere with the expansion of adult cells in vitro, yet little is known about how to counteract their induction and deleterious effects. Paracrine signals are increasingly recognized as important senescence triggers and understanding their regulation and mode of action may provide novel opportunities to reduce senescence-induced inflammation and improve cell-based therapies. Here, we show that the signalling protein WNT3A counteracts the induction of paracrine senescence in cultured human adult mesenchymal stem cells (MSCs). We find that entry into senescence in a small subpopulation of MSCs triggers a secretome that causes a feed-forward signalling cascade that with increasing speed induces healthy cells into senescence. WNT signals interrupt this cascade by repressing cytokines that mediate this induction of senescence. Inhibition of those mediators by interference with NF-κB or interleukin 6 signalling reduced paracrine senescence in absence of WNT3A and promoted the expansion of MSCs. Our work reveals how WNT signals can antagonize senescence and has relevance not only for expansion of adult cells but can also provide new insights into senescence-associated inflammatory and degenerative diseases.

With a dismally low median survival of less than two years after diagnosis, Glioblastoma (GBM) is the most lethal type of brain cancer. The standard-of-care of surgical resection, followed by DNA-damaging chemo-/radiotherapy, is often non-curative. In part, this is because individual cells close to the resection border remain alive and eventually undergo renewed proliferation. These residual, therapy-resistant cells lead to rapid recurrence, against which no effective treatment exists to date. Thus, new experimental approaches need to be developed against residual disease to prevent GBM survival and recurrence. Cellular senescence is an attractive area for the development of such new approaches. Senescence can occur in healthy cells when they are irreparably damaged. Senescent cells develop a chronic secretory phenotype that is generally considered pro-tumorigenic and pro-migratory. Age is a negative prognostic factor for GBM stage, and, with age, senescence steadily increases. Moreover, chemo-/radiotherapy can provide an additional increase in senescence close to the tumor. In light of this, we will review the importance of senescence in the tumor-supportive brain parenchyma, focusing on the invasion and growth of GBM in residual disease. We will propose a future direction on the application of anti-senescence therapies against recurrent GBM.

The introduction of rapid exome sequencing (rES) for critically ill neonates admitted to the neonatal intensive care unit has made it possible to impact clinical decision-making. Unbiased prospective studies to quantify the impact of rES over routine genetic testing are, however, scarce. We performed a clinical utility study to compare rES to conventional genetic diagnostic workup for critically ill neonates with suspected genetic disorders. In a multicenter prospective parallel cohort study involving five Dutch NICUs, we performed rES in parallel to routine genetic testing for 60 neonates with a suspected genetic disorder and monitored diagnostic yield and the time to diagnosis. To assess the economic impact of rES, healthcare resource use was collected for all neonates. rES detected more conclusive genetic diagnoses than routine genetic testing (20% vs. 10%, respectively), in a significantly shorter time to diagnosis (15 days (95% CI 10–20) vs. 59 days (95% CI 23–98, p  < 0.001)). Moreover, rES reduced genetic diagnostic costs by 1.5% (€85 per neonate). Conclusion : Our findings demonstrate the clinical utility of rES for critically ill neonates based on increased diagnostic yield, shorter time to diagnosis, and net healthcare savings. Our observations warrant the widespread implementation of rES as first-tier genetic test in critically ill neonates with disorders of suspected genetic origin. What is Known: • Rapid exome sequencing (rES) enables diagnosing rare genetic disorders in a fast and reliable manner, but retrospective studies with neonates admitted to the neonatal intensive care unit (NICU) indicated that genetic disorders are likely underdiagnosed as rES is not routinely used. • Scenario modeling for implementation of rES for neonates with presumed genetic disorders indicated an expected increase in costs associated with genetic testing. What is New: • This unique prospective national clinical utility study of rES in a NICU setting shows that rES obtained more and faster diagnoses than conventional genetic tests. • Implementation of rES as replacement for all other genetic tests does not increase healthcare costs but in fact leads to a reduction in healthcare costs.

PurposeProstate-specific membrane antigen radioligand therapy (PSMA-RLT) is a novel treatment for castration-resistant prostate cancer (mCRPC). While the majority of patients responds to PSMA-RLT, with 10–15% having an exceptional response, approximately 30% of patients is unresponsive to PSMA-RLT. The molecular underpinning may in part explain these varying responses. This study investigated alterations in DNA damage repair (DDR) genes in tumour biopsies and their association with response to PSMA-RLT.MethodsA predefined retrospective cohort study was performed in mCRPC patients of whom the tumours had undergone next-generation sequencing of 40 DDR genes and received Lu-177-PSMA and/or Ac-225-PSMA-RLT. The primary outcome of this study was to compare the progression free survival (PFS) after PSMA-RLT for patients with and without pathogenic DDR aberrations in their tumour. Secondary outcomes were prostate-specific antigen (PSA) response and overall survival (OS).ResultsA total of 40 patients were included of which seventeen had a tumour with a pathogenic DDR aberration (DDR+), of which eight had defects in BRCA1/2. DDR+ patients had an equal varying response to PSMA-RLT compared to those without pathological DDR anomalies (DDR-) in terms of PFS (5.9 vs. 6.4 months, respectively; HR 1.14; 95% CI 0.58-2.25; p = 0.71), ≥50% PSA response (59% vs. 65%, respectively; p = 0.75) or OS (11.1 vs. 10.7 months, respectively; HR 1.40; 95% CI: 0.68–2.91; p = 0.36).ConclusionIn this study of a selected cohort, pathogenic DDR aberrations were not associated with exceptional responsiveness to PSMA-RLT. Translational studies in larger prospective cohorts are warranted to associate DDR gene defects with differential responses to PSMA-RLT.