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Cells subjected to treatment with anti-cancer therapies can evade apoptosis through cellular senescence. Persistent senescent tumor cells remain metabolically active, possess a secretory phenotype, and can promote tumor proliferation and metastatic dissemination. Removal of senescent tumor cells (senolytic therapy) has therefore emerged as a promising therapeutic strategy. Here, using single-cell RNA-sequencing, we find that senescent tumor cells rely on the anti-apoptotic gene Mcl-1 for their survival. Mcl-1 is upregulated in senescent tumor cells, including cells expressing low levels of Bcl-2, an established target for senolytic therapy. While treatment with the Bcl-2 inhibitor Navitoclax results in the reduction of metastases in tumor bearing mice, treatment with the Mcl-1 inhibitor S63845 leads to complete elimination of senescent tumor cells and metastases. These findings provide insights on the mechanism by which senescent tumor cells survive and reveal a vulnerability that can be exploited for cancer therapy. Cell senescence remains a barrier to tumor elimination in many cancers. Here, the authors use single cell RNA-seq to identify a role for Mcl-1 in senescent cell survival, and show that Mcl-1 inhibition may be an effective therapeutic strategy.

Androgen deprivation therapy (ADT) is a standard therapy for prostate cancer (PCa). Though disseminated disease is initially sensitive to ADT, an important fraction of the patients progresses to castration-resistant prostate cancer (CRPC). For this reason, the identification of novel effective therapies for treating CRPC is needed. Immunotherapeutic strategies focused on macrophages as antitumor effectors, directly enhancing their tumoricidal potential at the tumor microenvironment or their adoptive transfer after ex vivo activation, have arisen as promising therapies in several cancer types. Despite several approaches centered on the activation of tumor-associated macrophages (TAMs) in PCa are under investigation, to date there is no evidence of clinical benefit in patients. In addition, the evidence of the effectiveness of macrophage adoptive transfer on PCa is poor. Here we find that VSSP, an immunomodulator of the myeloid system, decreases TAMs and inhibits prostatic tumor growth when administered to castrated Pten-deficient prostate tumor-bearing mice. In mice bearing castration-resistant Pten pc−/− ; Trp53 pc−/− tumors, VSSP administration showed no effect. Nevertheless, adoptive transfer of macrophages activated ex vivo with VSSP inhibited Pten pc−/− ; Trp53 pc−/− tumor growth through reduction of angiogenesis and tumor cell proliferation and induction of senescence. Taken together, our results highlight the rationale of exploiting macrophage functional programming as a promising strategy for CRPC therapy, with particular emphasis on ex vivo-activated proinflammatory macrophage adoptive transfer. Graphical abstract 5rwXuKXp78386xwRRkt56h Video abstract

The human body hosts a complex and dynamic population of trillions of microorganisms — the microbiota — which influences the body in homeostasis and disease, including cancer. Several epidemiological studies have associated specific urinary and gut microbial species with increased risk of prostate cancer; however, causal mechanistic data remain elusive. Studies have associated bacterial generation of genotoxins with the occurrence of TMPRSS2–ERG gene fusions, a common, early oncogenic event during prostate carcinogenesis. A subsequent study demonstrated the role of the gut microbiota in prostate cancer endocrine resistance, which occurs, at least partially, through the generation of androgenic steroids fuelling oncogenic signalling via the androgen receptor. These studies present mechanistic evidence of how the host microbiota might be implicated in prostate carcinogenesis and tumour progression. Importantly, these findings also reveal potential avenues for the detection and treatment of prostate cancer through the profiling and modulation of the host microbiota. The latter could involve approaches such as the use of faecal microbiota transplantation, prebiotics, probiotics, postbiotics or antibiotics, which can be used independently or combined with existing treatments to reverse therapeutic resistance and improve clinical outcomes in patients with prostate cancer.The microbiota influences the body in homeostasis and disease, including cancer, and, although specific urinary and gut microbial species have been associated with an increased risk of prostate cancer, causal mechanistic data remain elusive. In this Perspective article, the authors discuss the roles of the microbiota in prostate carcinogenesis and progression, and consider how these might be leveraged for diagnosis and treatment of the disease.

Accumulating senescent cells within tissues contribute to the progression of aging and age-related diseases. Botanical extracts, rich in phytoconstituents, present a useful resource for discovering therapies that could target senescence and thus improve healthspan. Here, we show that daily oral administration of a standardized extract of Salvia haenkei (Haenkenium (HK)) extended lifespan and healthspan of naturally aged mice. HK treatment inhibited age-induced inflammation, fibrosis and senescence markers across several tissues, as well as increased muscle strength and fur thickness compared with age-matched controls. We also found that HK treatment reduced acutely induced senescence by the chemotherapeutic agent doxorubicin, using p16 LUC reporter mice. We profiled the constituent components of HK by mass spectrometry, and identified luteolin—the most concentrated flavonoid in HK—as a senomorphic compound. Mechanistically, by performing surface plasmon resonance and in situ proximity ligation assay, we found that luteolin disrupted the p16–CDK6 interaction. This work demonstrates that administration of HK promotes longevity in mice, possibly by modulating cellular senescence and by disrupting the p16–CDK6 interaction.

Cancer is highly infiltrated by myeloid-derived suppressor cells (MDSCs). Currently available immunotherapies do not completely eradicate MDSCs. Through a genome-wide analysis of the translatome of prostate cancers driven by different genetic alterations, we demonstrate that prostate cancer rewires its secretome at the translational level to recruit MDSCs. Among different secreted proteins released by prostate tumor cells, we identified Hgf, Spp1 and Bgn as the key factors that regulate MDSC migration. Mechanistically, we found that the coordinated loss of Pdcd4 and activation of the MNK/eIF4E pathways regulate the mRNAs translation of Hgf, Spp1 and Bgn. MDSC infiltration and tumor growth were dampened in prostate cancer treated with the MNK1/2 inhibitor eFT508 and/or the AKT inhibitor ipatasertib, either alone or in combination with a clinically available MDSC-targeting immunotherapy. This work provides a therapeutic strategy that combines translation inhibition with available immunotherapies to restore immune surveillance in prostate cancer.

Vascular senescence is a key contributor to ageing-related diseases, including atherosclerosis. Initial intervention is based on aggressive management of traditional risk factors, yet microbial metabolites remain underestimated as modifiable factors. We recently identified phenylacetate (PAA), a gut microbiota-linked metabolite, as a potent accelerator of endothelial senescence, raising the question of its causal role in atherosclerosis. Here, we show that PAA promotes vascular niche senescence and perivascular adipose tissue (PVAT) dysfunction, associated with atherosclerosis in humans and mice. Furthermore, PAA administration to atherosclerosis-prone mice was sufficient to drive atherosclerosis without altering lipid profile. Mechanistically, we found that PAA induces senescence-messaging secretome, containing IL6, from endothelial cells, which stimulates Notch1 and disrupts insulin signaling in adipocytes. Blocking the PAA-IL6-Notch1 axis as well as senolytics rescued adipocyte senescence and dysfunction. Identification of the strong link between PAA and atherosclerosis opens new avenues for microbiome-targeted preventive and therapeutic strategies in ageing.Competing Interest StatementThe authors have declared no competing interest.Funder Information DeclaredSwiss National Science Foundation, https://ror.org/00yjd3n13, 229134Iten Kohaut Foundation, 2512Novartis Foundation for Medical-Biological Research, 21A053SwissLife Jubiläumsstiftung, 1565, 1438, 1563International Atherosclerosis SocietyWellcome Trust, https://ror.org/029chgv08, 212904/Z/18/ZBritish Heart Foundation, MR/M016560/1UK Research and Innovation, https://ror.org/001aqnf71, MR/W026813/1 and MR/Y010175

There is currently a debate about the timing and drivers of former glacier behaviour and climate change in the tropical Andes. Using 10 Be dating we determined the ages of 21 boulders on moraines in the Santa Cruz Valley, Peru (∼10°S, altitudes ~ 4100 to ~ 4300 m a.s.l.). Former glacier extent is marked by a suite of nested outer lateral and terminal moraines. These moraines are dated to 11.1 ka, 11.6 ka, 11.8 ka and 12.0 ka, falling within the Younger Dryas Chronozone (YDC; ∼12.9–11.6 ka). Nine 10 Be samples from the Lake Arhuaycocha catchment document a period of glacier thinning and lateral contraction between 12.0 ka and 11.8 ka. Reconstructed glacier Equilibrium Line Altitudes (ELA) at 11.0 to 12.0 ka with an area–altitude balance ratio (AABR) of 1.00-2.50 are between 4675 and 4835 m a.s.l. for the Arhuaycocha glacier, between 4692 and 4832 m a.s.l. for the Taullicocha glacier and between 4800 and 4940 m a.s.l. for the Artizon glacier. These values represent a depression of 300–400 m in elevation compared to contemporary values for the ELA. We infer that the glacier advances at this time were driven by increased precipitation and that these changes were most likely a response to seasonal changes in the position of the ITCZ.

High-latitude or high-altitude caves often preserve ice deposits that contain valuable signals of past climate conditions, sometimes even reflecting regional and local atmospheric variability. Phases of aggradation or degradation of underground ice can also provide insights into the temporal evolution of Alpine permafrost. Such data are typically obtained from ice cores, which require a well-constrained chronological framework to be meaningful. In recent years, several dating methods have been developed or refined for glacier and ice sheet cores. However, some of these techniques have not yet been applied to cave ice. In this study, the 39Ar dating technique using Argon Trap Trace Analysis is applied for the first time to an underground ice deposit in the southeastern Alps, specifically in the Canin-Kanin massif (Julian Alps). The results are compared with pollen markers extracted from the ice, with U-Th dating of cryogenic cave carbonates found in situ within the same ice block, and with radiocarbon (14C) dating of the water-insoluble organic carbon fraction embedded in the ice. This integrated approach enabled dating the ice deposit to the end of the Little Ice Age, at the onset of the subsequent warming phase.

Both proxies and models provide key resources to explore how palaeoenvironmental changes may have impacted diverse biotic communities and cultural processes. While proxies are thought to provide the “gold standard” in reconstructing the local environment, they only provide point estimates for a limited number of locations. On the other hand, models have the potential to afford more extensive and standardized geographic coverage of multiple bioclimatic variables. A key decision when using model output is the appropriate geographic resolution to adopt; models are coarse scale, in the order of several arc degrees, and so their outputs are usually downscaled to a higher resolution. Most publicly available model time series have been downscaled to 30 or 60 arcmin, but it is unclear whether such resolution is sufficient for certain applications like species distribution models or whether this may homogenize environments and mask the spatial variability that is often the primary subject of analysis. Here, we explore the impact of increasing the resolution of model output from 30 to 5 arcmin using the delta-downscaling method, which interpolates and applies the long-term difference between past and present model datasets to a higher-resolution grid of observed present-day climate. We seek to determine to what extent further downscaling captures climatic trends at the site level through direct comparison with proxy reconstructions, evaluating different versions of the output from the HadCM3 Global Circulation model for annual temperature, mean temperature of July, and annual precipitation against a large empirical dataset of pollen-based reconstructions from across the Northern Hemisphere. Our results demonstrate that models tend to provide broadly similar accounts of past climate to that obtained from proxy reconstructions, with coherence tending to decline with age and at higher altitudes. However, our results imply that using the delta method to downscale to a very fine resolution has a minimal net effect on the coherence of model output with pollen records in most cases. Optimal spatial resolution is therefore likely to be highly dependent on specific research contexts and questions, with careful consideration required regarding the trade-off between highlighting local-scale variations and increasing potential error via unreliable interpolation.