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Biology subjects

Alimonti, A.

Publications and source records attributed to Alimonti, A..

4 recordsLinked to original sources

Photographic age gap is associated with frailty and predicts survival in laboratory mice

Ageing studies in mice need biomarkers that are cheap, non-invasive and repeatable. We asked how much of a mouse's age can be read from an ordinary photograph, and whether the part that cannot be explained by age carries biological information. We assembled 2,846 photographs of 1,292 mice (four strains, 1 to 34 months old) from seven facilities and predicted age with a frozen self-supervised vision model (DINOv2) and a ridge regression, always tested on facilities the model had never seen. Absolute age transferred poorly between facilities (median absolute error 138 days), because each facility's photographs carried an offset. Relative age transferred well: among mice photographed in the same session, the older mouse was predicted older in 65% of pairs, rising above 95% for age differences over 500 days, and the later photograph of the same mouse was predicted older in 63% of repeat pairs. Sex, in comparison, was inferred more reliably (87%). Mice predicted older than their age were frailer (+0.12 SD per 100 days) and had shorter survival (hazard ratio 1.14 per 100 days), and fourth generation (G4) telomerase-deficient mice looked 151 days older than their wild-type controls. Routine photographs therefore carry a real biological age signal that can be read at no extra cost, best used to compare mice photographed together.

systems biology↗

Chemogenetic Hydrogen Sulfide Rescues Vascular Senescence in Ageing

Vascular senescence is a central driver of whole-body ageing, yet rescue strategies remain limited. Here we show that hydrogen sulfide (H2S) bioavailability declines in ageing and atherosclerosis and is associated with endothelial senescence. Developing a novel remote-control, endothelial-specific, mitochondria-targeted chemogenetic system, we spatiotemporally controlled H2S generation and thereby mitigated endothelial senescence-driven programs and reversed vascular remodeling in aged mice.

cell biology↗

Gut Microbiota Production of Phenylacetate Programs Vascular Niche Senescence and Drives Atherosclerosis

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 IL-6, from endothelial cells, which stimulates Notch1 and disrupts insulin signaling in adipocytes. Blocking the PAA-IL-6-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. HighlightsO_LIAge-dependent increase in gut microbial metabolite PAA causally promotes vascular niche senescence C_LIO_LIPAA indirectly accelerates PVAT senescence through endothelial senescence-messaging secretome C_LIO_LISASP upregulates Notch1 signaling, leading to PVAT dysfunction C_LIO_LISenolytic therapy restores PVAT function C_LIO_LIPAA-induced vascular niche senescence contributes to atherosclerosis progression C_LI

cell biology↗

Mitochondrial DNA released by senescent cells triggers immunosuppression in cancer

DNA is a potent damage-associated molecular pattern signaling that, once in the extracellular space, triggers the activation of the innate immune system. Here we find that senescent cells release mtDNA to both the cytosol and the extracellular space. In cells undergoing cellular senescence, the release of mtDNA precedes that of nuclear DNA resulting in the activation of the cGAS/STING pathway and establishment of cellular senescence. Intriguingly, by exploiting co-culture and in vivo cross-species experiments, we show that extracellular mtDNA released by senescent tumors cells is specifically captured by polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in the tumor microenvironment (TME). Mechanistically we find that PMN-MDSCs uptake mtDNA to enhance their immunosuppressive ability. Pharmacological inhibition of mtDNA released from senescent tumor cells blocks the PMN-MDSCs immunosuppressive activity, improving the efficacy of therapy-induced senescence (TIS) in cancer. These results reveal the crucial role of mtDNA in initiating cellular senescence and immunosuppression independently of the SASP. Thus, targeting mtDNA release-mediated pathway may hold promise to reprogram the immune suppressive microenvironment in patients treated with chemotherapy.

cell biology↗