bims-cesemi 2026-04-26 papers

Nat Rev Mol Cell Biol. 2026 Apr 20.

Aging Cell. 2026 May;25(5): e70493

Diminished and Altered Cellular Senescence Response in Delayed Wound Healing of Aging.

Maria Shvedova, Rex Jeya Rajkumar Samdavid Thanapaul, Qiaoling Wang, Grace Haeun Shin, Jannat Dhillon, Daniel Sam Roh.

The transient upregulation of cellular senescence within wound tissues has been demonstrated to be an important biological process facilitating efficient tissue repair. Dysregulation of this transient wound-induced senescence response can result in impaired healing outcomes. Given the established age-related decline in tissue regenerative capacity, we hypothesized that alterations in this senescence response contribute to the delayed healing of cutaneous wounds in aged individuals. Our investigation demonstrated a significant delay in the closure of full-thickness dorsal skin wounds in aged mice compared to their young counterparts. Analysis of the wound microenvironment revealed a transient upregulation of senescence-associated markers (p16, p21, senescence-associated β-galactosidase) and senescence-associated secretory phenotype factors in the wound tissue of young mice, a response that was markedly attenuated in aged mice. Single-cell RNA sequencing analysis of all cells isolated from day 6 wounds identified a distinct population of p16+/p21+/Ki67- senescent fibroblasts in young mice, characterized by a transcriptional signature indicative of prohealing extracellular matrix production, a finding corroborated in human wound tissue from young donors. Crucially, in aged wounds, we observed a lower quantity of these senescent cells, a deficit compounded by a qualitative, age-dependent shift in their function, moving away from beneficial extracellular matrix remodeling toward a more detrimental pro-inflammatory state, which ultimately can contribute to delayed wound healing.

Keywords: SASP; aging; mice; p16; p21; senescence; wound healing

DOI: https://doi.org/10.1111/acel.70493

Geroscience. 2026 Apr 24.

Vitamin B12 improves skeletal muscle mitochondrial biology in aged mice.

Abigail R Williamson, Angad Yadav, Wenxia Ma, Susan Schmitt, Shelby Rorrer, Lauren E Odom, Luisa F Castillo, Chloe T Purello, Olga V Malysheva, James Mobley, Martha Field, Anna E Thalacker-Mercer.

Age-related skeletal muscle deterioration is a commonly reported disability among older adults, attributed to several factors including mitochondrial dysfunction, a major hallmark of aging. Therapies to attenuate or reverse mitochondrial decline are limited. Despite identified positive relationships between vitamin B12 (B12) and mitochondrial biology, the impact of B12 supplementation on skeletal muscle mitochondria, in advanced age, has not been examined. Thus, the impact of B12 supplementation on skeletal muscle mitochondrial biology was examined in aged female mice, given 12 weeks of B12 supplementation (SUPP) or vehicle control. In the mouse model, mitochondrial DNA and content were measured with PCR and citrate synthase activity, respectively; mitochondrial morphology was examined using transmission electron microscopy; mitochondrial function was examined using extracellular metabolic flux analysis; and proteins and pathway enrichment was identified with proteomics. The results demonstrated that SUPP in aged mice increased muscle mitochondrial content and improved morphology. Further, differentially expressed proteins were enriched in TCA cycle, OXPHOS, and oxidative stress pathways. This is the first study, to our knowledge, examining the impact of B12 supplementation on skeletal muscle mitochondrial biology in aged female mice. Results suggest that B12 supplementation improves mitochondrial biology in aged female mice.

Keywords: Aging; Mitochondria; Sarcopenia; Skeletal muscle; Vitamin B12

DOI: https://doi.org/10.1007/s11357-026-02264-1

Cell Rep Med. 2026 Apr 23. pii: S2666-3791(26)00187-4. [Epub ahead of print] 102770

A ketogenic diet sensitizes pancreatic cancer to glutamine metabolism inhibitors.

Pancreatic cancer is the third leading cause of cancer-related death in the United States. Current chemotherapy options provide limited benefits. Emerging evidence suggests that a ketogenic diet (KD) exerts anti-tumor effects by reprogramming tumor metabolism and revealing therapeutic vulnerabilities. Efforts to target glutamine metabolism-an essential pathway in many cancers-have shown promise in preclinical models, but clinical efficacy has remained limited. Here, we show that a KD increases tricarboxylic acid (TCA) cycle activity and elevates reliance on glutamine-related metabolites in murine pancreatic cancer models and in vitro under KD-mimicking conditions. This metabolic adaptation occurs in response to reduced glucose availability. We demonstrate that combining glutamine metabolism inhibitors, such as CB-839 or 6-diazo-5-oxo-L-norleucine (DON), with a KD leads to robust anti-tumor effects in preclinical models of pancreatic cancer. Thus, metabolic vulnerability induced by dietary intervention provides a rationale for combining glutamine-targeted therapies with a ketogenic diet in future clinical studies.

Keywords: PDAC nutrient flux; chemotherapy; combination therapy; glutamine metabolism; glutamine tracing; ketogenic diet; ketogenic diet media; pancreatic cancer; targeted therapy

DOI: https://doi.org/10.1016/j.xcrm.2026.102770