Cellular senescence contributes to age-related disorders including physical dysfunction, disabilities and mortality caused by tissue inflammation and damage. Senescent cells accumulate in multiple tissues with aging and at etiological sites of multiple chronic disorders. The senolytic drug combination, Dasatinib plus Quercetin (D+Q), is known to reduce senescent cell abundance in aged mice. However, the effects of long-term D+Q treatment on intestinal senescent cell and inflammatory burden and microbiome composition in aged mice remain unknown. Here, we examine the effect of D+Q on senescence (p16 Ink4a and p21 Cip1) and inflammation (Cxcl1, Il1β, Il6, Mcp1, and Tnfα) markers in small (ileum) and large (caecum and colon) intestine in aged mice (n=10) compared to age-matched placebo-treated mice (n=10). Additionally, we examine microbial composition along the intestinal tract in these mice. D+Q-treated mice show significantly lower senescent cell (p16 and p21 expression) and inflammatory (Cxcl1, Il1β, Il6, Mcp1 and Tnfα expression) burden in small and large intestine compared with control mice. Further, we find specific microbial signatures in ileal, cecal, colonic and fecal regions that are distinctly modulated by D+Q, with modulation being most prominent in small intestine. Further analyses reveal specific correlation of senescence and inflammation markers with specific microbial signatures. Together, these data demonstrate that the senolytic treatment reduces intestinal senescence and inflammation while altering specific microbiota signatures and suggest that the optimized senolytic regimens might improve health via reducing intestinal senescence, inflammation and microbial dysbiosis in older subjects.

Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer worldwide. These tumors originate from epithelial cells of the upper aerodigestive tract. HNSCC tumors in different regions can have significantly different molecular characteristics. While many microRNAs (miRNAs) have been found to be involved in the regulation of the carcinogenesis and pathogenesis of HNSCC, new HNSCC related miRNAs are still being discovered. The aim of this study was to explore potential miRNA biomarkers that can be used to diagnose HNSCC and prognose survival of HNSCC patients. For this purpose, we chose a panel of 12 miRNAs: miR-146a-5p, miR-449a, miR-126-5p, miR-34a-5p, miR-34b-5p, miR-34c-5p, miR-217-5p, miR-378c, miR-6510-3p, miR-96-5p, miR-149-5p, and miR-133a-5p. Expression of these miRNAs was measured in tumor tissue and neighboring healthy tissue collected from patients diagnosed with HNSCC (n = 79) in either the oral cavity, oropharynx, or larynx. We observed a pattern of differentially expressed miRNAs at each of these cancer locations. Our study showed that some of these miRNAs, separately or in combination, could serve as biomarkers distinguishing between healthy and tumor tissue, and their expression correlated with patients’ overall survival.

Cellular senescence, a hallmark of aging, has been implicated in the pathogenesis of many major age-related disorders, including neurodegeneration, atherosclerosis, and metabolic disease. Therefore, investigating novel methods to reduce or delay the accumulation of senescent cells during aging may attenuate age-related pathologies. microRNA-449a-5p (miR-449a) is a small, noncoding RNA down-regulated with age in normal mice but maintained in long-living growth hormone (GH)-deficient Ames Dwarf (df/df) mice. We found increased fibroadipogenic precursor cells, adipose-derived stem cells, and miR-449a levels in visceral adipose tissue of long-living df/df mice. Gene target analysis and our functional study with miR-449a-5p have revealed its potential as a serotherapeutic. Here, we test the hypothesis that miR-449a reduces cellular senescence by targeting senescence-associated genes induced in response to strong mitogenic signals and other damaging stimuli. We demonstrated that GH downregulates miR-449a expression and accelerates senescence while miR-449a upregulation using mimetics reduces senescence, primarily through targeted reduction of p16 Ink4a , p21 Cip1 , and the PI3K-mTOR signaling pathway. Our results demonstrate that miR-449a is important in modulating key signaling pathways that control cellular senescence and the progression of age-related pathologies.

The proline-rich oligopeptide from Bothrops jararaca snake venom, Bj-PRO-7a, promotes acute effects in blood pressure in hypertensive animals. However, the cardiac effects of this heptapeptide are completely unknown. Thus, we sought to evaluate whether the Bj-PRO-7a could protect against cardiac remodelling in spontaneously How to cite this article: de Jesus ÉF, Nunes ADDC, Pontes CNR, et al. Cardioprotective effects of the proline-rich oligopeptide Bj-PRO-7a in spontaneously hypertensive rats.