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The role of the inflammasomes in aging and progeroid syndromes remain understudied. Recently, MCC950, a NLRP3 inhibitor, was used in Zmpste24−/− mice to ameliorate the phenotypes. However, the safety of MCC950 was questioned due to liver toxicity observed in humans. Nevertheless, inhibition of the inflammasomes would be a beneficial therapy for progeria. Here, we show that OLT1177 (dapansutrile), other NLRP3 inhibitor, improved cellular and animal phenotypes using progeroid fibroblasts and a LmnaG609G/G609G mouse model. In both cases dapansutrile reduced progerin accumulation, NLRP3‐inflammasome activation and secretory phenotype of senescence, extended the lifespan of progeroid animals, preserved bodyweight, and reduced kyphosis, inflammation, and senescence. Interestingly, dapansutrile further improved the effect of lonafarnib, the only FDA‐approved drug for the progeria. The combination of both drugs reduced the inflammation and senescence, extended survival and ameliorated various progeroid defects both in vitro and in vivo, compared with treatment using lonafarnib alone. These findings and the safety of dapansutrile demonstrated in several clinical trials proposes it as a possible co‐adjuvant treatment with lonafarnid in HGPS. [ABSTRACT FROM AUTHOR]

Inflammation causes a wide range of health disorders. In this process, the formation of inflammasome complexes plays a key role. Although inflammasomes have been extensively studied during kidney disease, their role in kidney transplantation has not been fully elucidated. In this study, we evaluate the gene and protein expression of several components of the inflammasome pathway before and at several time points after kidney transplantation in a cohort of patients of different ages and receiving an organ from older or younger donors. Our findings indicate the activation of the NLRP1 inflammasome in several immune cell population, monocytes and CD4+ and CD8+ cells mainly, in renal transplant, and its level increases gradually in patients who receive an older organ, whereas it has the opposite effect on older patients who receive a younger organ. Despite treatment with immunosuppressants, inflammation persists in some patients. These results lead to the hypothesis that the donor's age is a critical factor in post-transplant inflammasome activation and that specific NLRP1 inflammasome inhibitors should be considered to increase the success of kidney transplantation long-term.  Color images are available online. [ABSTRACT FROM AUTHOR]

Renal transplantation is an effective treatment for severe chronic kidney diseases. However, young patients often face a scarcity of kidneys from donors of similar age, resulting in the transplantation of older organs, which increase the risk of graft rejection and several complications compared with older individuals who receive kidneys from donors of similar age or younger. This article focuses on studying different senescence biomarkers in donors and patients who received kidneys from various age ranges complying with the STROBE requirements. We studied 61 patients subjected to renal transplant isolating blood samples 24 h before, and 24 h, 3 days, 7 days, 3 months, and 6 months after transplant. The patients were divided into three groups: older donor than the patient (Old Donor), younger donor than the patient (Young Donor), and similar age (Matched). We studied different senescence markers such as p16, p21, interleukin 6 (IL-6), and senescence-associated secretory phenotype (SASP) release. Young patients who receive older organs showed increased mRNA and protein expression of the senescence makers. Hence, increased SASP release was also observed in patients from older donor. In contrast, older patients who receive younger organs showed a slow but consistent improvement in their initial senescent phenotype. In addition, macrophage cell model treated with blood-derived serum from patients 6 months after the transplant showed a pro-senescence environment in macrophages proposed by the SASP from the patients. These results lead the hypothesis that senolytics could reduce the presence of senescent cells and mitigate the complications associated with the transplantation of older organs in young patients. [ABSTRACT FROM AUTHOR]