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Aging is the main risk factor for many chronic degenerative diseases and cancer. Increased senescent cell burden in various tissues is a major contributor to aging and age-related diseases. Recently, a new class of drugs termed senolytics were demonstrated to extending healthspan, reducing frailty and improving stem cell function in multiple murine models of aging. To identify novel and more optimal senotherapeutic drugs and combinations, we established a senescence associated β-galactosidase assay as a screening platform to rapidly identify drugs that specifically affect senescent cells. We used primary Ercc1 −/− murine embryonic fibroblasts with reduced DNA repair capacity, which senesce rapidly if grown at atmospheric oxygen. This platform was used to screen a small library of compounds that regulate autophagy, identifying two inhibitors of the HSP90 chaperone family as having significant senolytic activity in mouse and human cells. Treatment of Ercc1 −/∆ mice, a mouse model of a human progeroid syndrome, with the HSP90 inhibitor 17-DMAG extended healthspan, delayed the onset of several age-related symptoms and reduced p16 INK4a expression. These results demonstrate the utility of our screening platform to identify senotherapeutic agents as well as identified HSP90 inhibitors as a promising new class of senolytic drugs. The accumulation of senescent cells is thought to contribute to the age-associated decline in tissue function. Here, the authors identify HSP90 inhibitors as a new class of senolytic compounds in an in vitro screening and show that administration of a HSP90 inhibitor reduces age-related symptoms in progeroid mice.

Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by interstitial remodelling, leading to compromised lung function. Cellular senescence markers are detectable within IPF lung tissue and senescent cell deletion rejuvenates pulmonary health in aged mice. Whether and how senescent cells regulate IPF or if their removal may be an efficacious intervention strategy is unknown. Here we demonstrate elevated abundance of senescence biomarkers in IPF lung, with p16 expression increasing with disease severity. We show that the secretome of senescent fibroblasts, which are selectively killed by a senolytic cocktail, dasatinib plus quercetin (DQ), is fibrogenic. Leveraging the bleomycin-injury IPF model, we demonstrate that early-intervention suicide-gene-mediated senescent cell ablation improves pulmonary function and physical health, although lung fibrosis is visibly unaltered. DQ treatment replicates benefits of transgenic clearance. Thus, our findings establish that fibrotic lung disease is mediated, in part, by senescent cells, which can be targeted to improve health and function. Removal of senescent cells rejuvenates lungs of aged mice. Here the authors show that elimination of senescent cells using either genetic or pharmacological means improves lung function and physical health in a mouse model of idiopathic pulmonary fibrosis (IPF), suggesting potential therapy for treatment of human IPF.

Aging drives progressive loss of the ability of tissues to recover from stress, partly through loss of somatic stem cell function and increased senescent burden. We demonstrate that bone marrow‐derived mesenchymal stem cells (BM‐MSCs) rapidly senescence and become dysfunctional in culture. Injection of BM‐MSCs from young mice prolonged life span and health span, and conditioned media (CM) from young BM‐MSCs rescued the function of aged stem cells and senescent fibroblasts. Extracellular vesicles (EVs) from young BM‐MSC CM extended life span of Ercc1−/− mice similarly to injection of young BM‐MSCs. Finally, treatment with EVs from MSCs generated from human ES cells reduced senescence in culture and in vivo, and improved health span. Thus, MSC EVs represent an effective and safe approach for conferring the therapeutic effects of adult stem cells, avoiding the risks of tumor development and donor cell rejection. These results demonstrate that MSC‐derived EVs are highly effective senotherapeutics, slowing the progression of aging, and diseases driven by cellular senescence. Extracellular vesicles from young bone marrow‐derived mesenchymal stem cells (MSC) reduce markers of senescence in vitro. EVs derived from MSCs generated from human embryonic stem cells reduced expression of senescence markers in culture and in vivo in accelerated and naturally aged mice and improved measures of healthspan. This work demonstrates the senotherapeutic potential of extracellular vesicles in suppressing senescence‐driven age related disease.

Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly 1 , 2 . To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1 , which encodes a crucial DNA repair protein 3 , 4 , in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence 5 – 7 in the immune system only. We show that Vav-iCre +/− ;Ercc1 −/fl mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice 8 – 10 . Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre +/− ;Ercc1 −/fl or aged wild-type mice into young mice induced senescence in trans , whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre +/− ;Ercc1 −/fl mice with rapamycin reduced markers of senescence in immune cells and improved immune function 11 , 12 . These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing. An aged, senescent immune system has a causal role in driving systemic ageing, and the targeting of senescent immune cells with senolytic drugs has the potential to suppress morbidities associated with old age.

A new species of the augochlorine bee genus Chlerogelloides is described and figured as Chlerogelloides simplex sp. nov. The discovery of a second species has led to a slight modification of the generic concept. While several autapomorphic characters for the previously monotypic genus can now be considered as synapomorphies, two characters are here recognized as autapomorphic for the type species, C. femoralis. A new generic diagnosis is provided and key to the species given.

L read the two letters from the animal activists condemning the proposed Connecticut horse park and exhibition center as a project promoting vandalism and abuse of horses [April 4 \"An equestrian center would be inhumane\"]

I read die two letters from the animal activists condemning the proposed Connecticut horse park and exhibition center as a project promoting vandalism and abuse of horses [April 4 \"An equestrian center would be inhumane\"]

The female sweat bee Halictus (Seladonia) hesperus lines her nest entrance with a whitish material which originates in large part from her Dufour's gland and possibly from the salivary glands. The lining is formed from the same macrocyclic lactones and alkanes that together compose 88% of the total female's Dufour's gland extract. A possible function of the nest entrance lining is to reinforce the walls of loose excavated tumulus.

Nests of Tetralonia lepida from Oklahoma are described. The nests, probably second nests of each female, are similar to those of the Palearctic T. lanuginosa. Nests of only one other North American Tetralonia have been described.

Regulatory Encounters reports on a path-breaking study of how government regulation of business in the United States differs in practice from regulation in other economically advanced democracies. In each of ten in-depth case studies, the contributors to this volume compare a particular multinational corporation's experience with parallel regulatory regimes in the United States and in Japan, Canada, Great Britain, Germany, The Netherlands, and the European Union, noting precisely which regulatory precautions were actually implemented in each country. The regulatory systems analyzed include aspects of environmental protection, product safety, debt collection, employees' rights, and patent protection. The studies in Regulatory Encounters indicate that the adversarial and legalistic character of American regulation imposes higher costs and delays on economic activity than comparable regulatory regimes in other economically advanced democracies, and often does not generate higher levels of protection for the public.