Aging
Abstract
Aging commonly causes decline of testosterone or estrogen, leading to overaccumulation of fatness in males or females, respectively. Although such phenomenon can be readily explained by estrogen’s direct action on adipocytes in females, accumulative evidence does not support the direct action of testosterone in adipocyte lipid metabolism, suggesting that there is a missing intermediary link. Herein, we propose that glycoprotein hormone β5 (GPHB5) is the intermediary linkage between testosterone and the regulation of adiposity. In clinical samples, blood levels of GPHB5 were correlated negatively with men’s ages, and positively with circulating testosterone. Testosterone directly stimulated the expression of GPHB5 in cultured cells, pharmacological blockade of androgen receptor (AR) functions abrogated such effect. Knockout of AR led to not only development of obesity but also reduction of GPHB5 expression. Genetic ablation of GPHB5 in the males, but not in the females, lowered the browning of white adipose tissue, diminished energy expenditure and caused severe obesity. Importantly, elevated blood testosterone didn’t exert its catabolic actions in GPHB5 null mice, and yet, recombinant GPHB5 protein was able to stimulate energy expenditure and reduce adiposity. Taken together, these results provided the strong proof that GPHB5 is the “missing” intermediary hormone linking testosterone (and aging) and its well-known catabolic effect on adipose tissue.
Authors
Gengmiao Xiao, Aijun Qian, Zhuo Gao, Tingting Dai, Hui Liang, Shuai Wang, Mulan Deng, Yunjing Yan, Xindan Zhang, Xuedi Zhang, Yunping Mu, Jiqiu Wang, Aibo Gao, Huijie Zhang, Fanghong Li, Allan Zijian Zhao
Abstract
Cellular senescence is a heterogeneous phenotype characterized primarily in mesenchymal cells, but the extent to which immune cells differ in their senescence phenotype, or “senotype”, is unclear. Here, we applied single-cell approaches alongside both global and cell-specific genetic senolytic mouse models to evaluate the senotype of immune cells in the bone marrow of aging mice. We found that myeloid-lineage cells exhibited the highest expression of p16 and senescence-associated secretory phenotype markers among all immune cell types. In contrast to clearance of p16+ senescent mesenchymal cells, targeted clearance of p16+ myeloid cells in aged mice only had minor effects on age-related bone loss in male mice, with no effects in females. In more detailed analyses, p16+ myeloid cells were only acutely cleared, being repopulated back to basal levels within a short time period. This led to a lack of long-lasting reduction in senescent cell burden, unlike when targeting bone mesenchymal cells. In vitro, myeloid-lineage cells differed markedly from mesenchymal cells in the development of a senescent phenotype. Collectively, our findings indicate that aged bone marrow myeloid cells do not achieve the fully developed senescent phenotype originally described in mesenchymal cells, justifying further characterization of senotypes of immune cells across tissues.
Authors
Madison L. Doolittle, Mitchell N. Froemming, Jennifer L. Rowsey, Ming Ruan, Leena Sapra, Joshua N. Farr, David G. Monroe, Sundeep Khosla
Abstract
Authors
Robert Corty, Yash Pershad, J. Brett Heimlich, Caitlyn Vlasschaert, Leo Luo, Taralynn Mack, Kaushik Amancherla, Cassianne Robinson-Cohen, Michael Savona, Alexander G. Bick
Abstract
Calorie restriction (CR) extends maximal lifespan and maintains cellular homeostasis in various animal models. We have previously shown that CR induces a global reduction of protein fractional synthesis rates (FSRs) across the hepatic proteome in mice, but the timing and regulatory mechanisms remain unclear. Nitric oxide (NO), a bioactive molecule upregulated during CR, is a potential regulator of protein synthesis. To explore the role of NO in hepatic proteome fluxes during CR, we used in vivo deuterium labeling from heavy water and liquid chromatography/mass spectrometry–based (LC/MS-based) flux proteomics in WT and NO-deficient (NO–) mice. We observed a transition to reduced global protein FSRs that occurred rapidly between days 25 and 30 of CR. NO deficiency, whether genetic or pharmacological, disrupted the slowing of proteome-wide fluxes and the beneficial effects on body composition and physiology. Administering the NO donor molsidomine restored the reduction in hepatic FSRs in NO– mice. Furthermore, inhibiting NO pharmacologically, whether starting on day 1, day 14, or day 24 of CR, mitigated the reduction in hepatic protein FSRs at day 32, highlighting NO’s critical role during the transition period. These results underscore the importance of NO in CR-induced changes in proteostasis and suggest NO as a potential CR-mimetic target, while offering a specific time window for identifying other signals and testing therapeutic interventions.
Authors
Hector H. Palacios, Edward Cao, Adelaide Cahill, Hussein Mohamad, Marc K. Hellerstein
Abstract
Clonal hematopoiesis due to TET2-driver mutations (CH) is associated with coronary heart disease and worse prognosis among patients with aortic valve stenosis (AVS). However, it is unknown what role CH plays in the pathogenesis of AVS. In a meta-analysis of All Of Us, BioVU, and the UK Biobank, patients with CHIP exhibited an increased risk of AVS, with a higher risk among patients with TET2 or ASXL1 mutations. Single-cell RNA-sequencing of immune cells from AVS patients harboring TET2 CH-driver mutations revealed monocytes with heightened pro-inflammatory signatures and increased expression of pro-calcific paracrine signaling factors, most notably Oncostatin M (OSM). Secreted factors from TET2-silenced macrophages increased in vitro calcium deposition by mesenchymal cells, which was ablated by OSM silencing. Atheroprone Ldlr–/– mice receiving CH-mimicking Tet2–/– bone marrow transplants displayed greater calcium deposition in aortic valves. Together, these results demonstrate that monocytes with CH promote aortic valve calcification, and that patients with CH are at increased risk of AVS.
Authors
Wesley T. Abplanalp, Michael A. Raddatz, Bianca Schuhmacher, Silvia Mas-Peiro, María A. Zuriaga, Nuria Matesanz, José J. Fuster, Yash Pershad, Caitlyn Vlasschaert, Alexander J. Silver, Eric H. Farber-Eger, Yaomin Xu, Quinn S. Wells, Delara Shahidi, Sameen Fatima, Xiao Yang, Adwitiya A.P. Boruah, Akshay Ware, Maximilian Merten, Moritz von Scheidt, David John, Mariana Shumliakivska, Marion Muhly-Reinholz, Mariuca Vasa-Nicotera, Stefan Guenter, Michael R. Savona, Brian R. Lindman, Stefanie Dimmeler, Alexander G. Bick, Andreas M. Zeiher
Abstract
Intestinal function and white adipose tissue (WAT) function deteriorate with age, but whether and how their deterioration is intertwined remains unknown. Increased gut permeability, microbiota dysbiosis, and aberrant immune microenvironment are the hallmarks of intestinal dysfunctions in aging. Here, we show that subcutaneous WAT dysfunction triggered aging-like intestinal dysfunctions in mouse models. Removal of inguinal subcutaneous WAT (iWAT) increased intestinal permeability and inflammation and altered gut microbiota composition as well as susceptibility to pathogen infection in mouse models. These intestinal dysfunctions were accompanied by a reduction of immunoglobulin A–producing (IgA-producing) cells and IgA biosynthesis in the lamina propria of the small intestine. Retinoic acid (RA) is a key cargo within iWAT-derived extracellular vesicles (iWAT-EVs), which, at least in part, elicits IgA class-switching and production in the small intestine and maintains microbiota homeostasis. RA content in iWAT-EVs and intestinal IgA biosynthesis are reduced during aging in mice. Replenishment of “young” iWAT-EVs rejuvenates intestinal IgA production machinery and shifts microbiota composition of aged mice to a “youth” status, which alleviates leaky gut via RA. In conclusion, our findings suggest that iWAT-EVs with RA orchestrate IgA-mediated gut microbiota homeostasis by acting on intestinal B cells, thereby maintaining intestinal health during aging.
Authors
KeKao Long, Pujie Liu, Yi Wang, Jordy Evan Sulaiman, Moinul Hoque, Gloria Hoi Yee Li, Daisy Danyue Zhao, Pui-Kei Lee, Gilman Kit-hang Siu, Annie Wing-tung Lee, Zhuohao Liu, Pui-kin So, Yin Cai, Connie Wai-hong Woo, Chi-bun Chan, Aimin Xu, Kenneth King-yip Cheng
Abstract
The increased prevalence of GluA2-lacking, Ca2+-permeable AMPA receptors (CP-AMPARs) at spinal cord sensory synapses amplifies nociceptive transmission and maintains chronic neuropathic pain. Nerve injury–induced upregulation of α2δ-1 disrupts the assembly of GluA1/GluA2 heteromers, favoring the synaptic incorporation of GluA1 homotetramers in the spinal dorsal horn. Although GluA1-GluA3 subunits are broadly expressed, whether α2δ-1 regulates GluA3-containing AMPARs remains unknown. Here, we unexpectedly found that coexpression with α2δ-1—but not α2δ-2 or α2δ-3—diminished GluA3 AMPAR currents and protein levels, an effect blocked by pregabalin, an α2δ-1 C-terminus peptide, or proteasome inhibition. Both nerve injury and α2δ-1 overexpression reduced protein levels of GluA3 and GluA2/GluA3 heteromers in the spinal cord. Furthermore, α2δ-1 coexpression or nerve injury increased GluA3 ubiquitination, with Lys-861 at the C terminus of GluA3 identified as a key ubiquitination site mediating α2δ-1–induced GluA3 degradation. Additionally, intrathecal delivery of the Gria3 gene reversed nerve injury–induced nociceptive hypersensitivity and synaptic CP-AMPARs by restoring protein levels of GluA3 and GluA2/GluA3 heteromers in the spinal cord. These findings reveal that α2δ-1 promotes GluA1 homotetramer assembly and synaptic CP-AMPAR expression by driving ubiquitin-proteasomal degradation of GluA3, providing insights into the molecular mechanisms of neuropathic pain and the therapeutic actions of gabapentinoids.
Authors
Meng-Hua Zhou, Shao-Rui Chen, Daozhong Jin, Yuying Huang, Hong Chen, Guanxing Chen, Jiusheng Yan, Hui-Lin Pan
Abstract
Osteoarthritis (OA) is the most common joint disease. Controlling the complex pathogenesis is challenging, thus disease-modifying OA drugs are not available. Forkhead box O (FOXO) transcription factors contribute to cartilage homeostasis through autophagy and oxidative stress resistance. Here, we sought to discover FOXO activators and found that cyproheptadine, a histamine H1 receptor (HRH1) inverse agonist, promoted FOXO3 nuclear translocation and increased FOXO target genes while suppressing inflammation. In a murine OA model, cyproheptadine reduced structural joint tissue damage and pain behaviors. Mechanistically, the inhibition of HRH1 constitutive activity mediated the effects of cyproheptadine on calcium balance between endoplasmic reticulum (ER) and cytoplasm, and FOXO activation was part of this mechanism. The anti-inflammatory effect of cyproheptadine involved the inhibition of protein kinase C/NF-κB pathway. HRH1 inhibition also suppressed osteogenesis in mesenchymal stem cells and nerve growth factor expression, which are mechanisms of osteophyte formation and pain behaviors. Moreover, cyproheptadine suppressed ER stress-induced lipogenesis by upregulating insulin-induced gene 1. Our findings suggest that HRH1 constitutive activity controls important OA-promoting mechanisms and indicate that HRH1 inverse agonists are promising drug repurposing candidates for structure and pain improvement in OA.
Authors
Ichiro Kurakazu, Merissa Olmer, Hannah Swahn, Kevin Myers, Chelsea Kenvisay, Yukio Akasaki, Yasuharu Nakashima, Martin K. Lotz
Abstract
Authors
Nishanth S. Sadagopan, Rushmin Khazanchi, Rishi Jain, Amy B. Heimberger, Stephen T. Magill
Abstract
Despite effective antiretroviral therapy (ART), transcriptionally competent HIV-1 reservoirs persist and contribute to persistent immune activation in people living with HIV (PWH). HIV-1-infected macrophages are important mediators of chronic innate immune activation, though mechanisms remain unclear. We previously reported that nuclear export and cytoplasmic expression of HIV-1 intron-containing RNA (icRNA) activates mitochondrial antiviral signaling protein (MAVS)-mediated type I interferon (IFN) responses in macrophages. In this study, we demonstrate an essential role of melanoma differentiation-associated protein 5 (MDA5) in sensing HIV-1 icRNA and promoting MAVS-dependent IRF5 activation in macrophages. Suppression of MDA5, but not RIG-I expression nor disruption of endosomal TLR pathway, abrogated HIV-1 icRNA-induced type I IFN responses and IP-10 expression in macrophages. Furthermore, induction of IP-10 in macrophages upon HIV-1 icRNA sensing by MDA5 was dependent on IRF5. Additionally, monocytes and MDMs from older (>50 years) individuals exhibit constitutively higher levels of IRF5 expression compared to younger (<35 years) individuals, and HIV-1 icRNA induced IP-10 expression was significantly enhanced in older macrophages, which was attenuated upon ablation of IRF5 expression suggesting that IRF5 functions as a major mediator of pro-inflammatory response downstream of MDA5-dependent HIV-1 icRNA sensing, dysregulation of which might contribute to chronic inflammation in older PWH.
Authors
Sita Ramaswamy, Hisashi Akiyama, Jacob Berrigan, Andrés A. Quiñones-Molina, Alex J. Olson, Yunhan Chen, YanMei Liang, Andrew J. Henderson, Archana Asundi, Manish Sagar, Suryaram Gummuluru
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ISSN: 0021-9738 (print), 1558-8238 (online)