Aging
Abstract
In the mammalian cochlea, sensory hair cells are crucial for the transduction of acoustic stimuli into electrical signals, which are then relayed to the central auditory pathway via spiral ganglion neuron (SGN) afferent dendrites. The SGN output is directly modulated by inhibitory cholinergic axodendritic synapses from the efferent fibers originating in the superior olivary complex. When the adult cochlea is subjected to noxious stimuli or aging, the efferent system undergoes major rewiring, such that it reestablishes direct axosomatic contacts with the inner hair cells (IHCs), which occur only transiently during prehearing stages of development. The trigger, origin, and degree of efferent plasticity in the cochlea remains largely unknown. Using functional and morphological approaches, we demonstrate that efferent plasticity in the adult cochlea occurs as a direct consequence of mechanoelectrical transducer current dysfunction. We also show that, different from prehearing stages of development, the lateral olivocochlear — but not the medial olivocochlear — efferent fibers are those that form the axosomatic synapses with the IHCs. The study also demonstrates that in vivo restoration of IHC function using AAV-Myo7a rescue reestablishes the synaptic profile of adult IHCs and improves hearing, highlighting the potential of using gene-replacement therapy for progressive hearing loss.
Authors
Andrew P. O’Connor, Ana E. Amariutei, Alice Zanella, Sarah A. Hool, Adam J. Carlton, Fanbo Kong, Mauricio Saenz-Roldan, Jing-Yi Jeng, Marie-José Lecomte, Stuart L. Johnson, Saaid Safieddine, Walter Marcotti
Abstract
Radiotherapy (RT) remains a primary treatment modality for glioblastoma (GBM), but it induces cellular senescence and is strongly implicated in GBM progression and RT-related injury. Recently, eliminating senescent cells has emerged as a promising strategy for treating cancer and for mitigating radiation-induced brain injury (RBI). Here, we investigated the impact of all-trans retinoic acid (RA) on radiation-induced senescence. The findings of this study revealed that RA effectively eliminated astrocytes, which are particularly prone to senescence after radiation, and that the removal of senescence-associated secretory phenotype factor–producing astrocytes inhibited GBM cell proliferation in vitro. Moreover, RA-mediated clearance of senescent cells improved survival in GBM-bearing mice and alleviated radiation-induced cognitive impairment. Through RNA sequencing, we found that the AKT/mTOR/PPARγ/Plin4 signaling pathway is involved in RA-mediated clearance of senescent cells. In summary, these results suggest that RA could be a potential senolytic drug for preventing GBM progression and improving RBI.
Authors
Min Fu, Yiling Zhang, Bi Peng, Na Luo, Yuanyuan Zhang, Wenjun Zhu, Feng Yang, Ziqi Chen, Qiang Zhang, Qianxia Li, Xin Chen, Yuanhui Liu, Guoxian Long, Guangyuan Hu, Xiaohong Peng
Abstract
Given the potential fundamental function of osteal macrophages in bone pathophysiology, we study here their precise function in experimental osteoporosis. Gene profiling of osteal macrophages from ovariectomized mice demonstrated the upregulation of genes that were involved in oxidative stress, cell senescence and apoptotic process. A scRNA-seq analysis revealed that osteal macrophages were heterogenously clustered into 6 subsets that expressed proliferative, inflammatory, anti-inflammatory and efferocytosis gene signatures. Importantly, postmenopausal mice exhibited a 20-fold increase in subset-3 that showed a typical gene signature of cell senescence and inflammation. These findings suggest that the decreased production of estrogen due to postmenopause altered the osteal macrophages subsets, resulting in a shift toward cell senescence and inflammatory conditions in the bone microenvironment. Furthermore, adoptive macrophage transfer onto calvarial bone was performed and mice that received oxidative-stressed macrophages exhibited greater osteolytic lesions than control macrophages, suggesting the role of these cells in development of inflammaging in bone microenvironment. Consistently, depletion of senescent cells and oxidative-stressed macrophages subset alleviated the excessive bone loss in postmenopausal mice. Our data provided a new insight into the pathogenesis of osteoporosis and sheds light on a new therapeutic approach for the treatment/prevention of postmenopausal osteoporosis.
Authors
Yoshio Nishida, M. Alaa Terkawi, Gen Matsumae, Shunichi Yokota, Taiki Tokuhiro, Yuki Ogawa, Hotaka Ishizu, Junki Shiota, Tsutomu Endo, Hend Alhasan, Taku Ebata, Keita Kitahara, Tomohiro Shimizu, Daisuke Takahashi, Masahiko Takahata, Ken Kadoya, Norimasa Iwasaki
Abstract
The earliest MD/PhD programs were small and enrolled mostly men. Here we show that since 2014 there has been a steady increase in the number of women in MD/PhD programs, reaching parity with men in 2023. This change was due to an increase in female applicants, a decrease in male applicants, and an increase in the acceptance rate for women, which had previously been lower than for men. Data from the National MD/PhD Program Outcomes Study show that training duration has been similar for men and women, as have most choices of medical specialties and workplaces. However, women were less likely to have full-time faculty appointments, fewer had NIH grants, and those in the most recent graduation cohort at the time of the survey reported spending less time on research than men. Previously-cited reasons for these differences include disproportionate childcare responsibilities, a paucity of role models, insufficient recognition, and gender bias. Institutions can and should address these obstacles, but training programs can help by preparing their graduates to succeed despite the systemic obstacles. The alternative is a persistent gender gap in the physician-scientist workforce, lost opportunities to benefit from diverse perspectives, and a diminished impact of valuable training resources.
Authors
Lawrence F. Brass, Myles H. Akabas
Abstract
Mechanistically, S1P deficiency impeded COP II-mediated transport vesicles formation, which leads to proteins retention in the endoplasmic reticulum (ER) and subsequently ER distension. ER distension increased the contact between the ER and mitochondria, disrupting ER-to-mitochondria calcium flow, resulting in mitochondrial dysfunction and energy metabolism disturbance. Finally, using 2-APB to inhibit calcium ion channels and the senolytic drug dasatinib and quercetin (D + Q) partially rescued the aging and degenerative phenotypes caused by S1P deficiency. In conclusion, our findings suggest that S1P is a critical factor in causing IVDD in the process of aging and highlight the potential of targeting S1P as a therapeutic approach for age-related IVDD.
Authors
Bingjie Zheng, Xuyang Zhang, Xiangxi Kong, Jie Li, Bao Huang, Hui Li, Zhongyin Ji, Xiaoan Wei, Siyue Tao, Zhi Shan, Zemin Ling, Junhui Liu, Jian Chen, Fengdong Zhao
Abstract
People with HIV (PWH) have a higher age-adjusted mortality due to chronic immune activation and age-related comorbidities. PWH also have higher rates of clonal hematopoiesis (CH) than age-matched non-HIV cohorts, however, risk factors influencing the development and expansion of CH in PWH remain incompletely explored. We investigated the relationship between CH, immune biomarkers, and HIV-associated risk factors (CD4, CD8 T-cells, nadir CD4 count, opportunistic infections [OIs], and immune reconstitution inflammatory syndrome [IRIS]) in a diverse cohort of 197-PWH with median age of 42-years, using a 56-gene panel. Seventy-nine percent had a CD4 nadir < 200, 58.9% had prior OIs, and 34.5% had a history of IRIS. The prevalence of CH was high (27.4%), even in younger individuals, and CD8 T-cells and nadir CD4 counts strongly associated with CH after controlling for age. A history of IRIS was associated with CH in a subgroup analysis of ≥ 35-years-old patients. Inflammatory biomarkers were higher in CH carriers compared to non-carriers supporting a dysregulated immune state. These findings suggest PWH with low nadir CD4 and/or inflammatory complications may be at high risk of CH regardless of age and represent a high-risk group that could benefit from risk reduction and potentially targeted immunomodulation.
Authors
Joseph M. Rocco, Yifan Zhou, Nicholas S. Liu, Elizabeth Laidlaw, Frances Galindo, Megan V. Anderson, Adam Rupert, Silvia Lucena Lage, Ana M. Ortega-Villa, Shiqin Yu, Andrea Lisco, Maura Manion, George S. Vassiliou, Cynthia E. Dunbar, Irini Sereti
Abstract
Substantial evidence suggests a role for immunotherapy in treating Alzheimer’s disease (AD). While the precise pathophysiology of AD is incompletely understood, clinical trials of antibodies targeting aggregated forms of β amyloid (Aβ) have shown that reducing amyloid plaques can mitigate cognitive decline in patients with early-stage AD. Here, we describe what we believe to be a novel approach to target and degrade amyloid plaques by genetically engineering macrophages to express an Aβ-targeting chimeric antigen receptor (CAR-Ms). When injected intrahippocampally, first-generation CAR-Ms have limited persistence and fail to significantly reduce plaque load, which led us to engineer next-generation CAR-Ms that secrete M-CSF and self-maintain without exogenous cytokines. Cytokine secreting “reinforced CAR-Ms” have greater survival in the brain niche and significantly reduce plaque load locally in vivo. These findings support CAR-Ms as a platform to rationally target, resorb, and degrade pathogenic material that accumulates with age, as exemplified by targeting Aβ in AD.
Authors
Alexander B. Kim, Qingli Xiao, Ping Yan, Qiuyun Pan, Gaurav Pandey, Susie Grathwohl, Ernesto Gonzales, Isabella Xu, Yoonho Cho, Hans Haecker, Slava Epelman, Abhinav Diwan, Jin-Moo Lee, Carl J. DeSelm
Abstract
Accumulation of sphingolipids, especially sphingosines, in the lysosomes is a key driver of several lysosomal storage diseases. The transport mechanism for sphingolipids from the lysosome remains unclear. Here, we identified SPNS1, which shares the highest homology to SPNS2 - a sphingosine-1-phosphate (S1P) transporter, functions as a transporter for lysolipids from the lysosome. We generated Spns1 knockout cells and mice and employed lipidomic and metabolomic approaches to reveal SPNS1 ligand identity. Global knockout of Spns1 caused embryonic lethality between E12.5-E13.5 and an accumulation of sphingosine, lysophosphatidylcholines (LPC) and lysophosphatidylethanolamines (LPE) in the fetal livers. Similarly, metabolomic analysis of livers from postnatal Spns1 knockout (Spns1-KO) mice presented an accumulation of sphingosines and lysoglycerophospholipids including LPC and LPE. Subsequently, biochemical assays showed that SPNS1 is required for LPC and sphingosine release from lysosomes. The accumulation of these lysolipids in the lysosomes of Spns1-KO mice affected liver functions and altered the PI3K-AKT signaling pathway. Furthermore, we identified three human siblings with a homozygous variant in the SPNS1 gene. These patients suffer from developmental delay, neurological impairment, intellectual disability, and exhibiting cerebellar hypoplasia. These results reveal a critical role of SPNS1 as a promiscuous lysolipid transporter in the lysosomes and link its physiological functions with lysosomal storage diseases.
Authors
Hoa T.T. Ha, SiYi Liu, Xuan T.A. Nguyen, Linh K. Vo, Nancy C.P. Leong, Dat T. Nguyen, Shivaranjani Balamurugan, Pei Yen Lim, YaJun Wu, Eunju Seong, Toan Q. Nguyen, Jeongah Oh, Markus R. Wenk, Amaury Cazenave-Gassiot, Zuhal Yapici, Wei-Yi Ong, Margit Burmeister, Long N. Nguyen
Abstract
Aging-related abnormalities in gut microbiota are associated with cognitive decline, depression, and anxiety, but underlying mechanisms remain unstudied. Here, our study demonstrated that transplanting old gut microbiota to young mice induced inflammation in the gut and brain coupled with cognitive decline, depression, and anxiety. We observed diminished mucin formation and increased gut permeability (“leaky gut”) with a reduction in beneficial metabolites like butyrate because of decline in butyrate-producing bacteria in the aged gut microbiota. This led to suppressed expression of butyrate receptors, free fatty acid receptors 2 and 3 (FFAR2/3). Administering butyrate alleviated inflammation, restored mucin expression and gut barriers, and corrected brain dysfunction. Furthermore, young mice with intestine-specific loss of FFAR2/3 exhibited gut and brain abnormalities akin to those in older mice. Our results demonstrate that reduced butyrate-producing bacteria in aged gut microbiota result in low butyrate levels and reduced FFAR2/3 signaling, leading to suppressed mucin formation that increases gut permeability, inflammation, and brain abnormalities. These findings underscore the significance of butyrate-FFAR2/3 agonism as a potential strategy to mitigate aged gut microbiota–induced detrimental effects on gut and brain health in older adults.
Authors
Sidharth P. Mishra, Shalini Jain, Bo Wang, Shaohua Wang, Brandi C. Miller, Jea Y. Lee, Cesar V. Borlongan, Lin Jiang, Julie Pollak, Subhash Taraphder, Brian T. Layden, Sushil G. Rane, Hariom Yadav
Abstract
The human adult immune system maintains normal T-cell counts and compensates for T-cell loss over lifetime mainly through peripheral homeostatic proliferation after the ability of the thymus to generate new T cells has rapidly declined at adolescence. This process is mainly driven by STAT5-activating cytokines, most importantly IL-7, and is very effective in maintaining a large naïve CD4 T cell compartment into older age. Here, we describe that naïve CD4 T cells undergo adaptations to optimize IL-7 responses by upregulating the guanine-nucleotide exchange factor PREX1 at older age. PREX1 promotes nuclear translocation of phosphorylated STAT5, thereby supporting homeostatic proliferation in response to IL-7. Through the same mechanism, increased expression of PREX1 also biases naïve cells to differentiate into effector T cells. These findings are consistent with the concept that primarily beneficial adaptations during aging, i.e., improved homeostasis, account for unfavorable functions of the aged immune system, in this case biased differentiation.
Authors
Huimin Zhang, Hirohisa Okuyama, Abhinav Jain, Rohit R. Jadhav, Bowen Wu, Ines Sturmlechner, Jose Morales, Shozo Ohtsuki, Cornelia M. Weyand, Jörg J. Goronzy
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