BACKGROUND. At the onset of exercise, the speed at which PCr decreases towards a new steady state (PCr on-kinetics), reflects the readiness to activate mitochondrial ATP synthesis, which is secondary to Acetyl-CoA availability in skeletal muscle. We hypothesized that PCr on-kinetics are slower in metabolically compromised and older individuals, and associated with low carnitine acetyl-transferase (CrAT) protein activity and compromised physical function. METHODS. We applied 31P-Magnetic Resonance Spectroscopy (MRS) to assess PCr on-kinetics in two cohorts of human volunteers. Cohort 1: patients with type 2 diabetes, obese, lean trained and untrained individuals. Cohort 2: young and older individuals with normal physical activity and older trained. Previous results of CrAT protein activity and acetylcarnitine content in muscle tissue were used to explore the underlying mechanisms of PCr on-kinetics, along with various markers of physical function. RESULTS. PCr on-kinetics were significantly slower in metabolically compromised and older individuals (indicating mitochondrial inertia) as compared to young and older trained volunteers, regardless of in vivo skeletal muscle oxidative capacity (P<0.001). Mitochondrial inertia correlated with reduced CrAT protein activity, low acetylcarnitine content and also with functional outcomes (P<0.001). CONCLUSION. PCr on-kinetics are significantly slower in metabolically compromised and older individuals with normal physical activity compared to young and older trained, regardless of in vivo skeletal muscle oxidative capacity, indicating greater mitochondrial inertia. Thus, PCr on-kinetics are a currently unexplored signature of skeletal muscle mitochondrial metabolism, tightly linked to functional outcomes. Skeletal muscle mitochondrial inertia might emerge as a target of intervention to improve physical function. TRIAL REGISTRATION. clinicaltrials.gov: NCT01298375 and clinicaltrials.gov: NCT03666013. FUNDING. R.M and M.H were granted with an EFSD/Lilly grant from the European Foundation for the Study of Diabetes (EFSD). V.S was supported by an ERC staring grant (Grant no. 759161) "MRS in Diabetes".
Rodrigo F. Mancilla, Lucas Lindeboom, Lotte Grevendonk, Joris Hoeks, Timothy R. Koves, Deborah M. Muoio, Patrick Schrauwen, Vera Schrauwen-Hinderling, Matthijs K.C. Hesselink
The central physiological role of the bone marrow renders the bone marrow stromal cells (BMSCs) particularly sensitive to aging. With bone aging, BMSCs acquire a differentiation potential bias in favor of adipogenesis over osteogenesis, and the underlying molecular mechanisms remain unclear. Herein, we investigated the factors underlying age-related changes in the bone marrow, and their roles in BMSCs differentiation. Antibody array revealed that C-C motif chemokine ligand 3 (CCL3) accumulation occurred in the serum of naturally aged mice along with bone aging phenotypes, including bone loss, bone marrow adiposity, and imbalanced BMSCs differentiation. In vivo Ccl3 deletion could rescue these phenotypes in aged mice. CCL3 improved the adipogenic differentiation potential of BMSCs, with a positive feedback loop between CCL3 and C/EBPα. CCL3 activated C/EBPα expression via STAT3, while C/EBPα activated CCL3 expression through direct promoter binding, facilitated by DNA hypo-methylation. Moreover, CCL3 inhibited BMSCs osteogenic differentiation potential by blocking β-catenin activity mediated by ERK-activated DKK-1 upregulation. Blocking CCL3 in vivo via neutralization antibodies ameliorated trabecular bone loss and bone marrow adiposity in aged mice. This study provides insights regarding age-related bone loss and bone marrow adiposity pathogenesis, and lays a foundation for the identification of new targets for senile osteoporosis treatment.
Degang Yu, Shuhong Zhang, Chao Ma, Sen Huang, Long Xu, Jun Liang, Huiwu Li, Qiming Fan, Guangwang Liu, Zanjing Zhai
Myotonic dystrophy type 1 (DM1; MIM #160900) is an autosomal dominant disorder, clinically characterized by progressive muscular weakness and multisystem degeneration. The broad phenotypes observed in DM1 patients resemble the appearance of an accelerated aging process. However, the molecular mechanisms underlying these phenotypes remain largely unknown. Transcriptomic analysis of fibroblasts derived from DM1 patients and healthy individuals revealed a decrease in cell cycle activity, cell division, and DNA damage response in DM1, all of which related to the accumulation of cellular senescence. The data from transcriptome analyses were corroborated in human myoblasts and blood samples as well as in mouse and Drosophila models of the disease. Serial passage studies in vitro confirmed the accelerated increase in senescence and the acquisition of a senescence-associated secretory phenotype in DM1 fibroblasts, whereas DM1 Drosophila model showed reduced longevity and impaired locomotor activity. Moreover, functional studies highlighted the impact of BMI1 and downstream p16INK4A/RB and ARF/p53/p21CIP pathways in DM1-associated cellular phenotypes. Importantly, treatment with the senolytic compounds, Quercetin, Dasatinib, or Navitoclax, reversed the accelerated aging phenotypes in both DM1 fibroblasts in vitro and in Drosophila in vivo. Our results identified the accumulation of senescence as part of DM1 pathophysiology and therefore, demonstrated the efficacy of senolytic compounds in the pre-clinical setting.
Mikel García-Puga, Ander Saenz-Antoñanzas, Gorka Gerenu, Alex Arrieta, Roberto Fernandez-Torron, Miren Zulaica, Amets Saenz, Joseba Elizazu, Gisela Nogales-Gadea, Shahinaz M. Gadalla, Marcos J. Araúzo-Bravo, Adolfo Lopez de Munain, Ander Matheu
BACKGROUND. During ageing there is a functional decline in the pool of muscle stem cells (MuSCs) which influences the functional and regenerative capacity of skeletal muscle. Preclinical evidence have suggested that Nicotinamide Riboside (NR) and Pterostilbene (PT) can improve muscle regeneration e.g. by increasing MuSC function. The objective of the present study was to investigate if NRPT-supplementation promotes skeletal muscle regeneration after muscle injury in elderly humans by improved recruitment of MuSCs. METHODS. 32 elderly men and women (55-80 yr) were randomized to daily supplementation with either NRPT (1000 mg NR + 200 mg PT) or matched placebo. Two weeks after initiation of supplementation, a skeletal muscle injury was induced by electrically-induced eccentric muscle work. Skeletal muscle biopsies were obtained pre, 2h, 2, 8, and 30 days post injury. RESULTS. A substantial skeletal muscle injury was induced by the protocol and associated with release of myoglobin and creatine kinase, muscle soreness, tissue edema, and a decrease in muscle strength. MuSC content, proliferation and cell size revealed a large demand for recruitment post injury but was not affected by NRPT. Furthermore, histological analyses of muscle fiber area, internal nuclei and embryonic Myosin Heavy Chain showed no effect of NRPT supplementation. CONCLUSION. Daily supplementation with 1000 mg NR+200 mg PT is safe but does not improve recruitment of the MuSC pool or other measures of muscle recovery in response to injury or subsequent regeneration in elderly subjects. TRIAL REGISTRATION. NCT03754842. FUNDING. Novo Nordisk Foundation (Ref. NNF17OC0027242) given to JTT and NJ. JTT, ED, SC, MVD, KT, and TM are supported by the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR). CBMR is an independent Research Center at the University of Copenhagen that is partially funded by an unrestricted donation from the Novo Nordisk Foundation (NNF18CC0034900).
Jonas Brorson Jensen, Ole Lindgård Dollerup, Andreas Buch Møller, Tine B. Billeskov, Emilie Dalbram, Sabina Chubanava, Mads V. Damgaard, Ryan W. Dellinger, Kajetan Trošt, Thomas Moritz, Steffen Ringgaard, Niels Møller, Jonas T. Treebak, Jean Farup, Niels Jessen
Older people exhibit dysregulated innate immunity to respiratory viral infections, including influenza and SARS-CoV-2, to increase morbidity and mortality. Nanoparticles are a potential practical therapeutic that could reduce exaggerated innate immune responses within the lungs during viral infection. However, such therapeutics have not been examined for effectiveness during respiratory viral infection, particular in aged hosts. Here, we employed a lethal model of influenza viral infection in vulnerable aged mice to examine the ability of biodegradable, cargo-free nanoparticles, designated ONP-302, to resolve innate immune dysfunction and improve outcomes during infection. We administered ONP-302 via intravenous injection to aged mice at day 3 post-infection when the hyperinflammatory innate immune response is already established. During infection, we found that ONP-302 treatment reduced the numbers of inflammatory monocytes within the lungs and increased their number in both the liver and spleen, without impacting viral clearance. Importantly, cargo-free nanoparticles reduced lung damage, histological lung inflammation and improved gas exchange and, ultimately, the clinical outcomes in influenza-infected aged mice. In conclusion, ONP-302 improves outcomes in influenza-infected aged mice. Thus, our study provides fundamental information concerning a practical therapeutic which, if translated clinically, could improve disease outcomes for vulnerable older patients suffering from respiratory viral infections.
William J. Kelley, Kathleen M. Wragg, Judy Chen, Tushar Murthy, Qichen Xu, Michael T. Boyne II, Joseph R. Podojil, Adam Elhofy, Daniel R. Goldstein
Aging is known to be associated with hippocampus-dependent memory decline, but the underlying causes of this age-related memory impairment remain yet highly debated. Here we showed that fecal microbiota transplantation (FMT) from aged, but not young, animal donors in young mice is sufficient to trigger profound hippocampal alterations including astrogliosis, decreased adult neurogenesis, decreased novelty-induced neuronal activation and impairment in hippocampus-dependent memory. Furthermore, similar alterations were reported when mice were subjected to an FMT from aged human donors. To decipher the mechanisms involved in mediating these microbiota-induced effects on brain function, we mapped the vagus nerve (VN)-related neuronal activity patterns and report that aged-mice FM transplanted animals showed a reduction in neuronal activity in the ascending VN output brain structure, whether under basal condition or after VN stimulation. Targeted pharmacogenetic manipulation of VN-ascending neurons demonstrated that the decrease in vagal activity is detrimental to hippocampal functions. In contrast, increasing vagal ascending activity alleviated the adverse effects of aged mice FMT on hippocampal functions, and had a pro-mnesic effect in aged mice. Thus, pharmacogenetic VN stimulation is a potential therapeutic strategy to lessen microbiota-dependent age-associated impairments in hippocampal functions.
Damien Rei, Soham Saha, Marianne Haddad, Anna Haider Rubio, Blanca Liliana Perlaza, Marion Berard, Marie-Noelle Ungeheuer, Harry Sokol, Pierre-Marie Lledo
The ectonucleotidase CD39 functions as a checkpoint in purinergic signaling on effector T cells. By depleting eATP and initiating the generation of adenosine, it impairs memory cell development and contributes to T cell exhaustion, thereby causing defective tumor immunity and deficient T cell responses in older adults who have increased CD39 expression. Tuning enzymatic activity of CD39 and targeting the transcriptional regulation of ENTPD1 can be used to modulate purinergic signaling. Here, we describe that STAT6 phosphorylation downstream of IL-4 signaling represses CD39 expression on activated T cells by inducing a transcription factor network including GATA3, GFI1, and YY1. GATA3 suppresses ENTPD1 transcription through prevention of RUNX3 recruitment to the ENTPD1 promoter. Conversely, pharmacological STAT6 inhibition decreases T cell effector functions via increased CD39 expression, resulting in the defective signaling of P2X receptors by ATP and stimulation of A2A receptors by adenosine. Our studies suggest that inhibiting the STAT6 pathway to increase CD39 expression has the potential to treat autoimmune disease while stimulation of the pathway could improve T cell immunity.
Fengqin Fang, Wenqiang Cao, Yunmei Mu, Hirohisa Okuyama, Lingjie Li, Jingtao Qiu, Cornelia M. Weyand, Jörg J. Goronzy
Respiratory failure in COVID-19 is characterized by widespread disruption of the lung’s alveolar gas exchange interface. To elucidate determinants of alveolar lung damage, we performed epithelial and immune cell profiling in lungs from 24 COVID-19 autopsies and 43 uninfected organ donors ages 18-92 years. We found marked loss of type 2 alveolar epithelial (T2AE) cells and increased peri-alveolar lymphocyte cytotoxicity in all fatal COVID-19 cases, even at early stages before typical patterns of acute lung injury are histologically apparent. In lungs from uninfected organ donors, there is also progressive loss of T2AE with increasing age which may increase susceptibility to COVID-19 mediated lung damage in older individuals. In the fatal COVID-19 cases, macrophage infiltration differed according to the histopathological pattern of lung injury. In cases with acute lung injury, we found accumulation of CD4+ macrophages that express distinctly high levels of T-cell activation and co-stimulation genes and strongly correlate with increased extent of alveolar epithelial cell depletion and CD8 T-cell cytotoxicity. Together, our results show that T2AE deficiency may underlie age-related COVID-19 risk and initiate alveolar injury shortly after infection; and we define immune cell mediators that may contribute to alveolar injury in distinct pathological stages of lethal COVID-19.
Michael Chait, Mine M. Yilmaz, Shanila Shakil, Amy W. Ku, Pranay Dogra, Thomas J. Connors, Peter A. Szabo, Joshua I. Gray, Steven B. Wells, Masaru Kubota, Rei Matsumoto, Maya M.L. Poon, Mark E. Snyder, Matthew R. Baldwin, Peter A. Sims, Anjali Saqi, Donna L. Farber, Stuart P. Weisberg
Amyloidosis involves stepwise growth of fibrils assembled from soluble precursors. Transthyretin (TTR) naturally folds into a stable tetramer, whereas conditions and mutations that foster aberrant monomer formations facilitate TTR oligomeric aggregation and subsequent fibril extension. We investigated the early assembly of oligomers by WT TTR compared with its V30M and V122I variants. We monitored time-dependent redistribution among monomer, dimer, tetramer, and oligomer contents in the presence and absence of multimeric TTR seeds. The seeds were artificially constructed recombinant multimers that contained 20–40 TTR subunits via engineered biotin-streptavidin (SA) interactions. As expected, these multimer seeds rapidly nucleated TTR monomers into larger complexes, while having less effect on dimers and tetramers. In vivo, SA-induced multimers formed TTR-like deposits in the heart and the kidney following i.v. injection in mice. While all 3 variants prominently deposited glomerulus in the kidney, only V30M resulted in extensive deposition in the heart. The cardiac TTR deposits varied in size and shape and were localized in the intermyofibrillar space along the capillaries. These results are consistent with the notion of monomeric TTR engaging in high-avidity interactions with tissue amyloids. Our multimeric induction approach provides a model for studying the initiation of TTR deposition in the heart.
Li Gao, Xinfang Xie, Pan Liu, Jing Jin
MD-PhD trainees constitute an important source of physician-scientists. Persistence on this challenging path is facilitated by success in garnering independent (R grant) support from the NIH. Published research tracks academic appointments and global R01 success for MD-PhD trainees but has not included information on future funding success of individual MD-PhD predoctoral grant holders. Here, we used data from the NIH RePORTER database to identify and track the funding trajectory of physician-scientists who received predoctoral grant support through the F30 mechanism, which is specific for dual-degree candidates. Male and female F30 awardees did not differ in their success in garnering K (postdoctoral training) grants, but, among F30 grant awardees, men were 2.6 times more likely than women to receive R funding. These results underscore the need for analysis of factors that contribute to the disproportionate loss of NIH-supported female physician-scientists between the predoctoral F30 and the independent R grant–supported stages.
Shohini Ghosh-Choudhary, Neil Carleton, S. Mehdi Nouraie, Corrine R. Kliment, Richard A. Steinman
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