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The late Paleocene and early Eocene (LPEE) are characterized by long-term (million years, Myr) global warming and by transient, abrupt (kiloyears, kyr) warming events, termed hyperthermals. Although both have been attributed to greenhouse (CO2) forcing, the longer-term trend in climate was likely influenced by additional forcing factors (i.e., tectonics) and the extent to which warming was driven by atmospheric CO2 remains unclear. Here, we use a suite of new and existing observations from planktic foraminifera collected at Pacific Ocean Drilling Program Sites 1209 and 1210 and inversion of a multiproxy Bayesian hierarchical model to quantify sea surface temperature (SST) and atmospheric CO2 over a 6-Myr interval. Our reconstructions span the initiation of long-term LPEE warming (~58 Ma), and the two largest Paleogene hyperthermals, the Paleocene-Eocene Thermal Maximum (PETM, ~56 Ma) and Eocene Thermal Maximum 2 (ETM-2, ~54 Ma). Our results show strong coupling between CO2 and temperature over the long- (LPEE) and short-term (PETM and ETM-2) but differing Pacific climate sensitivities over the two timescales. Combined CO2 and carbon isotope trends imply the carbon source driving CO2 increase was likely methanogenic, organic, or mixed for the PETM and organic for ETM-2, whereas a source with higher δ13C values (e.g., volcanic degassing) is associated with the long-term LPEE. Reconstructed emissions for the PETM (5,800 Gt C) and ETM-2 (3,800 Gt C) are comparable in mass to future emission scenarios, reinforcing the value of these events as analogs of anthropogenic change.
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A key challenge in aging research is extending lifespan in tandem with slowing down functional decline so that life with good health (healthspan) can be extended. Here, we show that monthly clearance, starting from 20 months, of a small number of cells that highly express p21Cip1 (p21high) improves cardiac and metabolic function and extends both median and maximum lifespans in mice. Importantly, by assessing the health and physical function of these mice monthly until death, we show that clearance of p21high cells improves physical function at all remaining stages of life, suggesting healthspan extension. Mechanistically, p21high cells encompass several cell types with a relatively conserved proinflammatory signature. Clearance of p21high cells reduces inflammation and alleviates age-related transcriptomic signatures of various tissues. These findings demonstrate the feasibility of healthspan extension in mice and indicate p21high cells as a therapeutic target for healthy aging.
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Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Longevidad , Ratones Endogámicos C57BL , Animales , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Ratones , Masculino , Envejecimiento/metabolismo , FemeninoRESUMEN
BACKGROUND: The ubiquitin regulatory X (UBX) domain-containing proteins (UBXNs) are putative adaptors for ubiquitin ligases and valosin-containing protein; however, their in vivo physiological functions remain poorly characterised. We recently showed that UBXN3B is essential for activating innate immunity to DNA viruses and controlling DNA/RNA virus infection. Herein, we investigate its role in adaptive immunity. METHODS: We evaluated the antibody responses to multiple viruses and pathogenesis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza in tamoxifen-inducible global and constitutive B cell-specific Ubxn3b knockout mice; quantified various immune populations, B lineage progenitors/precursors, B cell receptor (BCR) signalling and apoptosis by flow cytometry, immunoblotting and immunofluorescence microscopy. We also performed bone marrow transfer, single-cell and bulk RNA sequencing. FINDINGS: Both global and B cell-specific Ubxn3b knockout mice present a marked reduction in small precursor B-II (>60%), immature (>70%) and mature B (>95%) cell numbers. Transfer of wildtype bone marrow to irradiated global Ubxn3b knockouts restores normal B lymphopoiesis, while reverse transplantation does not. The mature B population shrinks rapidly with apoptosis and higher pro and activated caspase-3 protein levels were observed following induction of Ubxn3b knockout. Mechanistically, Ubxn3b deficiency leads to impaired pre-BCR signalling and cell cycle arrest. Ubxn3b knockout mice are highly vulnerable to respiratory viruses, with increased viral loads and prolonged immunopathology in the lung, and reduced production of virus-specific IgM/IgG. INTERPRETATION: UBXN3B is essential for B lymphopoiesis by maintaining constitutive pre-BCR signalling and cell survival in a cell-intrinsic manner. FUNDING: United States National Institutes of Health grants, R01AI132526 and R21AI155820.
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Linfocitos B , Linfopoyesis , Ratones Noqueados , Animales , Linfopoyesis/genética , Ratones , Linfocitos B/inmunología , Linfocitos B/metabolismo , COVID-19/inmunología , SARS-CoV-2/fisiología , Transducción de Señal , Apoptosis , Receptores de Antígenos de Linfocitos B/metabolismo , HumanosRESUMEN
Clearance of senescent cells has demonstrated therapeutic potential in the context of chronic age-related diseases. Little is known, however, how clearing senescent cells affects the ability to respond to an acute infection and form quality immunological memory. We aimed to probe the effects of clearing senescent cells in aged mice on the immune response to influenza (flu) infection. We utilized a p16 trimodality reporter mouse model (p16-3MR) to allow for identification and selective clearance of p16-expressing cells upon administration of ganciclovir (GCV). While p16-expressing cells may exacerbate dysfunctional responses to a primary infection, our data suggest they may play a role in fostering memory cell generation. We demonstrate that although clearance of p16-expressing cells enhanced viral clearance, this also severely limited antibody production in the lungs of flu-infected aged mice. 30 days later, there were fewer flu-specific CD8 memory T cells and lower levels of flu-specific antibodies in the lungs of GCV-treated mice. Furthermore, GCV-treated mice were unable to mount an optimal memory response and demonstrated increased viral load following heterosubtypic challenge. These results suggest that targeting senescent cells may potentiate primary responses while limiting the ability to form durable and protective immune memory with age.
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Senescencia Celular , Infecciones por Orthomyxoviridae , Animales , Senescencia Celular/inmunología , Ratones , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/virología , Envejecimiento/inmunología , Ratones Endogámicos C57BL , Gripe Humana/inmunología , Gripe Humana/virologíaRESUMEN
Background: Little is known about the prevalence of cellular senescence among immune cells (i.e., immune cells expressing senescence markers, iSCs) nor is there a gold-standard to efficiently measure iSCs. Major depressive disorder (MDD) in older adults has been associated with many hallmarks of senescence in whole blood, leukocytes, and plasma, supporting a strong connection between iSCs and MDD. Here, we investigated the prevalence and phenotype of iSCs in older adults with MDD. Using a single-cell phenotypic approach, circulating immune cells were examined for iSC biomarkers and their relationship to depression and inflammation. Results: PBMCs from older adults with MDD (aged 69.75 ± 5.23 years) and healthy controls (aged 71.25 ± 8.8 years) were examined for immune subset distribution and senescence biomarkers (i.e., lack of proliferation, senescence-associated heterochromatin foci (SAHF), and DNA damage). Dual-expression of SAHF and DNA damage was categorized by low, intermediate, and high expression. A significant increase in the number of high expressing total PBMCs (p = 0.01), monocytes (p = 0.008), a trending increase in the number of high expressing CD4 T cells (p = 0.06) was observed overall in those with MDD. There was also a significantly lower proportion of intermediate expressing cells in monocytes and CD4 T cells in MDD (p = 0.01 and p = 0.05, respectively). Correlation analysis revealed associations between iSCs and mRNA expression of factors related to SASP and immune cell function. Conclusion: MDD is associated with increased senescent cell biomarkers in immune cell populations delineated by distinct levels of SAHF and DNA damage. Inflammatory markers might serve as potent indicators of iSC burden in MDD.
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INTRODUCTION: We have recently shown that readmission after EGS procedures carries a 4-fold higher mortality rate when compared to those not readmitted. Understanding factors associated with death after readmission is paramount to improving outcomes for EGS patients. We aimed to identify risk factors contributing to failure-to-rescue (FTR) during readmission after EGS. We hypothesized that most post-readmission deaths in EGS are attributable to FTR. METHODS: A retrospective cohort study using the NSQIP database 2013-2019 was performed. Patients who underwent 1 of 9 urgent/emergent surgical procedures representing 80% of EGS burden of disease, who were readmitted within 30 days post-procedure were identified. The procedures were classified as low- and high-risk. Patient characteristics analyzed included age, sex, BMI, ASA score comorbidities, postoperative complications, frailty, and FTR. The population was assessed for risk factors associated with mortality and FTR by uni- and multivariate logistic regression. RESULTS: Of 312,862 EGS cases, 16,306 required readmission. Of those, 10,748 (3.4%) developed a postoperative complication. Overall mortality after readmission was 2.4%, with 90.6% of deaths attributable to FTR. Frailty, high-risk procedures, pulmonary complications, AKI, sepsis, and the need for reoperation increased the risk of FTR. DISCUSSION: Death after a complication is common in EGS readmissions. The impact of FTR could be minimized with the implementation of measures to allow early identification and intervention or prevention of infectious, respiratory, and renal complications.
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The geological record encodes the relationship between climate and atmospheric carbon dioxide (CO2) over long and short timescales, as well as potential drivers of evolutionary transitions. However, reconstructing CO2 beyond direct measurements requires the use of paleoproxies and herein lies the challenge, as proxies differ in their assumptions, degree of understanding, and even reconstructed values. In this study, we critically evaluated, categorized, and integrated available proxies to create a high-fidelity and transparently constructed atmospheric CO2 record spanning the past 66 million years. This newly constructed record provides clearer evidence for higher Earth system sensitivity in the past and for the role of CO2 thresholds in biological and cryosphere evolution.
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Cellular senescence has been implicated in the pathophysiology of many age-related diseases. However, it also plays an important protective role in the context of tumor suppression and wound healing. Reducing senescence burden through treatment with senolytic drugs or the use of genetically targeted models of senescent cell elimination in animals has shown positive results in the context of mitigating disease and age-associated inflammation. Despite positive, albeit heterogenous, outcomes in clinical trials, very little is known about the short-term and long-term immunological consequences of using senolytics as a treatment for age-related conditions. Further, many studies examining cellular senescence and senolytic treatment have been demonstrated in non-infectious disease models. Several recent reports suggest that senescent cell elimination may have benefits in COVID-19 and influenza resolution and disease prognosis. In this review, we discuss the current clinical trials and pre-clinical studies that are exploring the impact of senolytics on cellular immunity. We propose that while eliminating senescent cells may have an acute beneficial impact on primary immune responses, immunological memory may be negatively impacted. Closer investigation of senolytics on immune function and memory generation would provide insight as to whether senolytics could be used to enhance the aging immune system and have potential to be used as therapeutics or prophylactics in populations that are severely and disproportionately affected by infections such as the elderly and immunocompromised.
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Age is the greatest risk factor for adverse outcomes following influenza (flu) infection. The increased burden of senescent cells with age has been identified as a root cause in many diseases of aging and targeting these cells with drugs termed senolytics has shown promise in alleviating many age-related declines across organ systems. However, there is little known whether targeting these cells will improve age-related deficits in the immune system. Here, we utilized a well characterized senolytic treatment with a combination of dasatinib and quercetin (D + Q) to clear aged (18-20 months) mice of senescent cells prior to a flu infection. We comprehensively profiled immune responses during the primary infection as well as development of immune memory and protection following pathogen reencounter. Senolytic treatment did not improve any aspects of the immune response that were assayed for including: weight loss, viral load, CD8 T-cell infiltration, antibody production, memory T cell development, or recall ability. These results indicate that D + Q may not be an appropriate senolytic to improve aged immune responses to flu infection.
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Clearance of senescent cells has demonstrated therapeutic potential in the context of chronic age-related diseases. Little is known, however, how clearing senescent cells affects the ability to respond to an acute infection and form quality immunological memory. We aimed to probe the effects of clearing senescent cells in aged mice on the immune response to influenza (flu) infection. We utilized a p16 trimodality reporter mouse model (p16-3MR) to allow for identification and selective deletion of p16-expressing senescent cells upon administration of ganciclovir (GCV). While p16-expressing senescent cells may exacerbate dysfunctional responses to a primary infection, our data suggest they may play a role in fostering memory cell generation. We demonstrate that although deletion of p16-expressing cells enhanced viral clearance, this also severely limited antibody production in the lungs of flu-infected aged mice. 30 days later, there were fewer flu-specific CD8 memory T cells and lower levels of flu-specific antibodies in the lungs of GCV treated mice. GCV treated mice were unable to mount an optimal memory response and demonstrated increased viral load following a heterosubtypic challenge. These results suggest that targeting senescent cells may potentiate primary responses while limiting the ability to form durable and protective immune memory with age.
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Older adults have diminished immune responses that increase susceptibility to infectious diseases, such as influenza (flu). In older adults, flu infection can lead to hospitalization, catastrophic disability, and mortality. We previously demonstrated severe and prolonged muscle degradation and atrophy in aged mice during flu infection. Here, we utilized an unbiased transcriptomic analysis to elucidate mechanisms of flu-induced muscular declines in a mouse model. Our results showed age-related gene expression differences including downregulation of genes associated with muscle regeneration and organization and upregulation of genes associated with pro-inflammatory cytokines and migratory immune pathways in aged mice when compared to young. Pathway analysis revealed significant enrichment of leukocyte migration and T cell activation pathways in the aged muscle during infection. Intramuscular CD4 T cells increased in both young and aged mice during infection, while intramuscular CD8 T cells increased exclusively in aged muscle. CD4 T cells in young muscle were regulatory T cells (Treg), while those in aged were T follicular helper (Tfh) and Th2 cells. Correspondingly, IL-33, an important cytokine for Treg accumulation within tissue, increased only in young flu-infected muscle. Conversely, CXCL10 (IP-10) increased only in aged muscle suggesting a continued recruitment of CD8 T cells into the aged muscle during flu infection. Overall, our findings elucidate a link between flu-induced disability and dysregulated intracellular T cell recruitment into flu-injured muscle with aging. Furthermore, we uncovered potential pathways involved that can be targeted to develop preventative and therapeutic interventions to avert disability and maintain independence following infection.
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Gripe Humana , Animales , Humanos , Ratones , Envejecimiento , Citocinas/metabolismo , Leucocitos/metabolismo , Músculo Esquelético/metabolismo , Linfocitos T/inmunologíaRESUMEN
Plasminogen activator inhibitor-1 (PAI-1), a member of the serine protease inhibitor superfamily of proteins, is unique among serine protease inhibitors for exhibiting a spontaneous conformational change to a latent or inactive state. The functional half-life for this transition at physiologic temperature and pH is â¼1 to 2 h. To better understand the molecular mechanisms underlying this transition, we now report on the analysis of a comprehensive PAI-1 variant library expressed on filamentous phage and selected for functional stability after 48 h at 37 °C. Of the 7201 possible single amino acid substitutions in PAI-1, we identified 439 that increased the functional stability of PAI-1 beyond that of the WT protein. We also found 1549 single amino acid substitutions that retained inhibitory activity toward the canonical target protease of PAI-1 (urokinase-like plasminogen activator), whereas exhibiting functional stability less than or equal to that of WT PAI-1. Missense mutations that increase PAI-1 functional stability are concentrated in highly flexible regions within the PAI-1 structure. Finally, we developed a method for simultaneously measuring the functional half-lives of hundreds of PAI-1 variants in a multiplexed, massively parallel manner, quantifying the functional half-lives for 697 single missense variants of PAI-1 by this approach. Overall, these findings provide novel insight into the mechanisms underlying the latency transition of PAI-1 and provide a database for interpreting human PAI-1 genetic variants.
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Inhibidor 1 de Activador Plasminogénico , Serpinas , Humanos , Inhibidor 1 de Activador Plasminogénico/metabolismo , Mutación , Cinética , Semivida , Serpinas/genética , Inhibidores de Serina ProteinasaRESUMEN
Aging results in systemic changes that leave older adults at much higher risk for adverse outcomes following respiratory infections. Much work has been done over the years to characterize and describe the varied changes that occur with aging from the molecular/cellular up to the organismal level. In recent years, the systemic accumulation of senescent cells has emerged as a key mediator of many age-related declines and diseases of aging. Many of these age-related changes can impair the normal function of the respiratory system and its capability to respond appropriately to potential pathogens that are encountered daily. In this review, we aim to establish the effects of cellular senescence on the disruption of normal lung function with aging and describe how these effects compound to leave an aged respiratory system at great risk when exposed to a pathogen. We will also discuss the role cellular senescence may play in the inability of most vaccines to confer protection against respiratory infections when administered to older adults. We posit that cellular senescence may be the point of convergence of many age-related immunological declines. Enhanced investigation into this area could provide much needed insight to understand the aging immune system and how to effectively ameliorate responses to pathogens that continue to disproportionately harm this vulnerable population.
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Senescencia Celular , Infecciones del Sistema Respiratorio , Anciano , Senescencia Celular/fisiología , Humanos , Pulmón , TóraxRESUMEN
Infection with the respiratory pathogen influenza A virus (IAV) causes significant morbidity and mortality each year. While host genotype is thought to contribute to severity of disease, naturally occurring genetic determinants remain mostly unknown. Moreover, more severe disease is seen in women compared with men, but genetic mechanisms underlying this sex difference remain obscure. Here, using IAV infection in a mouse model of naturally selected genetic diversity, namely C57BL6/J (B6) mice carrying chromosomes (Chr) derived from the wild-derived and genetically divergent PWD/PhJ (PWD) mouse strain (B6.ChrPWD consomic mice), we examined the effects of genotype and sex on severity of IAV-induced disease. Compared with B6, parental PWD mice were completely protected from IAV-induced disease, a phenotype that was fully recapitulated in the B6.Chr16PWD strain carrying the PWD-derived allele of Mx1. In contrast, several other consomic strains, including B6.Chr3PWD and B6.Chr5PWD, demonstrated greatly increased susceptibility. Notably, B6.Chr5PWD and B6.ChrX.3PWD strains, the latter carrying the distal one-third of ChrX from PWD, exhibited increased morbidity and mortality specifically in male but not female mice. Follow up analyses focused on B6 and B6.ChrX.3PWD strains demonstrated moderately elevated viral load in B6.ChrX3PWD male, but not female mice. Transcriptional profiling demonstrated genotype- and sex-specific gene expression profiles in the infected lung, with male B6.ChrX.3 mice exhibiting the most significant changes, including upregulation of a proinflammatory gene expression program associated with myeloid cells, and altered sex-biased expression of several X-linked genes that represent positional candidates, including Tlr13 and Slc25a53. Taken together, our results identify novel loci on autosomes and the X chromosome regulating IAV susceptibility and demonstrate that sex differences in IAV susceptibility are genotype-dependent, suggesting that future genetic association studies need to consider sex as a covariate.
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Virus de la Influenza A , Gripe Humana , Caracteres Sexuales , Animales , Femenino , Genotipo , Humanos , Gripe Humana/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Cromosoma XRESUMEN
BACKGROUND: Biological aging represents a loss of integrity and functionality of physiological systems over time. While associated with an enhanced risk of adverse outcomes such as hospitalization, disability and death following infection, its role in perceived age-related declines in vaccine responses has yet to be fully elucidated. Using data and biosamples from a 4-year clinical trial comparing immune responses of standard- and high-dose influenza vaccination, we quantified biological age (BA) prior to vaccination in adults over 65 years old (n = 292) using a panel of ten serological biomarkers (albumin, alanine aminotransferase, creatinine, ferritin, free thyroxine, cholesterol, high-density lipoprotein, triglycerides, tumour necrosis factor, interleukin-6) as implemented in the BioAge R package. Hemagglutination inhibition antibody titres against influenza A/H1N1, A/H3N2 and B were quantified prior to vaccination and 4-, 10- and 20- weeks post-vaccination. RESULTS: Counter to our hypothesis, advanced BA was associated with improved post-vaccination antibody titres against the different viral types and subtypes. However, this was dependent on both vaccine dose and CMV serostatus, as associations were only apparent for high-dose recipients (d = 0.16-0.26), and were largely diminished for CMV positive high-dose recipients. CONCLUSIONS: These findings emphasize two important points: first, the loss of physiological integrity related to biological aging may not be a ubiquitous driver of immune decline in older adults; and second, latent factors such as CMV infection (prevalent in up to 90% of older adults worldwide) may contribute to the heterogeneity in vaccine responses of older adults more than previously thought.