RESUMEN
Memory CD8(+) T cells are critical for host defense upon reexposure to intracellular pathogens. We found that interleukin 10 (IL-10) derived from CD4(+) regulatory T cells (Treg cells) was necessary for the maturation of memory CD8(+) T cells following acute infection with lymphocytic choriomeningitis virus (LCMV). Treg cell-derived IL-10 was most important during the resolution phase, calming inflammation and the activation state of dendritic cells. Adoptive transfer of IL-10-sufficient Treg cells during the resolution phase 'restored' the maturation of memory CD8(+) T cells in IL-10-deficient mice. Our data indicate that Treg cell-derived IL-10 is needed to insulate CD8(+) T cells from inflammatory signals, and reveal that the resolution phase of infection is a critical period that influences the quality and function of developing memory CD8(+) T cells.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Interleucina-10/inmunología , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Animales , Linfocitos T CD8-positivos/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Citometría de Flujo , Perfilación de la Expresión Génica , Interacciones Huésped-Patógeno/inmunología , Memoria Inmunológica/inmunología , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Coriomeningitis Linfocítica/genética , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/fisiología , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/trasplanteRESUMEN
Infiltration of regulatory T (Treg) cells into many tumor types correlates with poor patient prognoses. However, mechanisms of intratumoral Treg cell function remain to be elucidated. We investigated Treg cell function in a genetically engineered mouse model of lung adenocarcinoma and found that Treg cells suppressed anti-tumor responses in tumor-associated tertiary lymphoid structures (TA-TLSs). TA-TLSs have been described in human lung cancers, but their function remains to be determined. TLSs in this model were spatially associated with >90% of tumors and facilitated interactions between T cells and tumor-antigen-presenting dendritic cells (DCs). Costimulatory ligand expression by DCs and T cell proliferation rates increased in TA-TLSs upon Treg cell depletion, leading to tumor destruction. Thus, we propose that Treg cells in TA-TLSs can inhibit endogenous immune responses against tumors, and targeting these cells might provide therapeutic benefit for cancer patients.
Asunto(s)
Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T/inmunología , Adenocarcinoma/genética , Adenocarcinoma/inmunología , Adenocarcinoma/metabolismo , Animales , Proliferación Celular , Células Cultivadas , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Citometría de Flujo , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/inmunología , Factores de Transcripción Forkhead/metabolismo , Inmunohistoquímica , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Activación de Linfocitos/inmunología , Depleción Linfocítica , Linfocitos Infiltrantes de Tumor/metabolismo , Ratones Transgénicos , Microscopía Confocal , Neoplasias/genética , Neoplasias/metabolismo , Linfocitos T/metabolismo , Linfocitos T Reguladores/metabolismoRESUMEN
In this study, the safety of a red mud-loess mixture (RM-L) for the remediation of groundwater polluted by acid mine drainage (AMD) containing Cd(II) in mining areas was systematically analyzed and clarified. The effects of the initial concentration, flow rate, and packing height on the breakthrough performance and longevity of RM-L as a permeable reactive barrier (PRB) packing material were explored by column tests. The results show that the breakthrough time, saturation time, and adsorption capacity of Cd(II) in RM-L increased with decreasing initial concentration and flow rate, as well as increasing packing height. Moreover, RM-L had a long-term effective acid buffering capacity for acidic wastewater containing Cd(II). An increase in the packing height led to a longer longevity of the PRB than the theoretical value. In addition, the speciation of Cd on RM-L was dominated by carbonate form and iron-manganese oxide form. The surface of the RM-L particles evolved from a dense lamellar structure to small globular clusters after purifying the acidic wastewater containing Cd(II), due to the corrosion of H+ and the reoccupation and coverage by increasingly enriched adsorbates and precipitates of heavy metal ions.
Asunto(s)
Cadmio , Aguas Residuales , Contaminantes Químicos del Agua , Cadmio/química , Contaminantes Químicos del Agua/química , Aguas Residuales/química , Adsorción , Purificación del Agua/métodos , Eliminación de Residuos Líquidos/métodos , Minería , Concentración de Iones de HidrógenoRESUMEN
KEOPS complex is one of the most conserved protein complexes in eukaryotes. It plays important roles in both telomere uncapping and tRNA N6-threonylcarbamoyladenosine (t6A) modification in budding yeast. But whether KEOPS complex plays any roles in DNA repair remains unknown. Here, we show that KEOPS complex plays positive roles in both DNA damage response and homologous recombination-mediated DNA repair independently of its t6A synthesis function. Additionally, KEOPS displays DNA binding activity in vitro, and is recruited to the chromatin at DNA breaks in vivo, suggesting a direct role of KEOPS in DSB repair. Mechanistically, KEOPS complex appears to promote DNA end resection through facilitating the association of Exo1 and Dna2 with DNA breaks. Interestingly, inactivation of both KEOPS and Mre11/Rad50/Xrs2 (MRX) complexes results in synergistic defect in DNA resection, revealing that KEOPS and MRX have some redundant functions in DNA resection. Thus we uncover a t6A-independent role of KEOPS complex in DNA resection, and propose that KEOPS might be a DSB sensor to assist cells in maintaining chromosome stability.
Asunto(s)
ADN Helicasas/fisiología , ADN de Hongos , Exodesoxirribonucleasas/fisiología , Recombinación Homóloga , Reparación del ADN por Recombinación , Proteínas de Saccharomyces cerevisiae/fisiología , Unión Competitiva , Cromatina/química , ADN/química , Roturas del ADN de Doble Cadena , Reparación del ADN , Proteínas de Unión al ADN/metabolismo , Endodesoxirribonucleasas/metabolismo , Exodesoxirribonucleasas/metabolismo , Metaloendopeptidasas/metabolismo , Mutación , Unión Proteica , Proteínas Serina-Treonina Quinasas/metabolismo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Telómero/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Continuing efforts from large international consortia have made genome-wide epigenomic and transcriptomic annotation data publicly available for a variety of cell and tissue types. However, synthesis of these datasets into effective summary metrics to characterize the functional non-coding genome remains a challenge. Here, we present GenoSkyline-Plus, an extension of our previous work through integration of an expanded set of epigenomic and transcriptomic annotations to produce high-resolution, single tissue annotations. After validating our annotations with a catalog of tissue-specific non-coding elements previously identified in the literature, we apply our method using data from 127 different cell and tissue types to present an atlas of heritability enrichment across 45 different GWAS traits. We show that broader organ system categories (e.g. immune system) increase statistical power in identifying biologically relevant tissue types for complex diseases while annotations of individual cell types (e.g. monocytes or B-cells) provide deeper insights into disease etiology. Additionally, we use our GenoSkyline-Plus annotations in an in-depth case study of late-onset Alzheimer's disease (LOAD). Our analyses suggest a strong connection between LOAD heritability and genetic variants contained in regions of the genome functional in monocytes. Furthermore, we show that LOAD shares a similar localization of SNPs to monocyte-functional regions with Parkinson's disease. Overall, we demonstrate that integrated genome annotations at the single tissue level provide a valuable tool for understanding the etiology of complex human diseases. Our GenoSkyline-Plus annotations are freely available at http://genocanyon.med.yale.edu/GenoSkyline.
Asunto(s)
Enfermedad de Alzheimer/genética , Genoma Humano/genética , Estudio de Asociación del Genoma Completo , Especificidad de Órganos/genética , Bases de Datos Genéticas , Epigenómica , Humanos , Anotación de Secuencia Molecular , Polimorfismo de Nucleótido Simple , Transcriptoma/genéticaRESUMEN
Heparan sulfate proteoglycans (HSPGs) serve as co-receptors for growth factor signaling during development. It is well known that the level and patterns of sulfate groups of heparan sulfate (HS) chains, or HS fine structures, have a major impact on HSPG function. On the other hand, the physiological significance of other structural features of HS, including NS/NA domain organization, remains to be elucidated. A blueprint of the HS domain structures is mainly controlled by HS N-deacetylase/N-sulfotransferases (NDSTs). To analyze in vivo activities of differentially modified HS, we established two knock-in (KI) Drosophila strains with the insertion of mouse Ndst1 (mNdst1) or Ndst2 (mNdst2) in the locus of sulfateless (sfl), the only Drosophila NDST. In these KI lines, mNDSTs are expressed from the sfl locus, in the level and patterns identical to the endogenous sfl gene. Thus, phenotypes of Ndst1 KI and Ndst2KI animals reflect the ability of HS structures made by these enzymes to rescue sfl mutation. Remarkably, we found that mNdst1 completely rescued the loss of sfl. mNdst2 showed a limited rescue ability, despite a higher level of HS sulfation compared to HS in mNdst1 KI. Our study suggests that independent of sulfation levels, additional HS structural features controlled by NDSTs play key roles during tissue patterning.
RESUMEN
T follicular regulatory cells, or Tfr cells, are a discernable population of regulatory T (Treg) cells that migrate to the B cell follicle and germinal center (GC) upon immune challenge. These cells express the transcription factor Bcl6, the master regulator required for development and differentiation of T follicular helper cells, and are among a group of previously described Treg cells that use T helper cell-associated transcription factors to adapt their regulatory function to diverse milieus for maintenance of immune homeostasis. While there is consensus that Tfr cells control B-cell autoreactivity, it has been unclear whether they regulate productive, antigen-specific GC responses. Accordingly, understanding the regulatory balancing that Tfr cells play in maintenance of B-cell tolerance while optimizing productive humoral immunity is crucial for vaccine-design strategies. To this end, we discuss recent evidence that Tfr cells promote humoral immunity and memory following viral infections, fitting with the accepted role of Treg cells in maintaining homeostasis with promotion of productive immunity, while mitigating that which is potentially pathological. We also propose models in which Tfr cells regulate antigen-specific B cell responses.
Asunto(s)
Linfocitos T Reguladores/metabolismo , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Biomarcadores , Comunicación Celular/inmunología , Centro Germinal/inmunología , Centro Germinal/metabolismo , Humanos , Inmunidad , Inmunomodulación , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Linfocitos T Reguladores/inmunologíaRESUMEN
Unpaired1 (Upd1) is a ligand of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in Drosophila. In this study, using the CRISPR/Cas9 technique, we generate a transgenic fly strain in which a hemagglutinin (HA) epitope tag sequence is inserted into the endogenous locus of the upd1 gene. Anti-HA antibody staining confirms that the distribution of the epitope-tagged Upd1::HA in various tissues is consistent with upd1 expression patterns revealed by previous studies. This transgenic fly strain will be useful in studying the expression, localization, and association partners of Upd1, and thus will contribute to understanding how activation of the JAK/STAT pathway is regulated.
RESUMEN
The molecular mechanisms by which stem cell proliferation is precisely controlled during the course of regeneration are poorly understood. Namely, how a damaged tissue senses when to terminate the regeneration process, inactivates stem cell mitotic activity, and organizes ECM integrity remain fundamental unanswered questions. The Drosophila midgut intestinal stem cell (ISC) offers an excellent model system to study the molecular basis for stem cell inactivation. Here, we show that a novel gene, CG6967 or dMOV10, is induced at the termination stage of midgut regeneration, and shows an inhibitory effect on ISC proliferation. dMOV10 encodes a putative component of the microRNA (miRNA) gene silencing complex (miRISC). Our data, along with previous studies on the mammalian MOV10, suggest that dMOV10 is not a core member of miRISC, but modulates miRISC activity as an additional component. Further analyses identified direct target mRNAs of dMOV10-containing miRISC, including Daughter against Dpp (Dad), a known inhibitor of BMP/TGF-ß signaling. We show that RNAi knockdown of Dad significantly impaired ISC division during regeneration. We also identified six miRNAs that are induced at the termination stage and their potential target transcripts. One of these miRNAs, mir-1, is required for proper termination of ISC division at the end of regeneration. We propose that miRNA-mediated gene regulation contributes to the precise control of Drosophila midgut regeneration.
Asunto(s)
Drosophila/fisiología , Mucosa Intestinal/citología , Regeneración/fisiología , Células Madre/citología , Animales , Diferenciación Celular/genética , Proliferación Celular/genética , Autorrenovación de las Células/genética , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/fisiología , Enterocitos/citología , Intestinos/citología , MicroARNs/genética , MicroARNs/metabolismo , ARN Helicasas , Complejo Silenciador Inducido por ARN/genética , Complejo Silenciador Inducido por ARN/metabolismo , Transducción de Señal , Células Madre/metabolismoRESUMEN
CD4+ follicular regulatory T (Tfr) cells control B cell responses through the modulation of follicular helper T (Tfh) cells and germinal center development while suppressing autoreactivity; however, their role in the regulation of productive germinal center B cell responses and humoral memory is incompletely defined. We show that Tfr cells promote antigen-specific germinal center B cell responses upon influenza virus infection. Following viral challenge, we found that Tfr cells are necessary for robust generation of virus-specific, long-lived plasma cells, antibody production against both hemagglutinin (HA) and neuraminidase (NA), the two major influenza virus glycoproteins, and appropriate regulation of the BCR repertoire. To further investigate the functional relevance of Tfr cells during viral challenge, we used a sequential immunization model with repeated exposure of antigenically partially conserved strains of influenza viruses, revealing that Tfr cells promote recall antibody responses against the conserved HA stalk region. Thus, Tfr cells promote antigen-specific B cell responses and are essential for the development of long-term humoral memory.
Asunto(s)
Linfocitos B/inmunología , Betainfluenzavirus/inmunología , Antígenos CD4/metabolismo , Inmunidad , Linfocitos T Reguladores/inmunología , Animales , Formación de Anticuerpos/inmunología , Antígenos/metabolismo , Modelos Animales de Enfermedad , Epítopos/inmunología , Factores de Transcripción Forkhead/metabolismo , Centro Germinal/inmunología , Humanos , Memoria Inmunológica , Gripe Humana/inmunología , Gripe Humana/virología , Integrasas/metabolismo , Ratones Endogámicos C57BL , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/virología , Receptores de Antígenos de Linfocitos B/metabolismo , Especificidad de la Especie , VacunaciónRESUMEN
Inducible expression of neoantigens in mice would enable the study of endogenous antigen-specific naïve T cell responses in disease and infection, but has been difficult to generate because leaky antigen expression in the thymus results in central T cell tolerance. Here we develop inversion-induced joined neoantigen (NINJA), using RNA splicing, DNA recombination and three levels of regulation to prevent leakiness and allow tight control over neoantigen expression. We apply NINJA to create tumor cell lines with inducible neoantigen expression, which could be used to study antitumor immunity. We also show that the genetic regulation in NINJA mice bypasses central and peripheral tolerance mechanisms and allows for robust endogenous CD8 and CD4 T cell responses on neoantigen induction in peripheral tissues. NINJA will enable studies of how T cells respond to defined neoantigens in the context of peripheral tolerance, transplantation, autoimmune diseases and cancer.
Asunto(s)
Antígenos de Neoplasias , Ingeniería Celular/métodos , Animales , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Linfocitos T CD4-Positivos/química , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/química , Linfocitos T CD8-positivos/metabolismo , Femenino , Humanos , Ratones , Especificidad de Órganos/genética , Empalme del ARN/genética , Células Tumorales CultivadasRESUMEN
Cross-linking of high-affinity immunoglobulin E (IgE) results in the life-threatening allergic reaction anaphylaxis. Yet the cellular mechanisms that induce B cells to produce IgE in response to allergens remain poorly understood. T follicular helper (TFH) cells direct the affinity and isotype of antibodies produced by B cells. Although TFH cell-derived interleukin-4 (IL-4) is necessary for IgE production, it is not sufficient. We report a rare population of IL-13-producing TFH cells present in mice and humans with IgE to allergens, but not when allergen-specific IgE was absent or only low-affinity. These "TFH13" cells have an unusual cytokine profile (IL-13hiIL-4hiIL-5hiIL-21lo) and coexpress the transcription factors BCL6 and GATA3. TFH13 cells are required for production of high- but not low-affinity IgE and subsequent allergen-induced anaphylaxis. Blocking TFH13 cells may represent an alternative therapeutic target to ameliorate anaphylaxis.
Asunto(s)
Anafilaxia/inmunología , Inmunoglobulina E/inmunología , Interleucina-13/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Adolescente , Animales , Niño , Factor de Transcripción GATA3/metabolismo , Factores de Intercambio de Guanina Nucleótido/genética , Factores de Intercambio de Guanina Nucleótido/metabolismo , Humanos , Interleucina-13/genética , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Proteínas Proto-Oncogénicas c-bcl-6/metabolismoRESUMEN
In Saccharomyces cerevisiae, the highly conserved Sua5 and KEOPS complex (including five subunits Kae1, Bud32, Cgi121, Pcc1 and Gon7) catalyze a universal tRNA modification, namely N6-threonylcarbamoyladenosine (t6A), and regulate telomere replication and recombination. However, whether telomere regulation function of Sua5 and KEOPS complex depends on the t6A modification activity remains unclear. Here we show that Sua5 and KEOPS regulate telomere length in the same genetic pathway. Interestingly, the telomere length regulation by KEOPS is independent of its t6A biosynthesis activity. Cytoplasmic overexpression of Qri7, a functional counterpart of KEOPS in mitochondria, restores cytosolic tRNA t6A modification and cell growth, but is not sufficient to rescue telomere length in the KEOPS mutant kae1Δ cells, indicating that a t6A modification-independent function is responsible for the telomere regulation. The results of our in vitro biochemical and in vivo genetic assays suggest that telomerase RNA TLC1 might not be modified by Sua5 and KEOPS. Moreover, deletion of KEOPS subunits results in a dramatic reduction of telomeric G-overhang, suggesting that KEOPS regulates telomere length by promoting G-overhang generation. These findings support a model in which KEOPS regulates telomere replication independently of its function on tRNA modification.
Asunto(s)
Adenosina/análogos & derivados , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Telómero/genética , Adenosina/metabolismo , ADN de Cadena Simple/genética , Proteínas de Unión al ADN/metabolismoRESUMEN
Follicular helper T (Tfh) cells promote germinal center (GC) B cell survival and proliferation and guide their differentiation and immunoglobulin isotype switching by delivering contact-dependent and soluble factors, including IL-21, IL-4, IL-9, and IFN-γ. IL-21 and IFN-γ are coexpressed by Tfh cells during viral infections, but transcriptional regulation of these cytokines is not completely understood. In this study, we show that the T helper type 1 cell (Th1 cell) transcriptional regulators T-bet and STAT4 are coexpressed with Bcl6 in Tfh cells after acute viral infection, with a temporal decline in T-bet in the waning response. T-bet is important for Tfh cell production of IFN-γ, but not IL-21, and for a robust GC reaction. STAT4, phosphorylated in Tfh cells upon infection, is required for expression of T-bet and Bcl6 and for IFN-γ and IL-21. These data indicate that T-bet is expressed with Bcl6 in Tfh cells and is required alongside STAT4 to coordinate Tfh cell IL-21 and IFN-γ production and for promotion of the GC response after acute viral challenge.
Asunto(s)
Factor de Transcripción STAT4/metabolismo , Proteínas de Dominio T Box/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Virosis/inmunología , Virosis/metabolismo , Animales , Diferenciación Celular/inmunología , Diferenciación Celular/fisiología , Línea Celular , Regulación de la Expresión Génica/inmunología , Regulación de la Expresión Génica/fisiología , Centro Germinal/inmunología , Centro Germinal/metabolismo , Células HEK293 , Humanos , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interleucinas/inmunología , Interleucinas/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas c-bcl-6/inmunología , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Factor de Transcripción STAT4/inmunología , Proteínas de Dominio T Box/inmunología , Células TH1RESUMEN
CD4+ follicular regulatory T (Tfr) cells suppress B cell responses through modulation of follicular helper T (Tfh) cells and germinal center (GC) development. We found that Tfr cells can also promote the GC response through provision of interleukin-10 (IL-10) after acute infection with lymphocytic choriomeningitis virus (LCMV). Sensing of IL-10 by B cells was necessary for optimal development of the GC response. GC B cells formed in the absence of Treg cell-derived IL-10 displayed an altered dark zone state and decreased expression of the transcription factor Forkhead box protein 1 (FOXO1). IL-10 promoted nuclear translocation of FOXO1 in activated B cells. These data indicate that Tfr cells play a multifaceted role in the fine-tuning of the GC response and identify IL-10 as an important mediator by which Tfr cells support the GC reaction.
Asunto(s)
Infecciones por Arenaviridae/inmunología , Linfocitos B/inmunología , Centro Germinal/inmunología , Interleucina-10/inmunología , Linfocitos T Reguladores/inmunología , Animales , Linfocitos B/fisiología , Diferenciación Celular , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Centro Germinal/fisiología , Interleucina-10/metabolismo , Activación de Linfocitos , Virus de la Coriomeningitis Linfocítica/inmunología , Ratones , Análisis de Secuencia de ARN , Linfocitos T Reguladores/fisiologíaRESUMEN
Chronological aging of the yeast Saccharomyces cerevisiae is attributed to multi-faceted traits especially those involving genome instability, and has been considered to be an aging model for post-mitotic cells in higher organisms. Telomeres are the physical ends of eukaryotic chromosomes, and are essential for genome integrity and stability. It remains elusive whether dysregulated telomerase activity affects chronological aging. We employed the CDC13-EST2 fusion gene, which tethers telomerase to telomeres, to examine the effect of constitutively active telomerase on chronological lifespan (CLS). The expression of Cdc13-Est2 fusion protein resulted in overlong telomeres (2 to 4 folds longer than normal telomeres), and long telomeres were stably maintained during long-term chronological aging. Accordingly, genome instability, manifested by accumulation of extra-chromosomal rDNA circle species, age-dependent CAN1 marker-gene mutation frequency and gross chromosomal rearrangement frequency, was significantly elevated. Importantly, inactivation of Sch9, a downstream kinase of the target of rapamycin complex 1 (TORC1), suppressed both the genome instability and accelerated chronological aging mediated by CDC13-EST2 expression. Interestingly, loss of the CDC13-EST2 fusion gene in the cells with overlong telomeres restored the regular CLS. Altogether, these data suggest that constitutively active telomerase is detrimental to the maintenance of genome stability, and promotes chronological aging in yeast.