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Aging is the strongest contributor to the development and severity of many chronic and infectious diseases, primarily through age-related increases in low-grade inflammation (inflammaging) and decreases in immune function (immunosenescence). Metabolic reprogramming in immune cells is a significant contributor to functional and phenotypic changes in these cells, but little is known about the direct effect of aging on immunometabolism. This review highlights several recent advances in this field, focusing on mitochondrial dysfunction, NAD+ metabolism, and therapeutic reprogramming in aged monocytes and macrophages. Perspectives on opportunities for future research in this area are also provided. Targeting immunometabolism is a promising strategy for designing therapeutics for a wide variety of age-related diseases.

Modified cholesterols such as oxidized low-density lipoprotein (OxLDL) contribute to atherosclerosis and other disorders through the promotion of foam cell formation and inflammation. In recent years, it has become evident that immune cell responses to inflammatory molecules such as OxLDLs depend on cellular metabolic functions. This review examines the known effects of OxLDL on immunometabolism and immune cell responses in atherosclerosis and several other diseases. We additionally provide context on the relationship between OxLDL and aging/senescence and identify gaps in the literature and our current understanding in these areas. [ABSTRACT FROM AUTHOR]

Abstract Objective Age‐associated decreases in immune functions are precipitated by a variety of mechanisms and affect nearly every immune cell subset. In myeloid cells, aging reduces numbers of phagocytes and impairs their functional abilities, including antigen presentation, phagocytosis, and bacterial clearance. Recently, we described an aging effect on several functions in monocytes, including impaired mitochondrial function and reduced inflammatory cytokine gene expression during stimulation with lipopolysaccharide. We hypothesized that circulating factors altered by the aging process underly these changes. Growth differentiation factor‐15 (GDF‐15) is a distant member of the transforming growth factor‐β superfamily that has known anti‐inflammatory effects in macrophages and has been shown to be highly differentially expressed during aging. Methods We used biobanked plasma samples to assay circulating GDF‐15 levels in subjects from our previous studies and examined correlations between GDF‐15 and monocyte function. Results Monocyte interleukin‐6 production due to lipopolysaccharide stimulation was negatively correlated to plasma GDF‐15. Additionally, GDF‐15 was positively correlated to circulating CD16 + monocyte proportions and negatively correlated to monocyte mitochondrial respiratory capacity. Conclusions These results suggest that GDF‐15 is a potential circulating factor affecting a variety of monocyte functions and promoting monocyte immunosenescence and thus may be an attractive candidate for therapeutic intervention to ameliorate this.

Background: No consensus exists in the clinical transcranial magnetic stimulation (TMS) field as to the best method for targeting the left dorsolateral prefrontal cortex (DLPFC) for depression treatment. Two common targeting methods are the Beam F3 method and the 5.5 cm rule. Objective: Evaluate the anatomical reliability of technician-identified DLPFC targets and obtain consensus average brain and scalp MNI152 coordinates. Methods: Three trained TMS technicians performed repeated targeting using both the Beam F3 method and 5.5 cm rule in ten healthy subjects (n = 162). Average target locations were plotted on 7T structural MRIs to compare inter- and intra-rater reliability, respectively. Results: (1) Beam F3 inter- and intra-rater reliability was superior to 5.5 cm targeting (p = 0.0005 and 0.0035). (2) The average Beam F3 location was 2.6±1.0 cm anterolateral to the 5.5 cm method. Conclusions: Beam F3 targeting demonstrates greater precision and reliability than the 5.5 cm method and identifies a different anatomical target.

Aging increases susceptibility to and severity of a variety of chronic and infectious diseases. Underlying this is dysfunction of the immune system, including chronic increases in low-grade inflammation (inflammaging) and age-related immunosuppression (immunosenescence). Growth differentiation factor-15 (GDF-15) is a stress-, infection-, and inflammation-induced cytokine which is increased in aging and suppresses immune responses. This mini review briefly covers existing knowledge on the immunoregulatory and anti-inflammatory roles of GDF-15, as well as its potential importance in aging and immune function.

CDMS II data from the five-tower runs at the Soudan Underground Laboratory were reprocessed with an improved charge-pulse fitting algorithm. Two new analysis techniques to reject surface-event backgrounds were applied to the 612 kg days germanium-detector weakly interacting massive particle (WIMP)-search exposure. An extended analysis was also completed by decreasing the 10 keV analysis threshold to ∼5keV, to increase sensitivity near a WIMP mass of 8GeV/c2. After unblinding, there were zero candidate events above a deposited energy of 10 keV and six events in the lower-threshold analysis. This yielded minimum WIMP-nucleon spin-independent scattering cross-section limits of 1.8×10-44 and 1.18×10-41 at 90% confidence for 60 and 8.6GeV/c2 WIMPs, respectively. This improves the previous CDMS II result by a factor of 2.4 (2.7) for 60 (8.6)GeV/c2 WIMPs.

We examine the consequences of the effective field theory (EFT) of dark matter-nucleon scattering for current and proposed direct detection experiments. Exclusion limits on EFT coupling constants computed using the optimum interval method are presented for SuperCDMS Soudan, CDMS II, and LUX, and the necessity of combining results from multiple experiments in order to determine dark matter parameters is discussed. We demonstrate that spectral differences between the standard dark matter model and a general EFT interaction can produce a bias when calculating exclusion limits and when developing signal models for likelihood and machine learning techniques. We also discuss the implications of the EFT for the next-generation (G2) direct detection experiments and point out regions of complementarity in the EFT parameter space.

A hallmark of COVID-19 is a hyperinflammatory state associated with severity. Monocytes undergo metabolic reprogramming and produce inflammatory cytokines when stimulated with SARS-CoV-2. We hypothesized that binding by the viral spike protein mediates this effect, and that drugs which regulate immunometabolism could inhibit the inflammatory response. Monocytes stimulated with recombinant SARS-CoV-2 spike protein subunit 1 showed a dose-dependent increase in glycolytic metabolism associated with production of pro-inflammatory cytokines. This response was dependent on hypoxia-inducible factor-1α, as chetomin inhibited glycolysis and cytokine production. Inhibition of glycolytic metabolism by 2-deoxyglucose (2-DG) or glucose deprivation also inhibited the glycolytic response, and 2-DG strongly suppressed cytokine production. Glucose-deprived monocytes rescued cytokine production by upregulating oxidative phosphorylation, an effect which was not present in 2-DG-treated monocytes due to the known effect of 2-DG on suppressing mitochondrial metabolism. Finally, pre-treatment of monocytes with metformin strongly suppressed spike protein-mediated cytokine production and metabolic reprogramming. Likewise, metformin pre-treatment blocked cytokine induction by SARS-CoV-2 strain WA1/2020 in direct infection experiments. In summary, the SARS-CoV-2 spike protein induces a pro-inflammatory immunometabolic response in monocytes that can be suppressed by metformin, and metformin likewise suppresses inflammatory responses to live SARS-CoV-2. This has potential implications for the treatment of hyperinflammation during COVID-19.

We report on the results of a search for a Weakly Interacting Massive Particle (WIMP) signal in low-energy data of the Cryogenic Dark Matter Search experiment using a maximum likelihood analysis. A background model is constructed using geant4 to simulate the surface-event background from Pb210 decay-chain events, while using independent calibration data to model the gamma background. Fitting this background model to the data results in no statistically significant WIMP component. In addition, we perform fits using an analytic ad hoc background model proposed by Collar and Fields, who claimed to find a large excess of signal-like events in our data. We confirm the strong preference for a signal hypothesis in their analysis under these assumptions, but excesses are observed in both single- and multiple-scatter events, which implies the signal is not caused by WIMPs, but rather reflects the inadequacy of their background model.

While the standard model of particle physics does not include free particles with fractional charge, experimental searches have not ruled out their existence. We report results from the Cryogenic Dark Matter Search (CDMS II) experiment that give the first direct-detection limits for cosmogenically produced relativistic particles with electric charge lower than e/6. A search for tracks in the six stacked detectors of each of two of the CDMS II towers finds no candidates, thereby excluding new parameter space for particles with electric charges between e/6 and e/200.

We report a first search for weakly interacting massive particles (WIMPs) using the background rejection capabilities of SuperCDMS. An exposure of 577 kg days was analyzed for WIMPs with mass

SuperCDMS is an experiment designed to directly detect weakly interacting massive particles (WIMPs), a favored candidate for dark matter ubiquitous in the Universe. In this Letter, we present WIMP-search results using a calorimetric technique we call CDMSlite, which relies on voltage-assisted Luke-Neganov amplification of the ionization energy deposited by particle interactions. The data were collected with a single 0.6 kg germanium detector running for ten live days at the Soudan Underground Laboratory. A low energy threshold of 170  eVee (electron equivalent) was obtained, which allows us to constrain new WIMP-nucleon spin-independent parameter space for WIMP masses below 6  GeV/c2.

We report results of a search for weakly interacting massive particles (WIMPS) with the silicon detectors of the CDMS II experiment. This blind analysis of 140.2 kg day of data taken between July 2007 and September 2008 revealed three WIMP-candidate events with a surface-event background estimate of 0.41(-0.08)(+0.20)(stat)(-0.24)(+0.28)(syst). Other known backgrounds from neutrons and 206Pb are limited to

The SuperCDMS experiment in the Soudan Underground Laboratory searches for dark matter with a 9-kg array of cryogenic germanium detectors. Symmetric sensors on opposite sides measure both charge and phonons from each particle interaction, providing excellent discrimination between electron and nuclear recoils, and between surface and interior events. Surface event rejection capabilities were tested with two 210Pb sources producing ∼130 beta decays/hr. In ∼800 live hours, no events leaked into the 8-115 keV signal region, giving upper limit leakage fraction 1.7 × 10-5 at 90% C.L., corresponding to < 0.6 surface event background in the future 200-kg SuperCDMS SNOLAB experiment. © 2013 AIP Publishing LLC.

We report results of a search for weakly interacting massive particles (WIMPs) with the Si detectors of the CDMS II experiment. This report describes a blind analysis of the first data taken with CDMS II's full complement of detectors in 2006-2007; results from this exposure using the Ge detectors have already been presented. We observed no candidate WIMP-scattering events in an exposure of 55.9 kg-days before analysis cuts, with an expected background of ∼1.1 events. The exposure of this analysis is equivalent to 10.3 kg-days over a recoil energy range of 7-100 keV for an ideal Si detector and a WIMP mass of 10 GeV/c2. These data set an upper limit of 1.7×10-41 cm2 on the WIMP-nucleon spin-independent cross section of a 10 GeV/c2 WIMP. These data exclude parameter space for spin-independent WIMP-nucleon elastic scattering that is relevant to recent searches for low-mass WIMPs. © 2013 American Physical Society.

Abstract Background Inflammaging is a condition of chronic low-grade inflammation due to the aging process and is associated with a variety of chronic diseases. Monocytes are innate immune cells which contribute to inflammation and are dysregulated during aging, demonstrated reduced phagocytosis, increased inflammation, and alterations in subset proportions. Metabolism is known to determine immune cell function, with quiescent and anti-inflammatory cells primarily relying on fatty acid oxidation, while activated and inflammatory cells primarily rely on glycolysis. We have previously shown an age-related decrease in mitochondrial respiratory capacity in monocytes, so we hypothesized here that a compensatory shift toward glycolysis would occur which would also exacerbate inflammation. Results Using Seahorse assays, we profiled glycolysis in classical monocytes isolated from older (60–80 yr) and younger (18–35 yr) adults. Aging did not affect parameters of basal glycolysis in the glycolysis stress test, nor did it alter glycolytic activation early (2 h) or later (24 h) post-LPS stimulation. Cytokine gene expression was unchanged between aged and young subjects at 2 h post-LPS but was reduced in older subjects at 24 h post-LPS either significantly (IL1B) or near-significantly (IL6, IL10). Conclusions Aging appears not to affect glycolytic metabolism ex vivo in classical monocytes, but may reduce cytokine expression at later timepoints. Studies examining monocytes stimulated with age-altered circulating factors or with other pattern recognition receptor agonists may shed further light on monocyte metabolism as a determinant of immunosenescence and inflammaging.