Semelparous Death as one Element of Iteroparous Aging Gone Large

The aging process in semelparous and iteroparous species is different, but how different? Death in semelparous organisms (e.g., Pacific salmon) results from suicidal reproductive effort (reproductive death). Aging (senescence) in iteroparous organisms such as humans is often viewed as a quite different process. Recent findings suggest that the nematode Caenorhabditis elegans, widely used to study aging, undergoes reproductive death. In post-reproductive C. elegans hermaphrodites, intestinal biomass is repurposed to produce yolk which when vented serves as a milk to support larval growth. This apparent benefit of lactation comes at the cost of intestinal atrophy in the mother. Germline removal and inhibition of insulin/IGF-1 signaling (IIS) suppress C. elegans reproductive pathology and greatly increase lifespan. Blocking sexual maturity, e.g., by gonadectomy, suppresses reproductive death thereby strongly increasing lifespan in semelparous organisms, but typically has little effect on lifespan in iteroparous ones. Similarly, reduced IIS causes relatively modest increases in lifespan in iteroparous organisms. We argue that the more regulated and plastic mechanisms of senescence in semelparous organisms, involving costly resource reallocation under endocrine control, exist as one extreme of an etiological continuum with mechanisms operative in iteroparous organisms. We suggest that reproductive death evolved by exaggeration of mechanisms operative in iteroparous species, where other mechanisms also promote senescence. Thus, knowledge of C. elegans senescence can guide understanding of mechanisms contributing to human aging

Is "cellular senescence" a misnomer?

One of the most striking findings in biogerontology in the 2010s was the demonstration that elimination of senescent cells delays many late-life diseases and extends lifespan in mice. This implied that accumulation of senescent cells promotes late-life diseases, particularly through action of senescent cell secretions (the senescence-associated secretory phenotype, or SASP). But what exactly is a senescent cell? Subsequent to the initial characterization of cellular senescence, it became clear that, prior to aging, this phenomenon is in fact adaptive. It supports tissue remodeling functions in a variety of contexts, including embryogenesis, parturition, and acute inflammatory processes that restore normal tissue architecture and function, such as wound healing, tissue repair after infection, and amphibian limb regeneration. In these contexts, such cells are normal and healthy and not in any way senescent in the true sense of the word, as originally meant by Hayflick. Thus, it is misleading to refer to them as "senescent." Similarly, the common assertion that senescent cells accumulate with age due to stress and DNA damage is no longer safe, particularly given their role in inflammation-a process that becomes persistent in later life. We therefore suggest that it would be useful to update some terminology, to bring it into line with contemporary understanding, and to avoid future confusion. To open a discussion of this issue, we propose replacing the term cellular senescence with remodeling activation, and SASP with RASP (remodeling-associated secretory phenotype)

Reproductive Suicide: Similar Mechanisms of Aging in C. elegans and Pacific Salmon

In some species of salmon, reproductive maturity triggers the development of massive pathology resulting from reproductive effort, leading to rapid post-reproductive death. Such reproductive death, which occurs in many semelparous organisms (with a single bout of reproduction), can be prevented by blocking reproductive maturation, and this can increase lifespan dramatically. Reproductive death is often viewed as distinct from senescence in iteroparous organisms (with multiple bouts of reproduction) such as humans. Here we review the evidence that reproductive death occurs in C. elegans and discuss what this means for its use as a model organism to study aging. Inhibiting insulin/IGF-1 signaling and germline removal suppresses reproductive death and greatly extends lifespan in C. elegans, but can also extend lifespan to a small extent in iteroparous organisms. We argue that mechanisms of senescence operative in reproductive death exist in a less catastrophic form in iteroparous organisms, particularly those that involve costly resource reallocation, and exhibit endocrine-regulated plasticity. Thus, mechanisms of senescence in semelparous organisms (including plants) and iteroparous ones form an etiological continuum. Therefore understanding mechanisms of reproductive death in C. elegans can teach us about some mechanisms of senescence that are operative in iteroparous organisms

Unraveling effects of anti-aging drugs on C. elegans using liposomes

Liposome-mediated delivery is a possible means to overcome several shortcomings with C. elegans as a model for identifying and testing drugs that retard aging. These include confounding interactions between drugs and the nematodes' bacterial food source and failure of drugs to be taken up into nematode tissues. To explore this, we have tested liposome-mediated delivery of a range of fluorescent dyes and drugs in C. elegans. Liposome encapsulation led to enhanced effects on lifespan, requiring smaller quantities of compounds, and enhanced uptake of several dyes into the gut lumen. However, one dye (Texas red) did not cross into nematode tissues, showing that liposomes cannot ensure the uptake of all compounds. Of six compounds previously reported to extend lifespan (vitamin C, N-acetylcysteine, glutathione (GSH), trimethadione, thioflavin T (ThT), and rapamycin), this effect was reproduced for the latter four in a condition-dependent manner. For GSH and ThT, antibiotics abrogated life extension, implying a bacterially mediated effect. With GSH, this was attributable to reduced early death from pharyngeal infection and associated with alterations of mitochondrial morphology in a manner suggesting a possible innate immune training effect. By contrast, ThT itself exhibited antibiotic effects. For rapamycin, significant increases in lifespan were only seen when bacterial proliferation was prevented. These results document the utility and limitations of liposome-mediated drug delivery for C. elegans. They also illustrate how nematode-bacteria interactions can determine the effects of compounds on C. elegans lifespan in a variety of ways

Mitochondrial Signature in Human Monocytes and Resistance to Infection in C. elegans During Fumarate-Induced Innate Immune Training.

Monocytes can develop immunological memory, a functional characteristic widely recognized as innate immune training, to distinguish it from memory in adaptive immune cells. Upon a secondary immune challenge, either homologous or heterologous, trained monocytes/macrophages exhibit a more robust production of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, than untrained monocytes. Candida albicans, β-glucan, and BCG are all inducers of monocyte training and recent metabolic profiling analyses have revealed that training induction is dependent on glycolysis, glutaminolysis, and the cholesterol synthesis pathway, along with fumarate accumulation; interestingly, fumarate itself can induce training. Since fumarate is produced by the tricarboxylic acid (TCA) cycle within mitochondria, we asked whether extra-mitochondrial fumarate has an effect on mitochondrial function. Results showed that the addition of fumarate to monocytes induces mitochondrial Ca2+ uptake, fusion, and increased membrane potential (Δψm), while mitochondrial cristae became closer to each other, suggesting that immediate (from minutes to hours) mitochondrial activation plays a role in the induction phase of innate immune training of monocytes. To establish whether fumarate induces similar mitochondrial changes in vivo in a multicellular organism, effects of fumarate supplementation were tested in the nematode worm Caenorhabditis elegans. This induced mitochondrial fusion in both muscle and intestinal cells and also increased resistance to infection of the pharynx with E. coli. Together, these findings contribute to defining a mitochondrial signature associated with the induction of innate immune training by fumarate treatment, and to the understanding of whole organism infection resistance

Optimizing Sparse RFI Prediction using Deep Learning

Radio Frequency Interference (RFI) is an ever-present limiting factor among radio telescopes even in the most remote observing locations. When looking to retain the maximum amount of sensitivity and reduce contamination for Epoch of Reionization studies, the identification and removal of RFI is especially important. In addition to improved RFI identification, we must also take into account computational efficiency of the RFI-Identification algorithm as radio interferometer arrays such as the Hydrogen Epoch of Reionization Array grow larger in number of receivers. To address this, we present a Deep Fully Convolutional Neural Network (DFCN) that is comprehensive in its use of interferometric data, where both amplitude and phase information are used jointly for identifying RFI. We train the network using simulated HERA visibilities containing mock RFI, yielding a known "ground truth" dataset for evaluating the accuracy of various RFI algorithms. Evaluation of the DFCN model is performed on observations from the 67 dish build-out, HERA-67, and achieves a data throughput of 1.6$\times 10^{5}$ HERA time-ordered 1024 channeled visibilities per hour per GPU. We determine that relative to an amplitude only network including visibility phase adds important adjacent time-frequency context which increases discrimination between RFI and Non-RFI. The inclusion of phase when predicting achieves a Recall of 0.81, Precision of 0.58, and $F_{2}$ score of 0.75 as applied to our HERA-67 observations.Comment: 11 pages, 7 figure

Mitigating Internal Instrument Coupling for 21 cm Cosmology. II. A Method Demonstration with the Hydrogen Epoch of Reionization Array

We present a study of internal reflection and cross-coupling systematics in Phase I of the Hydrogen Epoch of Reionization Array (HERA). In a companion paper, we outlined the mathematical formalism for such systematics and presented algorithms for modeling and removing them from the data. In this work, we apply these techniques to data from HERA's first observing season as a method demonstration. The data show evidence for systematics that, without removal, would hinder a detection of the 21 cm power spectrum for the targeted Epoch of Reionization (EoR) line-of-sight modes in the range 0.2 h −1 Mpc−1 < ${k}_{\parallel }$ < 0.5 h −1 Mpc−1. In particular, we find evidence for nonnegligible amounts of spectral structure in the raw autocorrelations that overlaps with the EoR window and is suggestive of complex instrumental effects. Through systematic modeling on a single night of data, we find we can recover these modes in the power spectrum down to the integrated noise floor, achieving a dynamic range in the EoR window of 106 in power (mK2 units) with respect to the bright galactic foreground signal. Future work with deeper integrations will help determine whether these systematics can continue to be mitigated down to EoR levels. For future observing seasons, HERA will have upgraded analog and digital hardware to better control these systematics in the field

Detection of Cosmic Structures using the Bispectrum Phase. II. First Results from Application to Cosmic Reionization Using the Hydrogen Epoch of Reionization Array

Characterizing the epoch of reionization (EoR) at $z\gtrsim 6$ via the redshifted 21 cm line of neutral Hydrogen (HI) is critical to modern astrophysics and cosmology, and thus a key science goal of many current and planned low-frequency radio telescopes. The primary challenge to detecting this signal is the overwhelmingly bright foreground emission at these frequencies, placing stringent requirements on the knowledge of the instruments and inaccuracies in analyses. Results from these experiments have largely been limited not by thermal sensitivity but by systematics, particularly caused by the inability to calibrate the instrument to high accuracy. The interferometric bispectrum phase is immune to antenna-based calibration and errors therein, and presents an independent alternative to detect the EoR HI fluctuations while largely avoiding calibration systematics. Here, we provide a demonstration of this technique on a subset of data from the Hydrogen Epoch of Reionization Array (HERA) to place approximate constraints on the brightness temperature of the intergalactic medium (IGM). From this limited data, at $z=7.7$ we infer "$1\sigma$" upper limits on the IGM brightness temperature to be $\le 316$ "pseudo" mK at $\kappa_\parallel=0.33$ "pseudo" $h$ Mpc$^{-1}$ (data-limited) and $\le 1000$ "pseudo" mK at $\kappa_\parallel=0.875$ "pseudo" $h$ Mpc$^{-1}$ (noise-limited). The "pseudo" units denote only an approximate and not an exact correspondence to the actual distance scales and brightness temperatures. By propagating models in parallel to the data analysis, we confirm that the dynamic range required to separate the cosmic HI signal from the foregrounds is similar to that in standard approaches, and the power spectrum of the bispectrum phase is still data-limited (at $\gtrsim 10^6$ dynamic range) indicating scope for further improvement in sensitivity as the array build-out continues.Comment: 22 pages, 12 figures (including sub-figures). Published in PhRvD. Abstract may be slightly abridged compared to the actual manuscript due to length limitations on arXi