Aging clocks based on accumulating stochastic variation.

Aging clocks have provided one of the most important recent breakthroughs in the biology of aging, and may provide indicators for the effectiveness of interventions in the aging process and preventive treatments for age-related diseases. The reproducibility of accurate aging clocks has reinvigorated the debate on whether a programmed process underlies aging. Here we show that accumulating stochastic variation in purely simulated data is sufficient to build aging clocks, and that first-generation and second-generation aging clocks are compatible with the accumulation of stochastic variation in DNA methylation or transcriptomic data. We find that accumulating stochastic variation is sufficient to predict chronological and biological age, indicated by significant prediction differences in smoking, calorie restriction, heterochronic parabiosis and partial reprogramming. Although our simulations may not explicitly rule out a programmed aging process, our results suggest that stochastically accumulating changes in any set of data that have a ground state at age zero are sufficient for generating aging clocks.

baz-2 enhances systemic proteostasis in vivo by regulating acetylcholine metabolism.

Neurodegenerative disorders, such as Alzheimer's disease (AD) or Huntington's disease (HD), are linked to protein aggregate neurotoxicity. According to the "cholinergic hypothesis," loss of acetylcholine (ACh) signaling contributes to the AD pathology, and therapeutic restoration of ACh signaling is a common treatment strategy. How disease causation and the effect of ACh are linked to protein aggregation and neurotoxicity remains incompletely understood, thus limiting the development of more effective therapies. Here, we show that BAZ-2, the Caenorhabditis elegans ortholog of human BAZ2B, limits ACh signaling. baz-2 mutations reverse aggregation and toxicity of amyloid-beta as well as polyglutamine peptides, thereby restoring health and lifespan in nematode models of AD and HD, respectively. The neuroprotective effect of Δbaz-2 is mediated by choline acetyltransferase, phenocopied by ACh-esterase depletion, and dependent on ACh receptors. baz-2 reduction or ectopic ACh treatment augments proteostasis via induction of the endoplasmic reticulum unfolded protein response and the ubiquitin proteasome system.

An agile radio-frequency source using internal linear sweeps of a direct digital synthesizer.

Agile rf sources are a common requirement for control systems in quantum science and technology platforms. The direct digital synthesizer (DDS) often fills this role by allowing programmable control of the rf signals. Due to limitations of the DDS architecture, implementing an agile rf source requires rapid and precisely-timed programming of discrete updates that restrict the source's agility. Here, we describe a microcontroller-based interface that exploits the DDS's internal linear sweep accumulator to perform both sequential linear sweeps and standard discrete updates at the ∼10µs scale. This allows updates to the swept parameter as fast as every 8 ns with greatly reduced communication and memory overhead. We demonstrate the utility of this system by using it as the reference of an optical phase-locked loop to implement rapid, adjustable laser frequency sweeps in a Rydberg electromagnetically induced transparency spectroscopy measurement.

The DREAM complex functions as conserved master regulator of somatic DNA-repair capacities.

The DNA-repair capacity in somatic cells is limited compared with that in germ cells. It has remained unknown whether not only lesion-type-specific, but overall repair capacities could be improved. Here we show that the DREAM repressor complex curbs the DNA-repair capacities in somatic tissues of Caenorhabditis elegans. Mutations in the DREAM complex induce germline-like expression patterns of multiple mechanisms of DNA repair in the soma. Consequently, DREAM mutants confer resistance to a wide range of DNA-damage types during development and aging. Similarly, inhibition of the DREAM complex in human cells boosts DNA-repair gene expression and resistance to distinct DNA-damage types. DREAM inhibition leads to decreased DNA damage and prevents photoreceptor loss in progeroid Ercc1-/- mice. We show that the DREAM complex transcriptionally represses essentially all DNA-repair systems and thus operates as a highly conserved master regulator of the somatic limitation of DNA-repair capacities.

Inheritance of paternal DNA damage by histone-mediated repair restriction.

How paternal exposure to ionizing radiation affects genetic inheritance and disease risk in the offspring has been a long-standing question in radiation biology. In humans, nearly 80% of transmitted mutations arise in the paternal germline1, but the transgenerational effects of ionizing radiation exposure has remained controversial and the mechanisms are unknown. Here we show that in sex-separated Caenorhabditis elegans strains, paternal, but not maternal, exposure to ionizing radiation leads to transgenerational embryonic lethality. The offspring of irradiated males displayed various genome instability phenotypes, including DNA fragmentation, chromosomal rearrangement and aneuploidy. Paternal DNA double strand breaks were repaired by maternally provided error-prone polymerase theta-mediated end joining. Mechanistically, we show that depletion of an orthologue of human histone H1.0, HIS-24, or the heterochromatin protein HPL-1, could significantly reverse the transgenerational embryonic lethality. Removal of HIS-24 or HPL-1 reduced histone 3 lysine 9 dimethylation and enabled error-free homologous recombination repair in the germline of the F1 generation from ionizing radiation-treated P0 males, consequently improving the viability of the F2 generation. This work establishes the mechanistic underpinnings of the heritable consequences of paternal radiation exposure on the health of offspring, which may lead to congenital disorders and cancer in humans.

Intra-cavity frequency-doubled VECSEL system for narrow linewidth Rydberg EIT spectroscopy.

High-power, narrow-linewidth light sources in the visible and UV spectra are in growing demand, particularly as quantum information and sensing research proliferates. Vertical external-cavity surface-emitting lasers (VECSELs) with intra-cavity frequency conversion are emerging as an attractive platform to fill these needs. Using such a device, we demonstrate 3.5 MHz full-width half-maximum Rydberg-state spectroscopy via electromagnetically induced transparency (EIT). The laser's 690 mW of output power at a wavelength of 475 nm enables large Rabi frequencies and strong signal-to-noise ratio in shorter measurement times. In addition, we characterize the frequency stability of the VECSEL using the delayed self-heterodyne technique and direct comparison with a commercial external-cavity diode laser (ECDL). We measure the pre-doubled light's Lorentzian linewidth to be 2π × 5.3(2) kHz, and the total linewidth to be 2π × 23(2) kHz. These measurements provide evidence that intra-cavity frequency-doubled VECSELs can perform precision spectroscopy at and below the MHz level, and are a promising tool for contemporary, and future, quantum technologies.

BiT age: A transcriptome-based aging clock near the theoretical limit of accuracy.

Aging clocks dissociate biological from chronological age. The estimation of biological age is important for identifying gerontogenes and assessing environmental, nutritional, or therapeutic impacts on the aging process. Recently, methylation markers were shown to allow estimation of biological age based on age-dependent somatic epigenetic alterations. However, DNA methylation is absent in some species such as Caenorhabditis elegans and it remains unclear whether and how the epigenetic clocks affect gene expression. Aging clocks based on transcriptomes have suffered from considerable variation in the data and relatively low accuracy. Here, we devised an approach that uses temporal scaling and binarization of C. elegans transcriptomes to define a gene set that predicts biological age with an accuracy that is close to the theoretical limit. Our model accurately predicts the longevity effects of diverse strains, treatments, and conditions. The involved genes support a role of specific transcription factors as well as innate immunity and neuronal signaling in the regulation of the aging process. We show that this binarized transcriptomic aging (BiT age) clock can also be applied to human age prediction with high accuracy. The BiT age clock could therefore find wide application in genetic, nutritional, environmental, and therapeutic interventions in the aging process.

H3K4me2 regulates the recovery of protein biosynthesis and homeostasis following DNA damage.

DNA damage causes cancer, impairs development and accelerates aging. Transcription-blocking lesions and transcription-coupled repair defects lead to developmental failure and premature aging in humans. Following DNA repair, homeostatic processes need to be reestablished to ensure development and maintain tissue functionality. Here, we report that, in Caenorhabditis elegans, removal of the WRAD complex of the MLL/COMPASS H3K4 methyltransferase exacerbates developmental growth retardation and accelerates aging, while depletion of the H3K4 demethylases SPR-5 and AMX-1 promotes developmental growth and extends lifespan amid ultraviolet-induced damage. We demonstrate that DNA-damage-induced H3K4me2 is associated with the activation of genes regulating RNA transport, splicing, ribosome biogenesis and protein homeostasis and regulates the recovery of protein biosynthesis that ensures survival following genotoxic stress. Our study uncovers a role for H3K4me2 in coordinating the recovery of protein biosynthesis and homeostasis required for developmental growth and longevity after DNA damage.

Spin-Wave Multiplexed Atom-Cavity Electrodynamics.

We introduce multiplexed atom-cavity quantum electrodynamics with an atomic ensemble coupled to a single optical cavity mode. Multiple Raman dressing beams establish cavity-coupled spin-wave excitations with distinctive spatial profiles. Experimentally, we demonstrate the concept by observing spin-wave vacuum Rabi splittings, selective superradiance, and interference in the cavity-mediated interactions of two spin waves. We highlight that the current experimental configuration allows rapid, interchangeable cavity coupling to 4 profiles with an overlap parameter of less than 10%, enough to demonstrate, for example, a quantum repeater network simulation in the cavity. With further improvements to the optical multiplexing setup, we infer the ability to access more than 10^{3} independent spin-wave profiles.

Quantum-Limited Atomic Receiver in the Electrically Small Regime.

We use a quantum sensor based on thermal Rydberg atoms to receive data encoded in electromagnetic fields in the extreme electrically small regime, with a sensing volume over 10^{7} times smaller than the cube of the electric field wavelength. We introduce the standard quantum limit for data capacity, and experimentally observe quantum-limited data reception for bandwidths from 10 kHz up to 30 MHz. In doing this, we provide a useful alternative to classical communication antennas, which become increasingly ineffective when the size of the antenna is significantly smaller than the wavelength of the electromagnetic field.

Twists in nonlinear magneto-optic rotation with cold atoms.

We observe a narrow secondary dispersive feature nested within conventional nonlinear magneto-optical rotation (NMOR) signals obtained with a laser-cooled rubidium vapor. A similar feature has been previously named a "twist" by Budker et. al., in the context of warm vapor optical magnetometry [Phys. Rev. A. 81, 5788-5791 (1998)], and was ascribed to simultaneous optical pumping through multiple nearby hyperfine levels. In this work the twist is observed in a cold atom vapor, where the hyperfine levels are individually addressable, and thus is due to a different mechanism. We experimentally and numerically characterize this twist in terms of magnetic field strength, polarization, and optical intensity and find good agreement between our data and numerical models. We find that the twist width is proportional to the magnetic field in the transverse direction, and therefore two independent directions of the magnetic field can be measured simultaneously. This technique is useful as a simple and rapid in-situ method for nulling background magnetic fields.

Nonlinear polarization spectroscopy of a Rydberg state for laser stabilization.

We demonstrate modulation-free laser stabilization to an atomic Rydberg transition using nonlinear polarization spectroscopy. To stabilize a laser to the upper transition of a three-level ladder scheme, the techniques of standard polarization spectroscopy are adapted to use a narrow, nonlinear coherence feature. We obtain a subnatural linewidth dispersive signal that is directly suitable for laser frequency stabilization. We examine the effect of laser polarization on the dispersive line shape. This technique stabilizes the laser to an absolute frequency reference, can be used with numerous Rydberg levels, and eliminates laser modulation, which can enable high bandwidth feedback.

Ionic specificity in pH regulated charged interfaces: Fe3+ versus La3+.

We determine the distribution of two trivalent ions Fe(3+) and La(3+) next to two different amphiphilic charged interfaces as ions or complexes, consisting of the phosphate lipid dihexadecyl phosphate (DHDP) and the fatty acid arachidic acid (AA). These amphiphiles provide a wide range of pK(a) values, from 2.1 (DHDP) to 5.1 (AA), thus allowing manipulation of the surface charge over extremely low pH (pH ∼1 or larger), and the two ions provide two limiting cases of specificity for the amphiphiles. We find that La(3+) distribution is mostly sensitive to the surface charge, whereas the Fe(3+) binding depends on its character in the solution and is highly specific, as indicated by the crucial role played by iron complexes (Fe(OH)(3) or Fe(OH)(2+)) forming covalent bonds even for an uncharged interface. The implications of the results to other ions and/or amphiphilic interfaces are also discussed.