bims-ciryme 2026-06-07 papers

Nat Aging. 2026 Jun 02.

Time-restricted feeding extends healthspan in both sexes and lifespan in male C57BL/6 J mice.

Samantha E Iiams, Nathan J Skinner, Mary Wight-Carter, Victoria A Acosta-Rodríguez, Carla B Green, Joseph S Takahashi.

Time-restricted feeding (TRF) aligned with an organism's circadian rhythm has been shown to improve health, but its long-term effects on healthspan and lifespan in mammals, especially under standard dietary conditions that do not promote obesity, remain unclear. Here, we examined the impact of 12-h and 8-h nightly TRF windows in 264 male and 264 female C57BL/6 J mice fed regular chow. TRF improved multiple health measures, including behavioral rhythmicity, body weight and composition, frailty, and disease onset. These effects were most pronounced in the 8-h TRF group, which exhibited voluntary caloric restriction in addition to time restriction. A composite Healthspan Index revealed that TRF extended healthspan in both sexes, though the benefits were more prolonged in female mice relative to their total lifespan. Median lifespan was significantly extended in male mice under 8-h TRF by 12%, whereas female mice showed no significant lifespan extension. These results demonstrate sex-specific effects of TRF on mammalian aging.

DOI: https://doi.org/10.1038/s43587-026-01129-8

bioRxiv. 2026 May 22. pii: 2026.05.20.723021. [Epub ahead of print]

A Screen To Identify Protein Phosphatases with Roles in Circadian Period, Temperature Compensation and Output in the Neurospora Circadian Clock.

Adrienne K Mehalow, Bin Wang, Jennifer J Loros, Jay C Dunlap.

The circadian clock is a highly conserved evolutionary advantage which allows organisms to anticipate regular changes in daily environmental conditions. Clocks from fungi to mammals rely on a transcription-translation feedback loop (TTFL) mechanism. Phosphorylation is understood to be a critical regulatory step for maintaining the period of the circadian clock and feedback loop closure. The role of kinases in the Neurospora clock has been examined extensively; however, phosphatases have not been systematically interrogated. By re-examining the Neurospora genome using current informatic tools we identified the 30 genes previously identified as encoding protein phosphatases as well as 13 novel genes, and we assessed the function of the core circadian clock in 39 non-essential phosphatases using a real-time luciferase reporter. We observed both period lengthening and shortening effects, which are not restricted to a single phosphatase family or fold. All but one deletion mutant maintained a rhythmic core clock. In addition, we observed a new temperature compensation defect in the previously studied knockout of phosphatase pph-4 , the result of nutritional growth conditions.

DOI: https://doi.org/10.64898/2026.05.20.723021

bioRxiv. 2026 May 25. pii: 2026.05.23.726942. [Epub ahead of print]

Roles for Phosphatase PP4 in Rhythmicity and Compensation in the Neurospora Circadian System.

Adrienne K Mehalow, Ziyan Wang, Scott A Gerber, Jennifer J Loros, Jay C Dunlap.

The circadian clock is a highly conserved timer which allows organisms to anticipate future conditions driven by the 24-hour day on planet Earth. Circadian clocks from fungi to mammals are based on a transcription-translation feedback loop (TTFL) molecular architecture. Progressive phosphorylation of core clock proteins can alter both their activity and stability and is required for all known circadian TTFLs. The mechanism for kinase control of circadian period has been extensively studied; however, the mechanism(s) whereby phosphatases alter period remain less studied. Based on the observation that strains of Neurospora crassa lacking phosphatase pp 4 display a short circadian period, we investigated regulation of pp 4 and its role in the clockworks. In addition to period shortening, loss of pp 4 results in a significant loss of both temperature and nutritional compensation, consistent with substrates within the core clock. We identify the clock-relevant PP4 phosphatase holoenzyme as a heterotrimer, and identify two activators of PP4 which regulate circadian period. Biochemical and cell biological analyses suggest that PP4 acts in the nucleus, and a mass spectrometry-based screen identified NCU07414, a member of the HSP40 chaperone system, as a novel PP4 binding partner whose loss results in a dramatically shortened period of the clock when ablated. A model consistent with the data suggests that PP4 may act in opposition to kinases to influence the rate of accumulation of the clock-relevant phosphorylations that determine circadian period.

DOI: https://doi.org/10.64898/2026.05.23.726942

bioRxiv. 2026 May 18. pii: 2026.05.18.726011. [Epub ahead of print]

Longitudinal Tracking Reveals Developmental Transitions in Zebrafish Clock Gene Expression.

Camila Morales Fénero, Raina E Sacksteder, Jacqueline M Kimmey.

Circadian clocks coordinate physiological and behavioral rhythms by synchronizing biological processes with environmental cues. These rhythms emerge during development, but it remains unclear whether their component genes are activated by a common program or assembled through distinct regulatory pathways. To address this, we used longitudinal luciferase reporters to monitor per3 and per2 expression across zebrafish embryonic and larval development. Although both genes are canonical components of the circadian clock, they showed strikingly different developmental regulation. Two temporal frames of circadian gene expression were identified: an embryonic stage and a larval stage, each evident under different entrainment conditions. Per3 displayed early rhythmic expression in light/dark conditions, which was independent of per2 and cry1a light-entrainment regulation, but required bmal activity. Meanwhile, per2 displayed light-responsive transcription and remained largely bmal -independent. At the same time, both genes exhibited an endogenous embryonic expression that could not be explained solely by light-driven regulation, indicating that developmental inputs contribute to clock gene activation before mature larval rhythms are established. These findings demonstrate that the zebrafish circadian system is not assembled through a single synchronized onset of clock gene expression, but through gene-specific regulatory programs that shift across development.

DOI: https://doi.org/10.64898/2026.05.18.726011

Neuron. 2026 Jun 03. pii: S0896-6273(26)00381-8. [Epub ahead of print]

A hypothalamic circuit for anticipating future changes in energy balance.

Samuel J Walker, Elijah D Lowenstein, Amelia M Douglass, Callum M P Thomas, Joseph C Madara, Hakan Kucukdereli, Eunice A Barbosa-Meillon, Jenkang Tao, Jon M Resch, Bradford B Lowell.

AgRP neurons cause hunger, the drive to seek and consume food. Their activation by fasting is key for survival and is thought to be triggered by feedback when energy stores are low. However, we know that environmental cues can also regulate AgRP neurons since cues that predict future food intake rapidly inhibit AgRP neurons, but is the converse true: can the prediction of future fasting rapidly activate AgRP neurons? Here, we show in mice that such rapid fasting activation of AgRP neurons does occur. This rapid activation is driven by excitatory input from paraventricular hypothalamic (PVH) neurons expressing Sim2, which are bidirectionally sensitive to predictions of future energy state. Thus, cognitively processed contextual information conveyed by PVHSim2 neurons strongly activates AgRP neurons. Lastly, chronic silencing of PVHSim2 neurons causes persistent hypophagia. This PVHSim2-to-AgRP-neuron circuit, by anticipating and preventing negative energy balance, provides an important new dimension of hunger regulation.

Keywords: AGRP neurons; appetite; energy balance; feeding; food intake; homeostasis; hunger; hypothalamus; metabolism; neuroscience

DOI: https://doi.org/10.1016/j.neuron.2026.05.010

bioRxiv. 2026 May 18. pii: 2026.05.14.725282. [Epub ahead of print]

Time Restricted Feeding Mitigates High-Fat-Diet Induced Sleep Disruption and Amplifies NREM Substates.

Michael T Y Lam, Koorosh Askari, Kousha Changiz Ashtiani, Yushi Li, Nick A Andrews, Satchidananda Panda.

The effects of diet quality and timing on sleep quality remain poorly understood, particularly at the level of sleep microarchitecture. Traditional visual scoring captures only coarse sleep stages, overlooking the marked heterogeneity of electroencephalographic (EEG) patterns in non-rapid eye movement (NREM) sleep of mice. Here, we apply a pipeline that combines EEG feature extraction with unsupervised machine-learning-based clustering to resolve discrete NREM substates and ask how a high-fat diet (HFD) and time- restricted feeding (TRF) affect sleep microarchitectures. HFD increases sleep latency and sleep fragmentation; both abnormalities were ameliorated by active phase TRF. Clustering of 10s epochs identified two high-amplitude NREM substates sensitive to TRF: Cluster 1 , enriched in low-delta power and peaking early in the light phase (ZT 0-6), consistent with canonical slow-wave sleep, and Cluster 6, characterized by elevated alpha, sigma, and beta power and peaking in the latter half of the light phase (ZT6-12). TRF increases the frequency of both NREM substates, particularly within longer uninterrupted sleep episodes during the light phases. These findings introduce an objective framework for quantifying murine sleep microarchitecture and show that aligning caloric intake with the circadian active window mitigates HFD-induced macro-level sleep disruption while selectively enhancing two physiologically distinct NREM substates.
Significance Statement: Time-restricted eating - targeting food intake to a defined window during the circadian active phase - confers well-established metabolic benefits, but its impact on sleep is largely underexplored. Using continuous EEG/EMG recordings, we show that an active- phase eating window mitigates high-fat-diet-induced sleep disruption in mice. We employed a novel machine-learning pipeline, further revealing that timed eating selectively increases distinct NREM substates, demonstrating that "when we eat" fine-tunes the macro- and microarchitecture of sleep. These insights lay the foundation for future translational studies and clinical trials aimed at harnessing timed eating to enhance both metabolic and sleep health.

DOI: https://doi.org/10.64898/2026.05.14.725282