Aging is the greatest risk factor for numerous diseases and mortality, and establishing geroprotective interventions targeting aging is required. Previous studies have suggested that healthy dietary patterns, such as the Mediterranean diet, are associated with delayed biological aging; however, these associations depend on nationality and sex. Therefore, this study aimed to investigate the relationship between dietary patterns identified through principal component analysis and biological aging in older men of Japan, one of the countries with the longest life expectancies. Principal component analysis identified two dietary patterns: a healthy Japanese dietary pattern and a Western-style dietary pattern. Eight epigenetic clocks, some of the most accurate aging biomarkers, were identified using DNA methylation data from whole-blood samples. Correlation analyses revealed that healthy Japanese dietary patterns were significantly negatively or positively correlated with multiple epigenetic age accelerations (AgeAccel), including AgeAccelGrim, FitAgeAccel, and age-adjusted DNAm-based telomere length (DNAmTLAdjAge). Conversely, the Western-style dietary pattern was observed not to correlate significantly with any of the examined AgeAccels or age-adjusted values. After adjusting for covariates, the healthy Japanese dietary pattern remained significantly positively correlated with DNAmTLAdjAge. Regression analysis showed that healthy Japanese dietary pattern contributed less to epigenetic age acceleration than smoking status. These findings suggest that a Western-style dietary pattern may not be associated with biological aging, whereas a healthy Japanese dietary pattern is associated with delayed biological aging in older Japanese men. Our findings provide evidence that healthy dietary patterns may have mild beneficial effects on delayed biological aging in older Japanese men.

The origin of biological rhythms goes back to the very beginning of life. They are observed in the animal and plant world at all levels of organization, from cells to ecosystems. As early as the 18th century, plant scientists were the first to explain the relationship between flowering cycles and environmental cycles, emphasizing the importance of daily light-dark cycles and the seasons. Our temporal structure is controlled by external and internal rhythmic signals. Light is the main synchronizer of the circadian system, as daily exposure to light entrains our clock over 24 hours, the endogenous period of the circadian system being close to, but not exactly, 24 hours. In 1960, a seminal scientific meeting, the Cold Spring Harbor Symposium on Biological Rhythms, brought together all the biological rhythms scientists of the time, a number of whom are considered the founders of modern chronobiology. All aspects of biological rhythms were addressed, from the properties of circadian rhythms to their practical and ecological aspects. Birth of chronobiology dates from this period, with the definition of its vocabulary and specificities in metabolism, photoperiodism, animal physiology, etc. At around the same time, and right up to the present day, research has focused on melatonin, the circadian neurohormone of the pineal gland, with data on its pattern, metabolism, control by light and clinical applications. However, light has a double face, as it has positive effects as a circadian clock entraining agent, but also deleterious effects, as it can lead to chronodisruption when exposed chronically at night, which can increase the risk of cancer and other diseases. Finally, research over the past few decades has unraveled the anatomical location of circadian clocks and their cellular and molecular mechanisms. This recent research has in turn allowed us to explain how circadian rhythms control physiology and health.

Numerous physiological and behavioral processes in living organisms exhibit strong rhythmicity and are regulated within a 24-hour cycle. These include locomotor activity and sleep patterns, feeding-fasting cycles, hormone synthesis, body temperature, and even mood and cognitive abilities, all of which are segregated into different phases throughout the day. These processes are governed by the internal timing system, a hierarchical multi-oscillator structure conserved across all organisms, from bacteria to humans. Circadian rhythms have been seen across multiple taxonomic kingdoms. In mammals, a hierarchical internal timing system is comprised of so-called central and periphereal clocks. Although these rhythms are intrinsic, they are under environmental influences, such as seasonal temperature changes, photoperiod variations, and day-night cycles. Recognizing the existence of biological rhythms and their primary external influences is crucial when designing and reporting experiments. Neglecting these physiological variations may result in inconsistent findings and misinterpretations. Thus, here we propose to incorporate biological rhythms into all stages of human and animal research, including experiment design, analysis, and reporting of findings. We also provide a flowchart to support decision-making during the design process, considering biological rhythmicity, along with a checklist outlining key factors that should be considered and documented throughout the study. This comprehensive approach not only benefits the field of chronobiology but also holds value for various other research disciplines. The insights gained from this study have the potential to enhance the validity, reproducibility, and overall quality of scientific investigations, providing valuable guidance for planning, developing, and communicating scientific studies.

Diabetic retinopathy (DR) is a severe microvascular complication of diabetes mellitus and a major cause of blindness in young adults. Multiple potential factors influence DR; however, the exact mechanisms are poorly understood. Advanced treatments for DR, including laser therapy, vitrectomy, and intraocular drug injections, slow the disease\'s progression but fail to cure or reverse visual impairment. Therefore, additional effective methods to prevent and treat DR are required. The biological clock plays a crucial role in maintaining balance in the circadian rhythm of the body. Poor lifestyle habits, such as irregular routines and high-fat diets, may disrupt central and limbic circadian rhythms. Disrupted circadian rhythms can result in altered glucose metabolism and obesity. Misaligned central and peripheral clocks lead to a disorder of the rhythm of glucose metabolism, and chronically high sugar levels lead to the development of DR. We observed a disturbance in clock function in patients with diabetes, and a misaligned clock could accelerate the development of DR. In the current study, we examine the relationship between circadian rhythm disorders, diabetes, and DR. We conclude that: 1) abnormal function of the central clock and peripheral clock leads to abnormal glucose metabolism, further causing DR and 2) diabetes causes abnormal circadian rhythms, further exacerbating DR. Thus, our study presents new insights into the prevention and treatment of DR.

The study of circadian rhythms in bacteria was transformed by studies of the cyanobacterium Synechococcus elongatus. However, in a number of respects S. elongatus is atypical, and while those unusual characteristics were helpful for rapid progress in the past, another commonly used cyanobacterial species, Synechocystis sp. PCC 6803, may be more representative and therefore more productive for future insights into bacterial clock mechanisms. In the past, circadian studies of Synechocystis have suffered from not having an excellent reporter of circadian gene expression, but we introduce here a new luminescence reporter that rivals the reporters that have been used so successfully in S. elongatus. Using this new system, we generate for the first time in Synechocystis circadian period mutants resulting from point mutations. The temperature compensation and dark-pulse resetting that mediates entrainment to the environment is characterized. Moreover, we analyse the complex organization of clock genes in Synechocystis and identify which genes are essential for circadian rhythmicity and adaptive fitness for entrainment and optimal phase alignment to environmental cycles (and which genes are not). These developments will provide impetus for new approaches towards understanding daily timekeeping mechanisms in bacteria.

The temporal dynamics in biological systems displays a wide range of behaviors, from periodic oscillations, as in rhythms, bursts, long-range (fractal) correlations, chaotic dynamics up to brown and white noise. Herein, we propose a comprehensive analytical strategy for identifying, representing, and analyzing biological time series, focusing on two strongly linked dynamics: periodic (oscillatory) rhythms and chaos. Understanding the underlying temporal dynamics of a system is of fundamental importance; however, it presents methodological challenges due to intrinsic characteristics, among them the presence of noise or trends, and distinct dynamics at different time scales given by molecular, dcellular, organ, and organism levels of organization. For example, in locomotion circadian and ultradian rhythms coexist with fractal dynamics at faster time scales. We propose and describe the use of a combined approach employing different analytical methodologies to synergize their strengths and mitigate their weaknesses. Specifically, we describe advantages and caveats to consider for applying probability distribution, autocorrelation analysis, phase space reconstruction, Lyapunov exponent estimation as well as different analyses such as harmonic, namely, power spectrum; continuous wavelet transforms; synchrosqueezing transform; and wavelet coherence. Computational harmonic analysis is proposed as an analytical framework for using different types of wavelet analyses. We show that when the correct wavelet analysis is applied, the complexity in the statistical properties, including temporal scales, present in time series of signals, can be unveiled and modeled. Our chapter showcase two specific examples where an in-depth analysis of rhythms and chaos is performed: (1) locomotor and food intake rhythms over a 42-day period of mice subjected to different feeding regimes; and (2) chaotic calcium dynamics in a computational model of mitochondrial function.

Diverse transcranial electrical stimulation (tES) techniques have recently been developed to elucidate the role of neural oscillations, but critically, it remains questionable whether neural entrainment genuinely occurs and is causally related to the resulting behavior. Here, we provide a perspective on an emerging integrative research program across systems, species, theoretical and experimental frameworks to elucidate the potential of tES to induce neural entrainment. We argue that such an integrative agenda is a requirement to establish tES as a tool to test the causal role of neural oscillations and highlight critical issues that should be considered when adopting a translational approach.

Pacemaking dysfunction (PD) may result in heart rhythm disorders, syncope or even death. Current treatment of PD using implanted electronic pacemakers has some limitations, such as finite battery life and the risk of repeated surgery. As such, the biological pacemaker has been proposed as a potential alternative to the electronic pacemaker for PD treatment. Experimentally and computationally, it has been shown that bio-engineered pacemaker cells can be generated from non-rhythmic ventricular myocytes (VMs) by knocking out genes related to the inward rectifier potassium channel current (IK1) or by overexpressing hyperpolarization-activated cyclic nucleotide gated channel genes responsible for the \"funny\" current (If). However, it is unclear if a bio-engineered pacemaker based on the modification of IK1- and If-related channels simultaneously would enhance the ability and stability of bio-engineered pacemaking action potentials. In this study, the possible mechanism(s) responsible for VMs to generate spontaneous pacemaking activity by regulating IK1 and If density were investigated by a computational approach. Our results showed that there was a reciprocal interaction between IK1 and If in ventricular pacemaker model. The effect of IK1 depression on generating ventricular pacemaker was mono-phasic while that of If augmentation was bi-phasic. A moderate increase of If promoted pacemaking activity but excessive increase of If resulted in a slowdown in the pacemaking rate and even an unstable pacemaking state. The dedicated interplay between IK1 and If in generating stable pacemaking and dysrhythmias was evaluated. Finally, a theoretical analysis in the IK1/If parameter space for generating pacemaking action potentials in different states was provided. In conclusion, to the best of our knowledge, this study provides a wide theoretical insight into understandings for generating stable and robust pacemaker cells from non-pacemaking VMs by the interplay of IK1 and If, which may be helpful in designing engineered biological pacemakers for application purposes.

Biological clocks have been developed at different molecular levels and were found to be more advanced in the presence of somatic illness and mental disorders. However, it is unclear whether different biological clocks reflect similar aging processes and determinants. In ~3000 subjects, we examined whether five biological clocks (telomere length, epigenetic, transcriptomic, proteomic, and metabolomic clocks) were interrelated and associated to somatic and mental health determinants. Correlations between biological aging indicators were small (all r < 0.2), indicating little overlap. The most consistent associations of advanced biological aging were found for male sex, higher body mass index (BMI), metabolic syndrome, smoking, and depression. As compared to the individual clocks, a composite index of all five clocks showed most pronounced associations with health determinants. The large effect sizes of the composite index and the low correlation between biological aging indicators suggest that one\'s biological age is best reflected by combining aging measures from multiple cellular levels.

[Figure: see text].