When the 'biological clock' runs out: late night mortality.
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Conventional models of population dynamics of biological species do not take into account the fact that activity of most living organisms is under control of biological clocks, which are oscillators with periods near 1 day, 1 year, and so on. Here proposed are new categories of population dynamics models which are combinations of Lotka-Volterra type of equations (as a simplest example; in fact, an arbitrary type may be used) and equations of the biological oscillators. Such models may be particularly useful in addressing to those problems which are inaccessible with conventional models. A simple example of such models with distributed clock periods is proposed and studied numerically and analytically to consider why periods of biological rhythms are not precisely one day or one year, etc., as is often questioned. For this purpose, a notion of survival index is introduced to measure the degree of success in survival. It turns out that clock periods equal or close to that of the milieu are not necessarily advantageous for survival and can even lead to extinction; survival is then most successful at the edge of entrainment. This may provide a clue to answer the question. It is also found that survival is difficult for those species which cannot be entrained by the environmental cycle.
Every day, we experience profound changes in our mental and physical condition as body and brain alternate between states of high activity during the waking day and rest during night-time sleep. The fundamental evolutionary adaptation to these profound daily changes in our physiological state is an endogenous 24-h clock. This biological clock enables us to prepare ourselves to these daily changes, instead of only being able to show a passive and delayed response. During the past decade, enormous progress has been made in determining possible molecular components of the biological clock. An important question remains, however, regarding how the rhythmic signal from the biological clock is spread throughout the body to control its physiology and behavior. Indeed, ultimately, the only raison d'etre for the biological clock is its output (Green 1998). In the present review, we propose that the main mechanism for the spreading time-of-day information throughout the body consists of different circadian waves of suprachiasmatic nucleus (SCN) transmitter release, directed to a restricted number of specific SCN target areas, and affecting both neuroendocrine mechanisms and the peripheral autonomic nervous system.
Many aspects of life in plants, animals and humans are controlled by light. Endogenous, so-called circadian rhythms in the body deviate from the exact 24-hour day and have typically a period of around 25.5 hours in man. Normally these rhythms adapt to the external 24-hour day-and night changes but under constant conditions the rhythms can free run. Many studies show how important the interplay between light and the circadian rhythms are for man as well as for other organisms. The control of these rhythms by light is mediated via the retina and the melatonin system in man. The adaptation of the rhythms is very important in shift work, in rapid jet lag travels over time zones, etc. Organisms often use the circadian rhythm to determine the length of day and of night, a feature that has given rise to the term biological clocks. A biological clock provides possibilities to determine the proper time for physiological processes to start in plants and animals (flowering, hibernation etc). The importance of light and circadian rhythms for seasonal affective disorders and manic-depressive disorders is also discussed. For several organisms one has now been able to specify genes that determine the period of the clocks. The rhythmic physiologic processes, the light reactions and the general importance of light for rhythms and for man are now studied at the molecular level.
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Biological rhythms are driven in mammals by a central circadian clock located in the suprachiasmatic nucleus (SCN). Light-induced phase shifting of this clock is correlated with phosphorylation of CREB at Ser133 in the SCN. Here, we characterize phosphorylation of CREB at Ser142 and describe its contribution to the entrainment of the clock. In the SCN, light and glutamate strongly induce CREB Ser142 phosphorylation. To determine the physiological relevance of phosphorylation at Ser142, we generated a mouse mutant, CREB(S142A), lacking this phosphorylation site. Light-induced phase shifts of locomotion and expression of c-Fos and mPer1 in the SCN are significantly attenuated in CREB(S142A) mutants. Our findings provide genetic evidence that CREB Ser142 phosphorylation is involved in the entrainment of the mammalian clock and reveal a novel phosphorylation-dependent regulation of CREB activity.
The response of the Euglena gracilis (Klebs strain Z) photosynthesis circadian rhythm to three calmodulin antagonists was examined. In the presence of an antagonist, the photosynthetic reactions were uncoupled from the biological clock. Instead of the highly predictable rhythmic pattern characteristic of a biological clock-controlled circadian rhythm, the photosynthetic rate appears to be influenced by the light/dark cycle. The rate of O(2) evolution increases throughout the light portion of the cycle and does not decrease until the cells are exposed to darkness. Shortterm exposure to a calmodulin antagonist (2 hour pulses) failed to cause phase shifts in the timing of the rhythm. This suggests that calmodulin is not part of the clock controlling photosynthesis and that it has a clock-related role different from that reported for the cell division rhythm in Euglena.
Biological oscillations with an endogenous period of near 24 h (circadian rhythms) are generated by the master circadian pacemaker or clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus. This clock is synchronised to recurring environmental signals conveyed by selective neural pathways. One of the main chemical constituents of SCN neurones is vasoactive intestinal polypeptide (VIP). Such neurones are retinorecipient and activated by light. Exogenous application of VIP resets the SCN circadian clock in a light-like manner, both in vivo and in vitro. These resetting actions appear to be mediated through the VPAC2 receptor (a type of receptor for VIP). Unexpectedly, genetically ablating expression of the VPAC2 receptor renders the circadian clock arrhythmic at the molecular, neurophysiological and behavioural levels. These findings indicate that this intrinsic neuropeptide acting through the VPAC2 receptor participates in both resetting to light and maintenance of ongoing rhythmicity of the SCN.
The central biological clock of the mammalian brain is located in the suprachiasmatic nucleus. This hypothalamic region contains neurons that generate a circadian rhythm on a single-cell basis. Clock cells transmit their circadian timing signals to other brain areas by diurnal modulation of their spontaneous firing rate. The intracellular mechanism underlying rhythm generation is thought to consist of one or more self-regulating molecular loops, but it is unknown how these loops interact with the plasma membrane to modulate the ionic conductances that regulate firing behaviour. Here we demonstrate a diurnal modulation of Ca2+ current in suprachiasmatic neurons. This current strongly contributes to the generation of spontaneous oscillations in membrane potential, which occur selectively during daytime and are tightly coupled to spike generation. Thus, day-night modulation of Ca2+ current is a central step in transducing the intracellular cycling of molecular clocks to the rhythm in spontaneous firing rate.
Biological clocks are self-sustained and endogenous. Animals have biological clocks in a variety of frequencies. Biological clocks provide temporal coordination among physiological, behavioral, and environmental events. One important function of steroid hormones may be to alter the temporal coordination among those events. Biological clocks provide a referent mechanism for the timing of both current and future endogenous and exogenous events. Physiological time is a unifying principle in biology.
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Sex differentially shapes aging, neurodevelopment and neurodegenerative diseases such as Alzheimer's disease (AD). However, most biological aging clocks (artificial intelligence-predicted age minus chronological age) were trained on sex-pooled samples and implicitly assume sex invariance.Here we developed 38 sex-specific biological aging clocks across 15 organ systems. We first demonstrate the importance of sex-stratified training for constructing sex-specific healthy normative references and then reveal marked divergence between female and male clocks. Key genetic parameters and Mendelian randomization results indicate that organ-specific aging liability and its relationships to cardiometabolic, endocrine and mental traits are configured differently in females and males. Proteomic analyses identify distinct, organ-resolved synaptic, immune, vascular and metabolic networks that differentially track female and male biological aging. In longitudinal survival analyses, sex-specific clocks predict whole-body systemic diseases and all-cause mortality in a sex-dependent and organ-dependent manner. Further analyses reveal sex-dependent associations between the brain aging clock and cognitive decline trajectory during a preclinical AD clinical trial. Sex-stratified clocks may offer distinct value by defining biological age against sex-appropriate normative references and revealing sex-dependent genetic, molecular and clinical signatures that pooled models may obscure. Meanwhile, sex-pooled and sex-interaction approaches remain valuable, as human aging and disease also share fundamental biological similarities between females and males. Together, these findings reveal sex-specific biological aging signatures in aging, AD and systemic health, highlighting the need for explicitly sex-stratified modeling approaches.
The digestive system is a major port of entry for pathogens. To detect and combat pathogens, the innate immunity in the gut utilizes pattern recognition receptors, such as Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD) proteins, and broad-spectrum anti-bacterial polypeptides, such as defensins. We have previously shown that mouse enteric defensins (cryptdins) oscillate around the circadian cycle and peak at the end of the dark phase suggesting control by the biological clock. As the core mechanism of the biological clock has never been studied in the small intestine, our objective was to determine whether the biological clock is functional in mouse jejunum and examine whether mTlr and mNod2 mRNAs, similarly to cryptdins, oscillate throughout the circadian cycle. Mouse jejunum and Paneth-enriched crypt base cells were isolated around the circadian day and the levels of clock (mClock, mBmal1, mPer1, mPer2, mCry1) and innate immunity component (mTlr2, mTlr3, mTlr4, mTlr5, mTlr9, mNod2) genes were measured by real-time PCR. Analysis of mouse jejunum and Paneth-enriched crypt base cells revealed that all clock genes exhibited circadian oscillation. Similarly to cryptdins, mTlr2, mTlr3, mTlr4, mTlr5 displayed circadian rhythmicity in mouse jejunum. Although no circadian oscillation could be detected for mTlr9 and mNod2 in the whole jejunum, these genes oscillated in Paneth-enriched crypt base cells. In addition, mTlr3 exhibited the highest expression level. As the clock regulates intestinal motility and function, resetting of the clock in the small intestine may help not only to restore activity but also to gain better protection against pathogens.