Fundamental properties improve life outcomes?

Fundamental properties improve life outcomes?

Understanding feeding patterns and feeding times as they relate to coordination of circadian rhythms has huge implications for the well-being of commercial and companion animals.

*F.C. Madsen is with Nutrition Services Inc. in Highland, Ill. P.H. Frankel is with the City of Hope National Medical Center in Duarte, Cal. K.E. Jackson is with Trouw Nutrition International in Highland.

NOBEL laureate Joshua Lederberg was the first to suggest that we need to view ourselves and animals as super-organisms.

He stated that "we should think of each host and it's parasites as a super-organism with the respective genomes yoked into a chimera of sorts" (Lederberg, 2000). The concept was a novel way to describe animals, but entomologists have considered insect colonies to function in this manner for decades.

Initially, it was thought that the animal was more than 90% microbial, with about 10% self or animal cells. However, the difference between self and non-self is even less well defined if one considers the super-organism as a single, cooperating genome. Using the two genomes to differentiate the super-organism suggests that it is less than 1% self.

Even more interesting, it is now thought that animals are more viral than microbial (Duerkop et al., 2012). Wherever bacteria are found, there are viruses that infect them. There may be as many viruses and viral-like particles as microbes in the super-organism, with the identified numbers increasing as better metagenomic technology is developed (Reyes et al., 2012).

This represents a dramatic change just within the last decade in how animals are characterized. However, this is only the beginning of a new understanding of the super-organism.

The super-organism is even more complex than the "viral-microbe-self" concept. The totality of the organization has been classified as a superstructure system (Figure 1). The super-organism/superstructure system contains many orders of magnitude more quantities of information than first thought. It is a rich and diverse matrix of microbes, microbial metabolites, viral-like particles, viruses, plant material, plant metabolites, electromagnetic radiation, "self," "self" metabolites and biochemical imprints from the past (epigenetics).

Further, the super-organism appears to be organized into patterns of molecules, frequencies of molecular patterns and emerging higher orders of information (Prigogine and Stengers, 1984).

The animal is an emergent and evolving higher-order pattern resulting from these complex patterns of molecules. However, the molecules generated from their individual self-interested genomes and those randomly acquired from the environment would not seem likely to be able to organize themselves into functional, cooperative patterns and maintain life on their own. Therefore, there needs to be something extra in place to manage this process.

Systems biologists have identified oscillators and attractor-like processes (organizers and timers) to be able to serve this function.

The super-organism can be more appropriately viewed as a system of self-organizing molecules maintained and coordinated by very dynamic processes consisting of oscillators and attractor-like states.

(Attractor-like states are a representation of the oscillating constituents of the system. Mathematically, attractors are a collection of distinct sets toward which a variable — moving according to the demands of a dynamic system — evolves over time. They provide a perspective of the collective iterative dynamic activities that maintain phenotype and function).

These dynamic processes collectively enable the manifestation of phenotype from all of the possibilities, both determined and undetermined, and can be considered continuous or stochastic. Only in death does the system start to approximate the simplest attractor known as "steady-state" or equilibrium.

Oscillations play a basic role in many aspects of fundamental cellular biochemistry and physiology. They originate by the interaction of many cell components forming complex regulatory networks that appear to be basic for an organism to synchronize and coordinate the activities of the cell and animal.

Studies by Klevecz considered cells and whole organisms to systematically behave as oscillators and attractors (Klevecz and Li, 2007; Klevecz et al., 2008). They found that there is a genome-wide oscillation in transcription that gates cells into S (synthesis)-phase, coordinates mitochondrial and metabolic functions and helps maintain stable cellular phenotypes. They also produced evidence that everything oscillates and provided a rationale that the cell behaves as an attractor.

Oscillators appear to have a critical function in coordination of cell signaling and may change the way that process is viewed. Cai et al. (2008) discovered that frequency-modulated regulation of localized bursts may be a general control strategy used by the cell to coordinate multi-gene responses during cell signaling. They found that frequency-modulated (requiring oscillations) — not amplitude-modulated — signals were able to transduce a coherent multi-gene message.

It is now considered that most cell and animal activities — including metabolism, activity, growth, mood, immunity and how the animal changes with age — are regulated by oscillators, both internal and those created by external or environmental cues (zietgebers). There is a growing research effort underway to try to understand how oscillators regulate cellular phenotype at both the microscopic and macroscopic levels as well as to find ways to use this information to improve life outcomes.

Since 2000, the idea of humans and mammals being better described as super-organisms has led to many assumptions that would have been considered ridiculous just 10 years ago. However, to come away with any simple or usable hypotheses for understand the concept, it will require new ways of describing the seemingly endless complexity, i.e., overcoming the complexity brake (Allen and Greaves, 2011; Koch, 2012).

This will be a big chore as it is likely that everything in the super-organism oscillates, is highly connected and is coupled in ways that are only beginning to be appreciated. It is too complex for true human understanding, but fortunately, researchers have a rich history of making progress with limited understanding.

To begin, we would like to suggest that we consider super-organisms as self-organizing, dissipative systems that should only be compared to the mechanics and thermodynamics of machines with caution. Conventional descriptions of animals as machines misrepresent reality and can be counterproductive by misdirecting our pursuit away from critical issues (Mayer et al., 2009).

We are searching for a few observable, fundamental components of the system that we can utilize to improve phenotypic outcomes. We suggest that synchronization of zietgebers (time givers) be considered as a fundamental aspect that we can use to modify biological outcomes in commercial and companion animals.

This discussion is intended to influence professional animal scientists to more routinely and rigorously consider synchronization of zietgebers in managing feeding paradigms for commercial and companion animals. In this context, we would like to suggest that understanding feeding patterns and feeding times as they relate to coordination of circadian rhythms have huge implications for animal well-being.


Feeding/fasting patterns

From the beginning, life has been subject to the daily rhythms of light and dark. Light and dark periods have made a significant impact on the organization of living systems due to the drive for organisms to remain mirror-like images of the environment (Lipton, 2005).

In order for animals to cope with rapid and cyclical environmental changes, they have adapted rhythmic variations in their biochemical and physiological functions and activities. Most organisms, ranging from bacteria to animals, have evolved a circadian timing system to prepare their biochemistry for altering periods of feeding and fasting associated with circadian patterns (Schibler et al., 2003).

The effect on the animal is massive and includes activity and inactivity, digestion and metabolism, as well as energy utilization and storage. Of course, most of the rest of the animal's functions are connected to metabolism and energy utilization, so it becomes important to determine how feeding and fasting patterns influence the overall efficiency and well-being of the animal.

The circadian master clock, also known as the suprachiasmatic nucleus, has an approximate 24-hour cycle but only maintains this period under the proper influence of internal and environmental cues (Ramsey and Bass, 2009; Wikipedia). Circadian rhythms have a period of approximately 25 hours without the integration of external stimuli. In order to maintain clock/environment coordination, zeitgebers orchestrate changes in the concentrations of the molecular components of the circadian clocks to concentrations consistent with the appropriate stage in the 24-hour cycle — a process called entrainment.

It is, therefore, important to have appropriate intensity and timing of exposure to external stimuli. Feeding and fasting periods are major zeitgebers that modify and entrain peripheral circadian clocks in the liver, muscle, adipose tissue and pancreas (Bass and Takahashi, 2010). Transcriptional activities can be modified by disturbed circadian oscillators, resulting in metabolomic materials that are not necessary or even are detrimental to the robustness of the appropriate phenotypic state, either anabolic during the active period or catabolic during an inactive period.

Misalignment between gene transcription cycles in any of the digestive or storage tissues by modified feeding behavior is sufficient enough to alter energy metabolism and many other connected biological activities. A host of metabolic disorders have been linked to disturbed circadian rhythms, including diabetes, obesity, inflammatory disorders and cancer. Circadian clock disruption has been classified as carcinogenic by the International Agency for Research on Cancer (Richter et al., 2011).

A number of studies have examined how animals and humans respond to various feeding and fasting patterns (Vollmers et al., 2009; Scheer et al., 2009; Stenvers et al., 2012; Bass and Takahashi, 2010; Stokkan et al., 2001), and they all reported extensive coupling between circadian oscillators and feeding/fasting components that lead to either coordination or loss of coordination of metabolic activities. However, we have chosen a study by Hatori et al. (2012) that exemplifies how important normal circadian oscillation is to coordinated metabolism and how easily these oscillators can be disturbed by altered feeding and fasting behavior.

Hatori et al. (2012) fed genetically identical (C57BL/6J) mice using a normal schedule of 12 hours of light and 12 hours of dark for up to 18 weeks. The two dietary treatments were a normal diet (29% protein, 13% fat and 58% carbohydrate) or a high-fat diet (18% protein, 61% fat and 21% carbohydrate).

The two feeding treatments were provided either ad libitum (food was available for 24 hours) or time restricted (food was available from one hour after lights out until three hours prior to lights on for a total of eight hours). Since mice are nocturnal animals that are normally active and eat at night, the time-restricted group was only fed during their normal active period.

There were several striking observations during this trial. The most obvious was that although both the high-fat/ad libitum and high-fat/time-restricted mice consumed approximately the same number of calories, the mice on the high-fat/ad libitum treatment were 28% heavier than the mice on the high-fat/time-restricted treatment (Figure 2), 31% heavier than the normal/ad libitum treatment and 36% heavier than the mice on the normal/time-restricted diet (not shown).

The time-restricted treatment improved oscillations of the liver clock, resulting in better glucose and lipid homeostasis, preventing excessive bodyweight gain and liver damage from fatty liver disease. Improvement of liver function through a restricted feeding time coordinated the different parts involved in metabolism, including bile acid production, brown adipose tissue accumulation and inflammatory tone in white adipose tissue.

This portion of the study demonstrated that restricted feeding times affected multiple tissues, improved whole-body energy balance and reduced inflammation (Table).

Time-restricted feeding also changed CREB, mTOR and AMPK pathway function and oscillations of the circadian clock. It modified gene expression and the liver lipid and carbohydrate metabolome. Under the high-fat/ad libitum feeding treatment, perturbed total diurnal changes in CREB, mTOR and AMPK reduced mRNA levels and dampened the oscillations of Per1, Per2, Cry1, Bmal 1, Clock, Ror-alpha and Rev-erb (circadian clock genes) and their immediate output targets in the liver.

Under the high-fat/time-restricted feeding treatment, the imposed feeding rhythms resulted in improved oscillations of circadian clock components. The normal/ad libitum group had robust feeding oscillations that were moderately improved by restricting the feeding times to the normal activity period.

Also astounding was the amount of change in the liver fatty acid, sugar and nucleotide metabolome that was brought about by altered feeding windows. Liver metabolome analysis found 324 named metabolites that were common to all four groups of mice, of which 240 metabolites, or 74%, changed between at least one pair of treatments. Among the mice fed the low-fat diet, food access changed the overall levels of 56 metabolites, while 123 metabolites were changed between high-fat/ad libitum and high-fat/time-restricted feeding windows and indicates that feeding patterns are at least as important to the maintenance of liver phenotype as the nutrient content of the diets.

Besides the large differences in visual appearance of the mice, body lipid composition and oscillator characterizations, the mice on the different feeding regimes had dramatically different concentrations of liver metabolites.

If one adds to the comparison the differences in markers of inflammation, other associated biomolecules and perturbed oscillations found in the ad libitum fed groups of mice, it is easy to visualize that feeding behavior can have a profound effect on phenotype and function in the animal.

This study shows how feeding patterns can perturb biochemical pathways that are entrained by both circadian and food intake oscillators. It is also likely that disturbed oscillations, as the result of discordant zietgebers, can additionally influence other tissues and organs and may result in systemic consequences that modify phenotype.

This study demonstrated that this was the case as inflammation was disturbed due to altered feeding windows. Loss of coordination of circadian oscillators remarkably alters the animal's biochemical makeup and cellular phenotype.



The novel concept that animals should be described as super-organisms was advanced nearly 14 years ago by Joshua Lederberg. The super-organism is composed of several phyla and many small molecules produced endogenously and gathered from the environment. All of the components must cooperate collectively in a very precise manner to produce a stable, robust phenotype of a single being.

It doesn't seem possible that this diverse collection of phyla and enormous numbers of small molecules would be able to organize in a way that would be able to sustain life on their own. We suggest that it is vitally important for super-organisms to be able to coordinate and balance all of the partners and their activities in a manner that creates and maintains life processes as efficiently as possible.

Oscillators may be regarded as an attractive means to aid the super-organism in maintaining this delicate balance. Disturbances of these oscillators have implications in the well-being and efficiencies of animals.

Nearly all animals have self-contained oscillators (clocks) that couple endogenously generated rhythms with changes in the environment. Changes that require integration with the super-organism include light and dark periods, temperature and feeding and fasting windows. Although still at an early stage in discovery, emerging studies suggest that coordination of the endogenous oscillators by environmental cues, i.e., zietgebers, are essential to the long-term survival and well-being of the super-organism.

There is accumulating evidence that when an animal eats is just as important as what it eats. Synchronization of external cues such as feeding and fasting windows with circadian rhythms may be found to influence feed efficiency, immunity and the general well-being of the animal and have a positive effect on pollution and sustainability.



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Fundamental properties improve life outcomes?


2. A mouse from the fat/ad libitum treatment is shown on the left, while one from the fat/time-restricted treatment is on the right

Fundamental properties improve life outcomes?

Source: Hatori et al., 2012. Used with permission of Elsevier.


Effects of time-restricted feeding (adapted from Hatori et al., 2012)

Time-restricted feeding improved overt rhythms.

Temporal feeding pattern shaped rhythms in CREB, mTOR and AMPK activities as well as in the circadian oscillator.

Hepatic glucose metabolism improved under time-restricted feeding.

The temporal pattern of feeding determines lipid homeostasis.

Time-restricted feeding prevented excessive body weight gain, hepatosteatosis and liver damage.

Time-restricted feeding increased bile acid production, improved adipose tissue homeostasis and alleviated inflammation.


Volume:85 Issue:27

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