Living on the Brink of Chaos

Normal, healthy, physiological processes are regulated by a complex interplay of numerous, neuroendocrinal signaling pathways. Although there are many intermediary signaling events, the fundamental purpose of most signaling pathways is the transfer of regulatory information to and from the central nervous system (CNS). Functional CNS decline precedes the metabolic, reproductive, and cognitive disorders associated with aging. For example, recent advances in brain imaging technology have demonstrated that the structural changes eventually causing Alzeheimer’s Disease (AD), actually take place, long before the first symptoms are observed. Given the central role of the CNS in age-related pathologies, the dynamics of CNS function should, clearly, also be the central focus of anti-aging research. Preventing or slowing age-related changes in the CNS has the potential to maintain healthy physiologic function, as we grow older.

Nonlinear Dynamics and the Loss of Complexity Theory of Aging and Disease

In the past, simple reductionist approaches to the study of physiology have been very productive. However, given the inherent complexity of the dynamics of most physiological processes, including neurological function, future advances in the study of these processes will require the use of nonlinear, whole-systems approaches. (“Nonlinear” means that output is not proportional to input, but varies in more complex, often unexpected, ways.) In Neuroscience, the macro phenomena of cognition, emotion, motor activity, etc. are dependent upon the emergent, collective actions of billions of neurons, each of which is a nonlinear element. In general, physiology is the result of interactions of multiple feedback loops of nonlinear systems. The process of aging can be understood as a reduction in the complexity of these feedback and control systems. See: Loss of ‘Complexity’ and Aging.

Normal, healthy physiological processes function on the edge of “chaos”, which is to say, near a critical point. This allows for greater degree of resilient vitality, and resistance to disruption than systems of a simple periodic, or stochastic nature. The nonlinear dynamics of neural systems facilitate functional adaptation to changing environmental conditions. In contrast, the aging phenotype is characterized by a reduced ability to adapt to stress and trauma reflective of a reduction in complexity of underlying regulatory mechanisms. Such a reduction in complexity may reflect the loss of a component, or the disruption of feedback coupling between components. For example, normal secretion patterns of glucocorticoids, sex steroids, and GH result from shrinkage of the hippocampus, loss of neurons, and declining neurogenesis. The number of dopaminergic neurons also declines with age, accompanied by a corresponding reduction in nigrostriatal signaling, which, in turn, produces such age-related disorders as Parkinson’s disease. See: Dopaminergic Neuronal Loss.

Such changes result in reduced complexity of the signaling dynamics of neural networks, resulting in a reduced adaptive capacity. The increased vulnerability of the aging brain to anoxia and ischemia, is one example of reduced neural adaptive capacity, which appears to be the result of compromised ribonomic ability to selectively translate stress-induced mRNA. See: Towards a dynamical network view of brain ischemia.

Clearly, many age-related disorders are the direct result of alterations in regulatory pathways of the CNS. A loss of neurological complexity as measured in EEGs has been found to characterize patients in a vegetative state. See: Complexity loss in physiological time series of patients in a vegetative state.

Nonlinear methods have been applied to the modeling of circadian rhythms. See: Modeling biological complexity. Many physiological processes depend upon circadian rhythms, which are regulated by a complex network of signaling and feedback mechanisms. Disruption of normal circadian rhythm can have profound health consequences, and is implicated in many diseases of the aging including heart disease, obesity, metabolic syndrome, psychiatric/neurological disorders, and even cancer. Many regulatory factors diminish with age, such as the age-related decrease in melatonin signaling, which results in a loss of regulatory complexity leading to circadian dysfunction.

Systems biology and its application to the understanding of neurological diseases:

Recent advances in molecular biology, neurobiology, genetics, and imaging have demonstrated important insights about the nature of neurological diseases. However, a comprehensive understanding of their pathogenesis is still lacking. Although reductionism has been successful in enumerating and characterizing the components of most living organisms, it has failed to generate knowledge on how these components interact in complex arrangements to allow and sustain two of the most fundamental properties of the organism as a whole: its fitness, also termed its robustness, and its capacity to evolve. Systems biology complements the classic reductionist approaches in the biomedical sciences by enabling integration of available molecular, physiological, and clinical information in the context of a quantitative framework typically used by engineers. Systems biology employs tools developed in physics and mathematics such as nonlinear dynamics, control theory, and modeling of dynamic systems. The main goal of a systems approach to biology is to solve questions related to the complexity of living systems such as the brain, which cannot be reconciled solely with the currently available tools of molecular biology and genomics. As an example of the utility of this systems biological approach, network-based analyses of genes involved in hereditary ataxias have demonstrated a set of pathways related to RNA splicing, a novel pathogenic mechanism for these diseases. Network-based analysis is also challenging the current nosology of neurological diseases. This new knowledge will contribute to the development of patient-specific therapeutic approaches, bringing the paradigm of personalized medicine one step closer to reality.”

The loss of complexity theory of aging represents a fundamental paradigm shift away from the classical assumptions of normal physiologic homeostasis. By directly challenging the classical assumptions of health and disease, it also points the way to a new class of therapeutic approaches based on whole-system targets, as opposed to treatments based on individual components, in isolation. It is my belief that such large-scale approaches will be necessary to effectively treat aging.

Nonlinear methods have a distinguished history of application in statistical physics. However, their application to physiology is a recent development, often requiring interdisciplinary approaches, since biologists aren’t historically trained in such methods. Despite their limited use, nonlinear methods have already yielded remarkable successes in our understanding of very disparate physiological processes. In addition to the examples previously mentioned, it turns out that the apparently simple, periodic process of a regular heartbeat is actually a complex, multifactorial process on the edge of chaos. See: Nonlinear dynamics of cardiovascular aging. , Chaotic Signatures of Heart Rate Variability. Pathologies of irregular heartbeat, in contrast, are the result of a reduced complexity resulting from a loss of regulatory feedback control mechanisms. Measures of heartbeat chaos have even proven to be the best predictor of mortality in heart patients. See: Heart rate chaos as a mortality predictor in mild to moderate heart failure.

Nonlinear approaches have had success in modeling the complex dynamics of stem cell populations, a process with direct implications for aging. See: Modelling Perspectives on Aging.

Future advances in genetics and epigenetics will undoubtedly rely very heavily upon advanced computational methods. With the mapping of the human genome, many single-gene, Mendelian, diseases have been identified. In fact, I believe it is safe to say that nearly all such disease have already been identified. (There are surely more, however, many extremely rare Mendelian conditions will likely never be identified, simply due to the small number of people affected by them.) See: Rare Genetic Disorders.

However, most diseases do not result from a single gene, but from the complex interaction of many genes (and epigenetic factors), which individually may have little or no correlation with the pathological condition. In order to identify and better understand such multifactorial relationships, Multifactor Dimensionality Reduction (MDR) methods are now being used. For more information on modeling complex genetic interactions, please see the following references. A future discussion will focus, in greater detail, on the role of neuroendocrinal signaling pathways in aging and longevity.

Detecting nonlinear gene-gene interactions using multifactor dimensionality reduction.

Model-based multifactor dimensionality reduction in the presence of noise.

Gene expression model (in)validation by Fourier analysis.

Systems Approaches to Identifying Gene Regulatory Networks in Plants.

Functional data analysis for identifying nonlinear models of gene regulatory networks.

  1. hormone replacement therapy says:
    13. May 2011 at 08:13

    Aging is factor which gives ignition to so many diseases and health problems. I know its impossioble to stop this aging process………does it possible to make the aging process to its slow pace? nice post thanks for sharing it


  2. Victor says:
    14. May 2011 at 03:11

    Preventing or slowing age-related decline in the CNS, and related signaling pathways, has the potential to slow, or even reverse aging processes. Many encouraging examples of the reversal of age-related decline in physiologic systems, by restoring proper signaling, can be given. Unfortunately, our present understanding of the molecular effects of various pathways is inadequate.

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5 Responses to Living on the Brink of Chaos

  1. eric25001 says:

    What if you could reduce or block the chemical [N-acylethanolamines (NAEs] in the article? No Caloric Restriction, No Protein Restriction, and maybe the fountain of youth? Can we screen for NAE inhibitors? For the short term diet intervention seems available and reasonable.

    On the other hand I think it is prudent to look at several areas that show promise either directly via a metabolic path like caloric restriction or protein restriction or via regenerative medicine or rejuvination of gonadal tissue as in prevously cited articles:
    Ovarian Transplantation Restores Fertility to Old Mice and Also Lengthens Their Lives


    New Pathway Affecting Lifespan Identified: Discovery Advances Study of Diet and Longevity
    ScienceDaily (May 14, 2011) — A team led by a scientist from the Florida campus of The Scripps Research Institute has identified a new role for a biological pathway that not only signals the body’s metabolic response to nutritional changes, but also affects lifespan.

    The study, published in the May 12, 2011 issue of the journal Nature, was conducted on Caenorhabditis elegans (nematodes or roundworms), which are a widely accepted model for human aging research.

    “Not only have we been able to identify some of these molecules for the first time in the worm, but we have also been able to show they act as a signal of nutrient availability and ultimately influence the worm’s lifespan,” said Matthew Gill, PhD. Gill, an assistant professor in the Scripps Research Department of Metabolism and Aging, conducted the research while at The Buck Institute for Research on Aging in Novato, California. “What makes this important is that the same molecules are present in both humans and C. elegans, so these molecules may play similar roles in both organisms.”

    Dietary restriction is a well-known means of extending lifespan and postponing age-related disease in many species, including yeast, worms, flies, and rodents. However, until this study, little was known about the molecular signals involved.

    The molecules identified in the new study are N-acylethanolamines (NAEs), a group of signaling molecules derived from lipids that help indicate nutrient availability in the environment and maintain an animal’s internal energy balance. In the study, Gill and his colleagues showed that NAE abundance in the worm is reduced during periods of dietary restriction, and that NAE deficiency in the presence of abundant food is sufficient to extend the animal’s lifespan.

    “It is well known that if you put C. elegans on a restricted diet, you can extend its lifespan by 40 to 50 percent,” Gill said. “However, we were amazed to see that if you add back just one of these NAE molecules, eicosapentaenoyl ethanolamide, it completely abrogates the lifespan extension.”

    Importantly, this particular NAE is similar to endocannabinoids in mammals, which regulate many different physiological processes including nutrient intake and energy balance, as well as inflammation and neuronal function. “The identification of other components of a novel endocannabinoid system in the worm now brings a new model system to the many researchers studying NAE and endocannabinoid physiology,” said Gill.

    Intriguingly, the study also established a link among fat, NAE levels, and longevity. Other studies in rodents have shown that the availability of fatty acids can influence NAE levels. However, Gill and his colleagues found that in a genetically altered strain of C. elegans the inability to produce certain polyunsaturated fatty acids was not only associated with a reduction in levels of specific NAEs but also with lifespan extension. He added that the study’s findings could shape future drug development efforts to influence aging and age-related disease.

    The first author of the study is Mark Lucanic, a postdoctoral fellow at the Buck Institute for Research on Aging. Other authors include Jason M. Held, Maithili C Vantipalli, Jill B. Graham, Bradford W. Gibson, and Gordon J. Lithgow of the Buck Institute for Research on Aging; and Ida M. Klang of the Buck Institute for Research on Aging and the Karolinska Institute.

    The study was supported by the Larry L. Hillblom Foundation and the National Institutes of Health.

  2. eric25001 says:

    Also I think from time to time a review of Doctor Kenyon’s article shows the breadth of the research in aging [Ageing if your a Brit]

    Here is doctor Kenyon’s good review of some of the recent research in aging;

  3. eric25001 says:

    Sorry here is the link ==>

    Here is doctor Kenyon’s good review of some of the recent research in aging;

  4. eric25001 says:

    Here is the link I hope

    or search
    Cynthia J. Kenyon

    The Genetics of ageing

  5. Victor says:

    I have read Kenyon’s summary review article in Nature, that you mention.
    Concerning your questions about the recent NAE-nematode study, it is known that the sensation of hunger is necessary for many of the benefits of dietary restriction, so it is unlikely that reducing the activity of an endogenous agonist of the cannabinoid receptors could reproduce all of the benefits of dietary restriction. Though the possible role of NAEs in mammalian metabolic signaling certainly warrants further investigation.

    It is no surprise that the Science Daily article over-sensationalizes the significance of this study; however, the study itself, including the abstract, also seems to overstate its own importance. It says that little is known about possible metabolic signaling pathways involved in dietary-restriction and the maintenance of energy homeostasis, then goes on, as if their proposal of the endocannabinoid system as a possible candidate for such a signaling pathway were a significant breakthrough. In fact, a very substantial body of research exists clearly demonstrating the central role of the arcuate nucleus within the hypothalamus, and other brain areas including the brain stem in regulating energy homeostasis in response to known metabolic signaling pathways in humans. The leptin-melanicortin pathway is a particularly well-known example. The hypothalamus is also responsive to other metabolic signals, including ghrelin, insulin, glucose, etc. The prefrontal cortex also plays a role in processing sensory signals associated with food consumption. The “hunger molecule”, neuropeptide-Y, which is secreted by the hypothalamus, in response to these metabolic signals, like leptin, is known to play a necessary role in the benefits of dietary-restriction. NPY results in a cascade of downstream effects directly related to many of the anti-aging benefits of dietary-restriction. One recent study of NPY-knockout mice shows that NPY is necessary for the anti-cancer benefits of dietary-restriction. See: “The arcuate nucleus and neuropeptide Y contribute to the antitumorigenic effect of calorie restriction.”

    Of course, it is possible that cannabinoid signaling also plays a role in maintaining energy homeostasis and in mediating some effects of dietary restriction in humans. We do not know. This study certainly doesn’t demonstrate this. Even if true, although it would be a very significant discovery, adding to our understanding of these processes, it still, would not be the revolutionary breakthrough that seems to be suggested. What exactly does this study show? It is a very interesting study which shows that NAEs, especially EPEA, are involved in extending the lifespan of worms. Although human physiology is much more complex, it is possible that they play a similar role in humans, possibly via the cannabinoid receptor. The next logical step would be to conduct mice-knockout studies to see if similar effects can be reproduced in mammals.

    One problem that was not addressed in the study is the fact that of the six NAE’s discussed, only one of them, AEA is a ligand for the cannabinoid receptors. In this study, AEA seems to be the least important; it was the least abundant and had the weakest effect. EPEA was the most important, having the greatest effect. Exogenous EPEA administration was able to restore normal development, and was able to counteract the longevity effects. But EPEA does not activate cannabinoid receptors. The repeated mention of cannabinoid receptors, seems to suggest that other NAEs are able to bind to and activate cannabinoid receptors, but they offer no evidence whatsoever to support this. The only NAE known to interact with cannabinoid receptors does not mediate any of the longevity effects. Their failure to address this point seemed very strange, to say the least. Still, the results are very interesting and most definitely warrant further investigation. I will discuss in greater detail the known pathways involved in regulating human energy homeostasis, and their relationship to the benefits of dietary-restriction in a future blog entry.

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