Lloyd Demetrius

Of mice and men. When it comes to studying ageing and the means to slow it down, mice are not just small humans.

All mammalian cells use similar molecular mechanisms to regulate growth, replication, differentiation and death. Even specialized cells, such as fibroblasts or secretory epithelial cells, are often quite similar in structure and function between species. Mice and humans are good examples of this metabolic homogeneity—they have the same organs and systemic physiology, and they also show great similarities in disease pathogenesis. For example, mouse tumours have similar histological features to comparable human tumours. In addition, mice acquire mutations in an equivalent spectrum of proto‐oncogenes and tumour suppressor genes (Balmain & Harris, 2000). These similarities constitute one of the main reasons why mouse models are used to study human disease pathogenesis and ageing processes. They have also been the driving force behind efforts to understand the effects on humans of caloric restriction, which is the only experimental manipulation so far shown to reduce disease incidence and to significantly increase both mean and maximum lifespan in mammals (Weindruch & Walford, 1988). In view of the similarities between mice and human cells and physiology, will caloric restriction have an impact on humans similar to that observed in mice? Furthermore, how appropriate is the mouse as a model to study ageing in humans? Answering these questions requires an understanding of the general mechanisms that drive the ageing process. Ageing, in its broadest sense, is the continuous and irreversible decline in the efficiency of various physiological processes once the reproductive phase of life is over (Sohal & Weindruch, 1996). Species that belong to the same phyletic lineage and have similar rates of senescence would therefore have similar molecular mechanisms driving the ageing process. Consequently, caloric restriction in such species should have equivalent effects on their longevity. However, species with divergent rates of senescence would typically have dissimilar molecular mechanisms. When caloric restriction is imposed on such …

Aging in Mouse and Human Systems A Comparative Study

Abstract:  This article discusses the significance of mouse models as a basis for elucidating the aging process in humans. We identify certain parallels between mouse and human systems and review the theoretical and empirical support for the claim that the large divergence in the rate of aging between the two species resides in differences in the stability of their metabolic networks. We will show that these differences in metabolic stability have their origin in the different ecological constraints the species experience during their evolutionary history. We exploit these ideas to compare the effect of caloric restriction on murine and human systems. The studies predict that the large increases in mean life span and maximum life‐span potential observed in laboratory rodents subject to caloric restriction will not obtain in human populations. We predict that, in view of the different metabolic stability of the two systems, caloric restriction will have no effect on the maximum life‐span potential of humans, and a relatively minor effect on the mean life span of nonobese populations. This article thus points to certain intrinsic limitations in the use of mouse models in elucidating the aging process in humans. We furthermore contend the view that these limitations can be mitigated by considering the metabolic stability of the two species.

Alzheimer’s as a metabolic disease

Empirical evidence indicates that impaired mitochondrial energy metabolism is the defining characteristic of almost all cases of Alzheimer’s disease (AD). Evidence is reviewed supporting the general hypothesis that the up-regulation of OxPhos activity, a metabolic response to mitochondrial dysregulation, drives the cascade of events leading to AD. This mode of metabolic alteration, called the Inverse Warburg effect, is postulated as an essential compensatory mechanism of energy production to maintain the viability of impaired neuronal cells. This article appeals to the inverse comorbidity of cancer and AD to show that the amyloid hypothesis, a genetic and neuron-centric model of the origin of sporadic forms of AD, is not consistent with epidemiological data concerning the age-incidence rates of AD. A view of Alzheimer’s as a metabolic disease—a condition consistent with mitochondrial dysregulation and the Inverse Warburg effect, will entail a radically new approach to diagnostic and therapeutic strategies.

Cancer as a dynamical phase transition

This paper discusses the properties of cancer cells from a new perspective based on an analogy with phase transitions in physical systems. Similarities in terms of instabilities and attractor states are outlined and differences discussed. While physical phase transitions typically occur at or near thermodynamic equilibrium, a normal-to-cancer (NTC) transition is a dynamical non-equilibrium phenomenon, which depends on both metabolic energy supply and local physiological conditions. A number of implications for preventative and therapeutic strategies are outlined.

An inverse-Warburg effect and the origin of Alzheimer's disease

Glycolysis and oxidative phosphorylation (OxPhos) are the two major mechanisms involved in brain energetics. In this article we propose that the sporadic forms of Alzheimer’s disease (AD) are driven by age-related damage to macromolecules and organelles which results in the following series of dynamic processes. (1) Metabolic alteration: Upregulation of OxPhos activity by dysfunctional neurons. (2) Natural selection: Competition for the limited energy substrates between neurons with normal OxPhos activity [Type (1)] and dysfunctional neurons with increased OxPhos [Type (2)]. (3) Propagation, due to the fact that Type (1) neurons are outcompeted for limited substrate by Type (2) neurons which, because of increased ROS production, eventually become dysfunctional and die. Otto Warburg, in his studies of the origin of cancer, discovered that most cancer cells are characterized by an increase in glycolytic activity—a property which confers a selective advantage in oncologic environments. Accordingly, we propose the term “inverse-Warburg effect” to describe increased OxPhos activity—a property which we propose confers a selective advantage in neuronal environments, and which we hypothesize to underlie the shift from normal to pathological aging and subsequent AD.

Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect.

Epidemiological and biochemical studies show that the sporadic forms of Alzheimers disease (AD) are characterized by the following hallmarks: (a) An exponential increase with age; (b) Selective neuronal vulnerability; (c) Inverse cancer comorbidity. The present article appeals to these hallmarks to evaluate and contrast two competing models of AD: the amyloid hypothesis (a neuron-centric mechanism) and the Inverse Warburg hypothesis (a neuron-astrocytic mechanism). We show that these three hallmarks of AD conflict with the amyloid hypothesis, but are consistent with the Inverse Warburg hypothesis, a bioenergetic model which postulates that AD is the result of a cascade of three events—mitochondrial dysregulation, metabolic reprogramming (the Inverse Warburg effect), and natural selection. We also provide an explanation for the failures of the clinical trials based on amyloid immunization, and we propose a new class of therapeutic strategies consistent with the neuroenergetic selection model.

Age-related transcriptional changes in gene expression in different organs of mice support the metabolic stability theory of aging

Individual differences in the rate of aging are determined by the efficiency with which an organism transforms resources into metabolic energy thus maintaining the homeostatic condition of its cells and tissues. This observation has been integrated with analytical studies of the metabolic process to derive the following principle: The metabolic stability of regulatory networks, that is the ability of cells to maintain stable concentrations of reactive oxygen species (ROS) and other critical metabolites is the prime determinant of life span. The metabolic stability of a regulatory network is determined by the diversity of the metabolic pathways or the degree of connectivity of genes in the network. These properties can be empirically evaluated in terms of transcriptional changes in gene expression. We use microarrays to investigate the age-dependence of transcriptional changes of genes in the insulin signaling, oxidative phosphorylation and glutathione metabolism pathways in mice. Our studies delineate age and tissue specific patterns of transcriptional changes which are consistent with the metabolic stability–longevity principle. This study, in addition, rejects the free radical hypothesis which postulates that the production rate of ROS, and not its stability, determines life span.

Cancer proliferation and therapy: the Warburg effect and quantum metabolism

BackgroundMost cancer cells, in contrast to normal differentiated cells, rely on aerobic glycolysis instead of oxidative phosphorylation to generate metabolic energy, a phenomenon called the Warburg effect.ModelQuantum metabolism is an analytic theory of metabolic regulation which exploits the methodology of quantum mechanics to derive allometric rules relating cellular metabolic rate and cell size. This theory explains differences in the metabolic rates of cells utilizing OxPhos and cells utilizing glycolysis. This article appeals to an analytic relation between metabolic rate and evolutionary entropy - a demographic measure of Darwinian fitness - to: (a) provide an evolutionary rationale for the Warburg effect, and (b) propose methods based on entropic principles of natural selection for regulating the incidence of OxPhos and glycolysis in cancer cells.ConclusionThe regulatory interventions proposed on the basis of quantum metabolism have applications in therapeutic strategies to combat cancer. These procedures, based on metabolic regulation, are non-invasive, and complement the standard therapeutic methods involving radiation and chemotherapy

The inverse association of cancer and Alzheimer's: a bioenergetic mechanism

The sporadic forms of cancer and Alzheimers disease (AD) are both age-related metabolic disorders. However, the molecular mechanisms underlying the two diseases are distinct: cancer is described by essentially limitless replicative potential, whereas neuronal death is a key feature of AD. Studies of the origin of both diseases indicate that their sporadic forms are the result of metabolic dysregulation, and a compensatory increase in energy transduction that is inversely related. In cancer, the compensatory metabolic effect is the upregulation of glycolysis—the Warburg effect; in AD, a bioenergetic model based on the interaction between astrocytes and neurons indicates that the compensatory metabolic alteration is the upregulation of oxidative phosphorylation—an inverse Warburg effect. These two modes of metabolic alteration could contribute to an inverse relation between the incidence of the two diseases. We invoke this bioenergetic mechanism to furnish a molecular basis for an epidemiological observation, namely the incidence of sporadic forms of cancer and AD is inversely related. We furthermore exploit the molecular mechanisms underlying the diseases to propose common therapeutic strategies for cancer and AD based on metabolic intervention.

Implications of quantum metabolism and natural selection for the origin of cancer cells and tumor progression

Empirical studies give increased support for the hypothesis that the sporadic form of cancer is an age-related metabolic disease characterized by: (a) metabolic dysregulation with random abnormalities in mitochondrial DNA, and (b) metabolic alteration - the compensatory upregulation of glycolysis to offset mitochondrial impairments. This paper appeals to the theory of Quantum Metabolism and the principles of natural selection to formulate a conceptual framework for a quantitative analysis of the origin and proliferation of the disease. Quantum Metabolism, an analytical theory of energy transduction in cells inspired by the methodology of the quantum theory of solids, elucidates the molecular basis for differences in metabolic rate between normal cells, utilizing predominantly oxidative phosphorylation, and cancer cells utilizing predominantly glycolysis. The principles of natural selection account for the outcome of competition between the two classes of cells. Quantum Metabolism and the principles of natural selection give an ontogenic and evolutionary rationale for cancer proliferation and furnish a framework for effective therapeutic strategies to impede the spread of the disease.