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

Epidemiological and biochemical studies show that the sporadic forms of Alzheimer's 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

Cancer proliferation and therapy: the Warburg effect and quantum metabolism

Background: Most 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. Model: Quantum 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. Conclusion: The 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 chemotherapyMolecular and Cellular Biolog

Evolutionary Entropy Determines Invasion Success in Emergent Epidemics

Background: Standard epidemiological theory claims that in structured populations competition between multiple pathogen strains is a deterministic process which is mediated by the basic reproduction number (R0) of the individual strains. A new theory based on analysis, simulation and empirical study challenges this predictor of success. Principal Findings: We show that the quantity R0 is a valid predictor in structured populations only when size is infinite. In this article we show that when population size is finite the dynamics of infection by multi-strain pathogens is a stochastic process whose outcome can be predicted by evolutionary entropy, S, an information theoretic measure which describes the uncertainty in the infectious age of an infected parent of a randomly chosen new infective. Evolutionary entropy characterises the demographic stability or robustness of the population of infectives. This statistical parameter determines the duration of infection and thus provides a quantitative index of the pathogenicity of a strain. Standard epidemiological theory based on R0 as a measure of selective advantage is the limit as the population size tends to infinity of the entropic selection theory. The standard model is an approximation to the entropic selection theory whose validity increases with population size. Conclusion: An epidemiological analysis based on entropy is shown to explain empirical observations regarding the emergence of less pathogenic strains of human influenza during the antigenic drift phase. Furthermore, we exploit th

Implausibility of radical life extension in humans in the twenty-first century.

Over the course of the twentieth century, human life expectancy at birth rose in high-income nations by approximately 30 years, largely driven by advances in public health and medicine. Mortality reduction was observed initially at an early age and continued into middle and older ages. However, it was unclear whether this phenomenon and the resulting accelerated rise in life expectancy would continue into the twenty-first century. Here using demographic survivorship metrics from national vital statistics in the eight countries with the longest-lived populations (Australia, France, Italy, Japan, South Korea, Spain, Sweden and Switzerland) and in Hong Kong and the United States from 1990 to 2019, we explored recent trends in death rates and life expectancy. We found that, since 1990, improvements overall in life expectancy have decelerated. Our analysis also revealed that resistance to improvements in life expectancy increased while lifespan inequality declined and mortality compression occurred. Our analysis suggests that survival to age 100 years is unlikely to exceed 15% for females and 5% for males, altogether suggesting that, unless the processes of biological aging can be markedly slowed, radical human life extension is implausible in this century

On the Macroscopic Origins and Consequences of Economic Inequality: An Evolutionary Perspective *

Abstract Income inequality can vary rather dramatically across societies. While in some countries the average income of the richest 10% does not exceed 5 or 6 times that of the poorest 10%, in others the same ratio can reach up to 90 or 100. Moreover, such differences can persist and even increase over long periods of time. In order to address such facts, we develop a theory, based on socio-cultural evolution, that highlights the stability and heterogeneity of a society's economic environment as a fundamental source of long-term inequality. We show that steady and diverse economic environments provide a selective advantage for cooperative or mutualistic behavior, thereby generating economic equality, whereas fluctuating and singular ones favor selfish behavior, thereby inducing economic inequality. We also show that more equal societies exhibit a higher degree of income and social mobility and are more resilient and robust in the sense of being quicker to recover from shocks and to return to normalcy than unequal ones. We thus provide a rationale for the emergence of inequality, its persistence and negative correlation with income and social mobility, and highlight its role in determining the fragility and robustness of a society. Recent empirical evidence for our main results and policy implications to promote cooperation and equality are also briefly discussed

Evolutionary Entropy: A Predictor of Body Size, Metabolic Rate and Maximal Life Span

Body size of organisms spans 24 orders of magnitude, and metabolic rate and life span present comparable differences across species. This article shows that this variation can be explained in terms of evolutionary entropy, a statistical parameter which characterizes the robustness of a population, and describes the uncertainty in the age of the mother of a randomly chosen newborn. We show that entropy also has a macroscopic description: It is linearly related to the logarithm of the variables body size, metabolic rate, and life span. Furthermore, entropy characterizes Darwinian fitness, the efficiency with which a population acquires and converts resources into viable offspring. Accordingly, entropy predicts the outcome of natural selection in populations subject to different classes of ecological constraints. This predictive property, when integrated with the macroscopic representation of entropy, is the basis for enormous differences in morphometric and life-history parameters across species