What is Volume 2 About

In short, Volume 2 focuses on the metabolic basis for the development of chronic diseases of aging including diabetes, cardiovascular disease, dementias, and cancers through complex interactions of multiple parameters.

Volume 2 focuses on the intersections of the body’s stress response, the biology of time as mediated by molecular clocks and the thyroid and steroid superfamily of nuclear hormone receptors, changes in intestinal microbiota composition and diversity, insulin signaling and resistance, and mitochondrial function and malfunction. The interactions of these aspects are proposed as a model of the evolution of the chronic diseases of aging and promotion of health, termed the Physiological Fitness Landscape (PFL). Specifically, diet, activity, circadian behaviors, and stress can be considered a quartet of interwoven extrinsic “control” parameters of human health and disease, Volume 2 proposes that the stress response and molecular clocks are the fundamental intrinsic “order” parameters that mediate human health and chronic diseases of aging. Microbiota, which lies at the intersection of diet and these intrinsic order parameters, is largely responsible for the self-amplifying connection of all of these parameters, both extrinsic and intrinsic.

Because the PFL is something that we can break down into quantitative measurements, we can use discrete metabolic data to help diagnose current medical conditions and predict future medical conditions. As a PFL model would be specific to the disease and the patient, it would provide an etiologic and mechanistic roadmap for the evolution and foundation of chronic diseases of aging, encompassing diabetes, cardiovascular disease, cancers, dementias, and accelerated cognitive decline of aging. Circadian biology will also play an important role in the future of PFL models.

Volume 2 defines circadian biology as an elegantly orchestrated synchronization of metabolism, within and across tissues and organ systems. The PFL speaks to this exquisitely beautiful organization of metabolic features, which in an optimal state, reflects a synchronized precision of the human body. Chronic diseases cause spatial and temporal desynchronization of organ systems that interfere with energy production. As such there are three fundamental metabolic characteristics of the PFL that define “fitness”: redox, free energy, and acid-base balance. In the state of health, each is maintained within a narrow physiological range. Volume 2 centralizes its attention on two of these characteristics, redox and free energy, as homeostatic coordinates of health. It describes human disease in terms of the loss of homeostasis of these phenomena (see chart below).

Central Regulators Responsible for Health and Disease

Extrinsic “Control” ParametersIntrinsic “Order” ParametersExtrinsic “Control” Parameters and Intrinsic “Order” ParameterFundamental Triad of Metabolic Parameters
Diet*Stress responseMicrobiota (symbiotic) – intrinsic order parameter**Free energy^^
Activity^Circadian molecular clocks (host cells and symbiotic microbiota)Microbiota (dysbiotic) – extrinsic control parameter**Redox^^
Circadian behaviorsAcid-base

*Note: toxins and allergens may fall under “diet” or “stress”, and microbes may be considered either extrinsic or intrinsic.

^Activity may be physical, social, and/or mental and in the context of work or recreation.

**The temporal organization of host cell metabolism and physiology is mediated by circadian molecular clocks, which also synchronize with that of the symbiotic microbiota, which have their own circadian clocks. In the latter case for example, the biosynthesis of neurotransmitters in some cases are initiated by microbiota, with host neural cell metabolism following up in phase to complete the process. It thus can be argued that microbiota in contexts such as these are “intrinsic” parameters of the host and host cell metabolism. It follows that the human host immune system is tolerogenic to these microbes. Conversely, dysbiotic microbes inhabiting the human host are destructive to circadian physiology and to optimum health, eliciting immunogenic, as well as catabolic and inflammatory, neural and hormonal responses.

^^The states of free energy, redox and acid-base are inextricably entangled in unison as characterized by the Gibbs free energy, Nernst and Henderson Hasselbalch equations respectively. While biological homeostasis is defined by these 3 parameters maintained within narrow physiological ranges, the focus for the purposes of book discussions is limited to redox and free energy as intertwined fundamental regulators of health and disease.

Volume 2 speaks to the transition from health to a disease state, which involves prolonged and/or exaggerated stress. Stress, a function of age and personal history may originate in the mind or body and shift metabolism out of balance. Stress drives an immune response that intersects with the immune system, gut microbiome, and insulin signaling and can be vastly exacerbated by redox-mediated inflammation. Acutely, an exaggerated psychogenic stress response, mediated by the hormonal and autonomic branches of the neuroendocrine stress response, triggers the innate instinct of “fight or flight”. This adaptively modulates the immune system, and promotes energy mobilization to fuel the process. Uncontrolled redox that causes local inflammation to spread throughout the body, lowers the thresholds for future stress responses and primes the body for exaggerated, chronic activation of the autonomic nervous system, kicking the hormonal branches of the neuroendocrine stress response into overdrive. Chronically, a prolonged stress response disrupts the natural circadian cycles of insulin secretion and signaling, which can cause pathological insulin resistance to ensue. Since insulin signaling is an important circadian regulator of clock-controlled rhythms, persistent hyperinsulinemia, a consequence of disrupted patterns of insulin secretion, promotes the loss of synchronized metabolism within and between tissues of the body. The stress response, deranged microbiota, disrupted redox, inflammation, insulin resistance and perturbation of molecular clocks/circadian biology all amplify one another in a vicious cycle, and physiological fitness therefore declines in a manner tantamount to the aging process.

Physiological fitness declines when the body becomes bioenergetically less efficient at transforming energy from food to the currency of ATP, which is primarily responsible for generating free energy. This is largely underpinned by mitochondrial dysfunction and is fundamentally, multidirectionally, and inseparably connected to other central components of pathophysiology, which include insulin resistance, altered redox, and inflammation. These in turn are drivers of and integral components of an inextricable self-amplifying web that includes an exaggerated and chronic stress response and disturbed microbiota. Moreover, these core intrinsic parameters of physiology are also inextricably linked in a bidirectional fashion to the regulation/dysregulation of the major extrinsic control parameters of health and disease: circadian behaviors, activity and the quality/quantity of diet.

Volume 2 emphasizes that losing free energy from the system causes the organized complexity of energy-producing structures to degrade. Any injury that compromises metabolic function at the local tissue level can change the dynamic equilibrium of molecular interactions with surrounding tissues, which creates cascading errors that may lead to metabolic defects in energy production at the organism level.

One hallmark metabolic parameter of healthy organ system function is the coupling of mitochondrial and the cytosol’s glycolytic bioenergetic pathways. Any breakdown of this intricate coupling results not only in compromised ATP production, but also in an array of mechanisms that pathogenically amplify redox and inflammatory stress in both the mitochondria and the cytosol.