by drbob Melamede

Free Radicals as the Foundation of Homeostasis

Life, liberty, and the Pursuit of Happiness

drbob Melamede


Whenever there is an abundance of paradoxes that emerge from studies in a particular field, the need for a new conceptualization is indicated. Consistently, when trying to understand life, much apparently contradictory data has been generated. The linear, machinelike, reductionist thinking that characterizes Newtonian physics is built upon time reversibility as a basic quality of nature despite its obvious contradiction with real world experiences. This foundational logic was carried into the development of modern quantum theory, where probabilistic wave functions collapse into reality only when a measurement is made. A significant problem with old thinking is that, from a simple statistical perspective, life is too improbable to exist. Obviously since life does exist, new underlying principles are required. Fortunately, Nobel laureate Ilya Prigogine provided the foundation for new thinking.

Prigogine’s far from equilibrium thermodynamic perspective is based on breaking the symmetry of reversible time and the emergence of the arrow of time1. From this perspective life must exist and is characterized by the time-dependent emergence of complexity, i.e. evolution.  The movement from a linear mechanical, reductionist point of view (equilibrium concepts), to one of creativity and emergent phenomena needs to be integrated with the power of modern biology. Far from equilibrium concepts provide the opportunity. The intent of this manuscript is to show how making the transition from old to new thinking creates a holistic interpretation of life that resolves many existing apparent conceptual contradictions. Specifically the application of these concepts provides a resolution to the many paradoxes that arise when studying the life, death, and differentiation of living systems. Importantly, this view provides for new therapeutic approaches for broad-spectrum improvement in health (see discussion) via rational, science-based approaches.

There is an intrinsic problem with trying to describe the fundamental nature of nature. The more the principles are referenced, the more references there are to explore and reference. The process becomes a metastasizing intellectual cancer. However that expansion is the result of the conceptual power to successfully categorize and predict biological phenomena.  Consequentially, the solution was to provide enough conceptual raw material to promote individual exploration and development guided by the concepts presented. Hence, the book is annotated with numerous “additional readings” that will serve as the basis for developing a Wiki.

Below is an outline of the concepts developed in the manuscript:

1. Flowing energy and matter have a natural ability to organize into entropy producing dissipative structures (generate more entropy to surroundings than if the negentropic, flow dependent structure was not formed (consistent with Second Law of Thermodynamics for far from equilibrium systems.

2.The nervous system monitors all information that enters a living system (sensory systems).
The immune system monitors all mass that enters a living system.
The endocrine system coordinates the information and mass flow that comes in from the nervous and immune systems

3. Flow dependent dissipative structures are spacio-temporal structures that balance opposing forces such as redox (reduction-oxidation) reactions and their associated free radical production and neutralization.
Cellular activities are characterized by far from equilibrium phase changes that include: the emergence of life, evolution of species, cell division, phases of the cell cycle, dissipative structures within and between cells.

4. Efficient energy production (electron transport system) generates free radicals with the inherent associated danger (a single free radical molecule can kill a multicellular organism as a consequence the loss of cellular complexity resulting from the phase change to higher entropy.

5. The collective production and regulation of free radical production and associated damages is the foundation of homeostasis

Antioxidants scavenge free radicals, whereas free radical production can be metabolically controlled.
6. Alternative energy producing pathways, including glycolysis, glutaminolysis, aerobic fermentation, are less efficient, but reduce free radical production.

7. Biochemical pathways expand and contract to minimize excess free radical production (production that would otherwise kill a cell).

8. Anabolic storage (fat, glycogen, fibrosis), as well as cell division can reduce free radical production and consequences to avoid apoptosis (anabolic protection)

9. Free radicals, because of their broad reactivity, are naturally entropic, but can be negentropic when functioning as homeostatic regulators of their own production through biochemical modifications that serve as homeostatic signaling agents that can prevent cell death.

10.The ultimate cellular adaptation to oxidative stress, in an effort to prevent excess free radical production and apoptosis, results in reduced cellular communication (mass and energy) with the environment and the concomitant reduction of free radical production that results from turning on autophagy, beta oxidation and turning down electron transport system generated ATP production.

11.Autophagy is negentropic in that free radical-damaged bio-molecules, including whole mitochondria, are selectively digested for energy production and recycling of molecules.

12.Autophagy is naturally self-limiting (self-eating can only go on for so long), resulting in: repair and cell survival, or when not sufficiently controlled, cell death from necrosis or apoptosis, or cellular senescence.

13. Autophagy occurs concomitant with beta-oxidation of fatty acids
Active, differentiated cells typically require efficient energy production. They communicate with their environment via receptors that monitor cell signaling bio-molecules (autocrine/paracrine).

14. The different spacio-temporal patterns that characterize the systemic redox state act as diffuse indicators/regulators of health and provide novel approaches for health maintenance and restoration.

15. Lipid rafts are critical components necessary for autocrine and paracrine communication. They are embedded with, and concentrate, plasma membrane receptors.

16. Lipid rafts are rich in, and dependent on, saturated lipid products including cholesterol and sphingomyelin that are produced from carbohydrates by de novo synthetic pathways as well as dietary consumption and recycling pathways.

17. Lipid rafts “dissolve” with polyunsaturated fatty acids, inhibitors of cholesterol synthesis, and the up-regulation of autophagy and beta-oxidation.

18. Sphingomyelin breakdown produces ceramide.

19.Ceramide can induce apoptosis

20.Cells reduce environmental communication when autophagy and beta oxidation are stimulated via AMPK associated pathways. In contrast, mTOR, and associated cell surface receptor signaling pathways, are inhibited to protect cells from free radical damage.

21.Nuclear receptors function as transcription factors as well as functioning by non-genomic means.

22.Nuclear receptor genomic activities are enhanced by AMPK pathways, whereas the non-genomics activities are up regulated by cell surface receptor and mTOR activities.

23.Cells oscillate between the different energy generating and utilizing pathways as determined by free radical generation and associated cellular damage.

24.Cell survival under damaging environmental conditions, natural or artificially induced, can trap a cell (or one of many statistically equivalent states?) in a particular biochemical pattern and predispose the cell to both dynamic (epigenetic) and genetic modifications that are compatible with the survival-promoting state.

25.Alternatively, holistic metabolic manipulation can be used to promote a state of health (distance fro equilibrium).

26.The endocannabinoid system regulates all body systems (circulatory, digestive, endocrine, immune, musculo-skeletal, nervous, reproductive, tegumentary) by controlling metabolism and free radical production.

27.The endocannabinoid system protects differentiated cells from electron transport system generated free radicals via the CB1 receptor.

28.The endocannabinoid system, via activation of the CB2 receptor, supports the metabolic shift to the more protective fat-burning mode.

29.Cannabinoids can effectively prevent and treat many illness in a uniquely holistic manner by virtue of their central role as system wide homeostatic agents.

30.Cannabinoids are anti-aging compounds that inhibit all age-related illnesses including neurological, immunological, hormonal, and skeletal disorders as well as cancers and viral infections including HIV, herpes, and papilloma infections.

31.Evolution has continuously increased the role that the endocannabinoid system plays in the adaptive complexity of vertebrate evolution.

32.Endocannabinoid receptors emerged in, and are significant contributors to the adaptability of vertebrates. Adaptability is the basis of evolution.

33.Speciation is a biochemical far from equilibrium phase change.
34.The endocannabinoid system is a critical component driving the adaptability that characterizes vertebrates and their adaptability within a generation.

35.Invertebrates have strong survivability characteristics by virtue of their size, lifespan and genetic substitution rate. However, they do not have the intra-generational adaptability of vertebrates, nor do they have cannabinoid receptors.

36.A cancerous tumor may be viewed as multicellular organism where the molecular diversity of the tumor represents an evolving flow dependent synergy that generates its own genetic diversity to satisfy the evolving metabolic complexity.