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Hormesis, Autophagy, Mitochondrial Health, Fasting, Melatonin, And Circadian Biology

Discussion in 'Mitochondrial Rx' started by KalosKaiAgathos, Jun 22, 2018.

  1. KalosKaiAgathos

    KalosKaiAgathos New Member

    So, I'm currently working on a blog post with a topic that's been bugging me for very long.

    In the last few months, I've had some discussions with Ray Peat proponents. Some of these proponents deny the value of hormesis, which leads to a cascade of effects:

    Hormesis is bad -> Hormesis-induced autophagy is bad (fasting, cold exposure) + melatonin at night is bad (Ray Peat proponents consider melatonin a stress hormone) -> you need light and food 24/7 for health.

    Of course, this website's quantum paradigm is different:

    Hormesis (when applied correctly) is good -> hormesis-induced autophagy in the right balance is good (fasting, cold exposure) + melatonin is good (stimulates autophagy) -> light and food 24/7 is bad (because both need to be cycled throughout the day).

    As an alternative to using hormesis to stimulate autophagy, Peat proponents claim that autophagy can be stimulated in other ways, such as lowering PUFAs in the diet.

    Peat's argument against hormetic processes is that they are always accompanied with a stress response (increased cortisol and andrenaline). Peat wants to avoid this stress response as much as possible, because according to him, this response leads to health issues (a bit oversimplified).

    My view is that increasing stress hormones is not necessarily a problem, if these moments are balanced by enough time to recuperate. If you're unhealthy, however, engaging in deep CT or doing 3-day fasting sessions are probably not the right idea--but a 12-14 hour daily fasting window and mild cold exposure are probably very beneficial.

    (I equate mild cold exposure to walking, in terms of how intense the stress response is).

    Will probably be posting some studies here in the coming weeks :)
    Charyam likes this.
  2. KalosKaiAgathos

    KalosKaiAgathos New Member


    Posted this picture elsewhere yesterday. Someone commented that this is Moore's law, but then applied to lighting. That person was correct. Light intensity seems to double every 20-25 years in a predictable pattern.

    To me, this is one of the strongest - almost intuitive arguments - against Ray Peat's acceptance that melatonin should be avoided.
  3. KalosKaiAgathos

    KalosKaiAgathos New Member

    Crazy (emphasis mine):

    Long-term Levodopa Treatment Accelerates the Circadian Rhythm Dysfunction in a 6-hydroxydopamine Rat Model of Parkinson's Disease.
    Parkinson's disease (PD) patients with long-term levodopa (L-DOPA) treatment are suffering from severe circadian dysfunction. However, it is hard to distinguish that the circadian disturbance in patients is due to the disease progression itself, or is affected by L-DOPA replacement therapy. This study was to investigate the role of L-DOPA on the circadian dysfunction in a rat model of PD.

    The rat model of PD was constructed by a bilateral striatal injection with 6-hydroxydopamine (6-OHDA), followed by administration of saline or 25 mg/kg L-DOPA for 21 consecutive days. Rotarod test, footprint test, and open-field test were carried out to evaluate the motor function. Striatum, suprachiasmatic nucleus (SCN), liver, and plasma were collected at 6:00, 12:00, 18:00, and 24:00. Quantitative real-time polymerase chain reaction was used to examine the expression of clock genes. Enzyme-linked immunosorbent assay was used to determine the secretion level of cortisol and melatonin. High-performance liquid chromatography was used to measure the neurotransmitters. Analysis of variance was used for data analysis.

    L-DOPA alleviated the motor deficits induced by 6-OHDA lesions in the footprint and open-field test ( P < 0.01, P < 0.001, respectively). After L-DOPA treatment, Bmal1 decreased in the SCN compared with 6-OHDA group at 12:00 ( P < 0.01) and 24:00 ( P < 0.001). In the striatum, the expression of Bmal1, Rorα was lower than that in the 6-OHDA group at 18:00 (P < 0.05) and L-DOPA seemed to delay the peak of Per2 to 24:00. In liver, L-DOPA did not affect the rhythmicity and expression of these clock genes (P > 0.05). In addition, the cortisol secretion was increased (P > 0.05), but melatonin was further inhibited after L-DOPA treatment at 6:00 (P < 0.01).

    In the circadian system of advanced PD rat models, circadian dysfunction is not only contributed by the degeneration of the disease itself but also long-term L-DOPA therapy may further aggravate it.
    Link: https://www.ncbi.nlm.nih.gov/pubmed/28469105/

    So, when you raise dopamine levels artificially, without the regular photonic energy and information, a negative feedback loop might be activated that will not give you the benefits that sunlight-mediated dopamine increases have.

    This is a strong indication that there might not be a free lunch through prescription medicine.
  4. KalosKaiAgathos

    KalosKaiAgathos New Member

    Back to the original topic. Autophagy.

    I'm getting close to dealing with the intuitive issue I have with Peat. To exemplify why I have this issue, I've found this paper:


    Autophagy and Disease: always two sides to a problem

    Autophagy is a process traditionally known to contribute to cellular cleaning through the removal of intracellular components in lysosomes. In recent years, the intensive scrutiny that autophagy has been subjected to at the molecular level, has also contributed to expand our understanding of the physiological role of this pathway. Added to the well-characterized role in quality control, autophagy has proven important in the maintenance of cellular homeostasis and of the energetic balance, in cellular and tissue remodeling and in the cellular defense against extracellular insults and pathogens. It is not a surprise that in light of this growing number of physiological functions, connections between autophagic malfunctioning and human pathologies have also been strengthened. In this review, we focus on several pathological conditions associated to primary or secondary defects in autophagy, and comment on a recurring theme for many of them, that is the fact that autophagy can often exert both beneficial and aggravating effects on the progression of disease. Elucidating the factors that determine the switch between these dual functions of autophagy in disease has become a priority when considering the potential therapeutic implications of the pharmacological modulation of autophagy in many of these pathological conditions.​

    In general, autophagy seems to be working really well for preventing disease. But in certain instances, such as end-stage cancer, a heart attack, neurodegenerative diseases, and immune problems, autophagy can also wreak havoc on cells.


    The abstract of this article does not describe this process in enough detail, but what seems to be happening is that at a certain point, the relative sufficient homeostasis of cells seems to be overloaded. When that happens, autophagy no longer seems to be have beneficial effects.

    In these instances, instead, autophagy seems to make the metabolic problem in cells worse. To solution to prevent that overload from happening, is - contra Ray Peat - hormesis while you're still healthy I think.

    Healthy people can use hormesis to keep their heteroplasmy rate down, which promotes autophagy, which helps cells function, which keeps you away from the circumstances in which autophagy no longer helps you...
    Jenelle likes this.
  5. KalosKaiAgathos

    KalosKaiAgathos New Member

    Damn, crazy (emphasis mine):

    Differential Phasing between Circadian Clocks in the Brain and Peripheral Organs in Humans.
    The daily timing of mammalian physiology is coordinated by circadian clocks throughout the body. Although measurements of clock gene expression indicate that these clocks in mice are normally in phase with each other, the situation in humans remains unclear. We used publicly available data from five studies, comprising over 1000 samples, to compare the phasing of circadian gene expression in human brain and human blood. Surprisingly, after controlling for age, clock gene expression in brain was phase-delayed by ~8.5 h relative to that of blood. We then examined clock gene expression in two additional human organs and in organs from nine other mammalian species, as well as in the suprachiasmatic nucleus (SCN). In most tissues outside the SCN, the expression of clock gene orthologs showed a phase difference of ~12 h between diurnal and nocturnal species. The exception to this pattern was human brain, whose phasing resembled that of the SCN. Our results highlight the value of a multi-tissue, multi-species meta-analysis, and have implications for our understanding of the human circadian system.​

    Fascinating: peripheral clocks do not follow the central clock in the SNC exactly, but under a phase delay...

  6. Sheddie

    Sheddie Silver

    I have ideas and information that bug me, too! So very often contradictory opinion, including peer-reviewed research 'opinion' results, is all too confusing. Sometimes it leaves me in a state of unresolved cognitive dissonance, one palpable source of 'environmental stress!' In the concepts you're concerned with understanding it's okay to generalize although when in debate with others some parameters could be established.

    I agree with your view that increasing stress hormones, as in deliberate exercise, fasting, CT... can bring about health improvements -- in a relatively young, healthy adult. I wouldn't elect to argue an 85-year old living in poverty might thrive if poorly nourished through a northeast US winter, neither, a starving village child would thrive living under equatorial African sun even with ample water. Age, health status and environmental conditions require looking at endocrine system 'stress' sociologically as well as from the bio-physics perspective. Fortunately, most human biochemistry-biased research designs do use age as a factor, and would likely have much more meaningful value if, say, ZIP Code was another standard factor. I would argue "young, healthy" cannot be assumed to be what it meant before enormous environmental challenges of the last 100 or so years, and what we know of 'stress' hormone function may no longer have enough variation except perhaps compared with tribal populations untouched by globalist agenda ingress.

    That being said, comprehending enough to confidently self-experiment is probably our best means to deciding which proponents of many-sided issues might be helpful. Source credibility for information we're assessing as personally useful is especially critical in these times as previous authorities for trustworthy information have become suspect in terms of system contamination like... research funding, gatekeeper media information controls, even 'fake' information production and distribution, and subliminal influences. Careful assessment of how others appear to use information includes discerning the platform where they stand to give voice, the more 'personal' the better in terms of what their interests and identifications are. We're getting very good at detecting who aims to sell what to which 'targets' and have 'filters' that we use -- ignoring what we're not interested in as one. When we are invested to be aware of contradictory details it can be frustrating to make genuine progress especially when the 'stress' of a health crisis is at hand.

    Someone like me now, chronically ill for a very long time, is both uplifted and fascinated to hear from younger and/or healthier new paradigm participants reporting their 'results' with protocols that I can barely tolerate occasional mini-trials in my n=1. Reflecting on habits I once practiced, like being fueled on two thermos liters of coffee during my work hours, indoor lunch time exercise classes, long evening hours of study, to name a few, I don't wonder why my health 'crashed' permanently after my first serious 'accident' and interaction with medical system elements in early middle age. I could feel pretty victimized by the lifestyle interests in work and family I shared with most everyone else around me.

    I endorse fully that it is a harsh reality to accept that our health is so hugely impacted by environmental modifications that seem to offer disease and degeneration so much sooner without making huge, timely, supremely personal decisions about where and how to live. I'm counting on growing awareness and critical mass to outrun what all is racing to prevent health in people past the age 44, the 'expiration date' that globalist forces designate for human economic value. That we hear about dopaminergic stimuli from wireless hand-held devices, and frequency damage to gonads from laptops provided to school children and still consent to using these as they are now engineered is a sign of impending species extinction distracted by delusions that the very same who are effectively and knowingly killing us off will 'give' some of our selected progeny new genes to function by remote control. Aside from consumer boycotts and something where factory and office workers leave their workstations and offices to go outdoors to protest work conditions... I don't know what to think can affect positive Change on the scale it must take. Maybe I 'made it' to retirement with mornings free to get some natural light but it hurts my heart to see where the majority of children and their income earners parents are simply not free, by socioeconomic system design, to have sunlight, pure water, uncontaminated food & air, free of electrosmog at ground level and from satellite installations.

    Yes, the delicate subject of hormone management in this circadian disconnect context is central to population-wide immunity, endocrine, health and life-span preservation. Each new study has to refer back to the literature knowledge base that came before, with the very same empirical consideration of how previous paradigm constructs are furthered, or necessarily re-directed. We have precedents for big problems like margarine and soy erroneously promoted as healthful and turning out anything but. I see research results that still defend, or minimize the deep harm, in this line of thinking. Or, like the example of drugs that are first approved by the FDA, then are taken off the market only to return after a little tweaking of the molecule... There's a great deal that is rotten in the state of The Information Age. Watching some news about apparently intellectually-crippled 'Millennials" maybe more instruction in comprehensive reading and writing skills instruction could address the faulty public schooling curricula. Noting the 'soft' media-delivered health statistics that we should be shocked to hear, maybe demanding real butter and natural ingredients in food servings would affect diseases triggered and become chronic from toxin loaded substitutes. Maybe a better way to organize socioeconomic activity is to re-schedule the school and workday to run from noon to 6 or 8pm allowing human family health pursuits in the mornings; to reclaim the more natural health enjoyed by our ancestors? For now, approach wireless devices as if they had hazard labels on them and preserve what remains of your best thinking potential to come together and survive what we're up against.
    Last edited: Jun 24, 2018
    Charyam, Jenelle and KalosKaiAgathos like this.
  7. KalosKaiAgathos

    KalosKaiAgathos New Member

    Amazing post Sheddie! I agree with almost everything you're saying, many great red pills in there! My hope is the internet changes a lot over the coming 2 decades--at least if we can keep internet freedom.

    100% agree on the work environments. I chose my job to avoid these environments, so that I can get sunlight during the day. That fact alone should set me apart and help me succeed in the long-term, where others cannot. It absolutely boggles my mind to think about a life where I cannot get any sun, and need to work under fluorescent lights all day.

    On the loss of critical thinking and reading skills in many populations: agree. I wonder what came first, Western populations who chose "bread and games" (or: beer, McDonalds, and Netflix), or governments who preferred people without thinking abilities. My guess is that the former came first, which was capitalized on by governments.

    Scheduling workdays from noon to 6-8PM: amazing idea!
    Sheddie likes this.
  8. KalosKaiAgathos

    KalosKaiAgathos New Member

    Another day, another post (emphasis mine):

    Differential effects of diet composition and timing of feeding behavior on rat brown adipose tissue and skeletal muscle peripheral clocks

    The effects of feeding behavior and diet composition, as well as their possible interactions, on daily (clock) gene expression rhythms have mainly been studied in the liver, and to a lesser degree in white adipose tissue (WAT), but hardly in other metabolic tissues such as skeletal muscle (SM) and brown adipose tissues (BAT). We therefore subjected male Wistar rats to a regular chow or free choice high-fat-high sugar (fcHFHS) diet in combination with time restricted feeding (TRF) to either the light or dark phase. In SM, all tested clock genes lost their rhythmic expression in the chow light fed group. In the fcHFHS light fed group rhythmic expression for some, but not all, clock genes was maintained, but shifted by several hours. In BAT the daily rhythmicity of clock genes was maintained for the light fed groups, but expression patterns were shifted as compared with ad libitum and dark fed groups, whilst the fcHFHS diet made the rhythmicity of clock genes become more pronounced. Most of the metabolic genes in BAT tissue tested did not show any rhythmic expression in either the chow or fcHFHS groups. In SM Pdk4 and Ucp3 were phase-shifted, but remained rhythmically expressed in the chow light fed groups. Rhythmic expression was lost for Ucp3 whilst on the fcHFHS diet during the light phase. In summary, both feeding at the wrong time of day and diet composition disturb the peripheral clocks in SM and BAT, but to different degrees and thereby result in a further desynchronization between metabolically active tissues such as SM, BAT, WAT and liver.

    Another proof that both meal type and meal timing affect peripheral clocks in your body. The last part of the demonstration - the specific effects of peripheral clock programming on health - is still missing in my opinion, in the literature.

    Link: https://www.sciencedirect.com/science/article/pii/S2451994417300135
  9. Jack Kruse

    Jack Kruse Administrator

    Why don't they? Because humans have the melanopsin/retinol system in the largest organ of their body that controls the peripheral clock genes.
    Sajid Mahmood likes this.
  10. Jason Coates

    Jason Coates Losing the Shade.

    Melanopsin—Shedding Light on the Elusive Circadian Photopigment
    R. Lane Brown and Phyllis R. Robinson,*

    Circadian photoentrainment is the process by which the brain’s internal clock becomes synchronized with the daily external cycle of light and dark. In mammals, this process is mediated exclusively by a novel class of retinal ganglion cells that send axonal projections to the suprachiasmatic nuclei (SCN), the region of the brain that houses the circadian pacemaker. In contrast to their counterparts that mediate image-forming vision, SCN-projecting RGCs are intrinsically sensitive to light, independent of synaptic input from rod and cone photoreceptors. The recent discovery of these photosensitive RGCs has challenged the long-standing dogma of retinal physiology that rod and cone photoreceptors are the only retinal cells that respond directly to light and has explained the perplexing finding that mice lacking rod and cone photoreceptors can still reliably entrain their circadian rhythms to light. These SCN-projecting RGCs selectively express melanopsin, a novel opsin-like protein that has been proposed as a likely candidate for the photopigment in these cells. Research in the past three years has revealed that disruption of the melanopsin gene impairs circadian photoentrainment, as well as other nonvisual responses to light such as the pupillary light reflex. Until recently, however, there was no direct demonstration that melanopsin formed a functional photopigment capable of catalyzing G-protein activation in a light-dependent manner. Our laboratory has recently succeeded in expressing melanopsin in a heterologous tissue culture system and reconstituting a pigment with the 11-cis-retinal chromophore. In a reconstituted biochemical system, the reconstituted melanopsin was capable of activating transducin, the G-protein of rod photoreceptors, in a light-dependent manner. The absorbance spectrum of this heterologously expressed melanopsin, however, does not match that predicted by previous behavioral and electophysiological studies. Although melanopsin is clearly the leading candidate for the elusive photopigment of the circadian system, further research is needed to resolve the mystery posed by its absorbance spectrum and to fully elucidate its role in circadian photoentrainment.
  11. Jason Coates

    Jason Coates Losing the Shade.

  12. KalosKaiAgathos

    KalosKaiAgathos New Member

    Posted this one on Jack's dr's page. Jack posted about how mitochondria have their own circadian rhythm as well:


    I then posted this study:


    (emphasis mine again):
    Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics


    Melatonin has been speculated to be mainly synthesized by mitochondria. This speculation is supported by the recent discovery that aralkylamine N-acetyltransferase/serotonin N-acetyltransferase (AANAT/SNAT) is localized in mitochondria of oocytes and the isolated mitochondria generate melatonin. We have also speculated that melatonin is a mitochondria-targeted antioxidant. It accumulates in mitochondria with high concentration against a concentration gradient. This is probably achieved by an active transportation via mitochondrial melatonin transporter(s). Melatonin protects mitochondria by scavenging reactive oxygen species (ROS), inhibiting the mitochondrial permeability transition pore (MPTP), and activating uncoupling proteins (UCPs). Thus, melatonin maintains the optimal mitochondrial membrane potential and preserves mitochondrial functions. In addition, mitochondrial biogenesis and dynamics is also regulated by melatonin. In most cases, melatonin reduces mitochondrial fission and elevates their fusion. Mitochondrial dynamics exhibit an oscillatory pattern which matches the melatonin circadian secretory rhythm in pinealeocytes and probably in other cells. Recently, melatonin has been found to promote mitophagy and improve homeostasis of mitochondria.

    Mitochondria are important organelles. They not only provide the chemical energy to power the cell, but also regulate cellular homeostasis of calcium, apoptosis, and cellular metabolism. Preservation of the structural and functional integrity of mitochondria is essential for a healthy cell. One of the mitochondrial-targeted molecules is melatonin. Melatonin may be synthesized by mitochondria, a capacity that was inherited from bacteria, the precursors of mitochondria. As a result, all cells with mitochondria likely have the capacity to produce melatonin. This is strongly supported by the observations that the products of AANAT are exclusively located in mitochondria of pinealocytes, the AANAT/SNAT has been identified in the mitochondria of oocytes and the suitable substrate (acetyl CoA) availability for AANAT in mitochondria. In addition, the high level of melatonin is detected in the medium of cultured mitochondria. The protective effects of melatonin on mitochondria depend on its accumulation in these organelles. To achieve this, it requires an active melatonin transport against a concentration gradient. Melatonin mitochondrial carriers have been reported recently, and their levels in mitochondria were positively associated with mitochondrial melatonin concentration. An important protective mechanism of melatonin on mitochondria is that melatonin influences the mitochondrial membrane potential (Δψ). Melatonin blocks MPTP to preserve the Δψ under stressful conditions and activates the UCPs to slightly reduce the Δψ in normal condition. These activities are not in conflict with each other. Blockage of MPTP prevents the Δψ collapse and cellular apoptosis. Activation of UCPs reduces ROS formation because a slight lowering of Δψ accelerates the electron transportation and reduces electron leakage. Activation of UCPs seems not to reduce ATP production as expected. A potential mechanism is that the fewer leaked electrons under the UCP activation contribute their energy to ATP production. A balanced Δψ is ideal for the function of mitochondria. The detailed information as to the mechanisms is summarized in Figure 4. In addition to mitochondrial protection, melatonin also influences mitochondrial dynamics. The daily oscillations of mitochondrial functions as well as the morphology seem to fit well with the melatonin circadian rhythm. Melatonin reduces mitochondrial fission and increases their fusion, thereby preserving their normal function. Recently, it has been reported that melatonin modified mitophagy by either the enhancement or the reduction of this process, depending on conditions and cell types. The exact mechanisms require further investigation.

    Jason Coates likes this.
  13. KalosKaiAgathos

    KalosKaiAgathos New Member

    Another one:


    (emphasis mine):

    Melatonin as a mitochondria-targeted antioxidant: one of evolution's best ideas.
    Melatonin is an ancient antioxidant. After its initial development in bacteria, it has been retained throughout evolution such that it may be or may have been present in every species that have existed. Even though it has been maintained throughout evolution during the diversification of species, melatonin's chemical structure has never changed; thus, the melatonin present in currently living humans is identical to that present in cyanobacteria that have existed on Earth for billions of years. Melatonin in the systemic circulation of mammals quickly disappears from the blood presumably due to its uptake by cells, particularly when they are under high oxidative stress conditions. The measurement of the subcellular distribution of melatonin has shown that the concentration of this indole in the mitochondria greatly exceeds that in the blood. Melatonin presumably enters mitochondria through oligopeptide transporters, PEPT1, and PEPT2. Thus, melatonin is specifically targeted to the mitochondria where it seems to function as an apex antioxidant. In addition to being taken up from the circulation, melatonin may be produced in the mitochondria as well. During evolution, mitochondria likely originated when melatonin-forming bacteria were engulfed as food by ancestral prokaryotes. Over time, engulfed bacteria evolved into mitochondria; this is known as the endosymbiotic theory of the origin of mitochondria. When they did so, the mitochondria retained the ability to synthesize melatonin. Thus, melatonin is not only taken up by mitochondria but these organelles, in addition to many other functions, also probably produce melatonin as well. Melatonin's high concentrations and multiple actions as an antioxidant provide potent antioxidant protection to these organelles which are exposed to abundant free radicals.
    Jason Coates likes this.

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