AMPK links cognitive decline reversal in Alzheimer’s disease with Progeria, HIV-1 latency, & Oocyte activation: The "Shock and Live" approach

Hey Blogger Fam, take a look at my most recent post on LinkedIn when you have a minute.  Basically, a recent human study showed that Alzheimer's disease is likely reversible, contradicting what's commonly accepted in the medical profession (i.e. that it's irreversible). The super interesting thing about this study was that the protocol that the patients adhered to is just a contextual redefinition of the “Shock and Live” approach, consisting of changes in diet, exercise, and vitamin and herbal supplementation that synergistically causes the induction of cellular stress (i.e. "shock"), leading to a beneficial response in brain cells (i.e. "live”) mediated by the activation of the master metabolic regulator AMPK.  Indeed, most of the components of the protocol, including a low carb/sugar diet, fasting, caloric restriction, exercise, EPA/DHA (fish oil), melatonin, folic acid, selenium, alpha-lipoic acid, acetyl-l-carnitine, resveratrol, curcumin, CoQ10, probiotics, and prebiotics all induce a cellular stress response, activating AMPK and bringing “life” back into cells of the brain. AMPK activation has been shown to promote neurogenesis (birth of new brain cells), increase the growth of new neurons and synapses, promote the viability of neural stem cells (which produce new brain cells), and promote learning and memory formation.

Two things that really caught my eye were the use of brain stimulation and vitamin D.  Although the patients used learning-based simulations to stimulate the brain, electrical pulses/stimulation (“shock”) have been shown to activate AMPK and produce beneficial effects in many people with neurological disorders (Parkinson’s, depression, tremor, obsessive-compulsive disorder).  The cool connection is that electrical pulses have also been shown to activate oocytes, leading to the birth of healthy children.  Thus, AMPK activation via a “shock” likely explains how invasive procedures like deep-brain stimulation produce efficacious results as well as how all human life is created.  The other REALLY cool thing about the study is vitamin D.  Not only does vitamin D promote the activation of T cells (enhances the immune response), but it also induces a slight “shock” (in the form of an increase in calcium), bringing back to life (i.e. “live”) cells taken from Progeria kids that are rapidly aging and nearing death. This slight “shock” (calcium) is also what activates oocytes, bringing forth new life.  Interestingly, vitamin D has also been shown to induce the acrosome reaction in human sperm, a process that allows sperm to penetrate the egg, and without which no human being could be created via “the old fashion way”:-).  That “shock”, in the form of calcium, also ignites the acrosome reaction in sperm.  Unsurprisingly, vitamin D as well as compounds that increase calcium (“shock”) and have been used to activate both human oocytes and induce the acrosome reaction in human sperm activate AMPK.  And here’s a little extra nugget from something I’m working on.  AMPK activation is critical during a  “shock” to embryonic stem cells, forcing those cells to develop into different cells (liver, pancreas, gut, urethra, etc.) that will eventually form the baby, another rendition of the “Shock and Live” approach.  Let’s see….a “shock” induces oocyte activation, the sperm acrosome reaction, neural stem cell viability, progeria cell growth, and development of a baby from an embryo.  It looks as if the “Shock and Live” approach may be a universal theme in human biology.  If this turns out to be true…………..:-)  

AMPK links cognitive decline reversal in Alzheimer’s disease with Progeria, HIV-1 latency, & Oocyte activation: The "Shock and Live" approach 


https://www.linkedin.com/pulse/ampk-links-cognitive-decline-reversal-alzheimers-disease-finley?trk=prof-post  

In a small but highly publicized study conducted by researchers from the University of California, Los Angeles and the Buck Institute for Research on Aging, the use of a personalized therapeutic program to improve or reverse cognitive decline in 10 patients with early Alzheimer’s disease led to a clear improvement in mild and subjective cognitive impairment (MCI and SCI, respectively--Alzheimer’s precursors) for all ten patients, with a dramatic and unprecedented reversal of cognitive decline for two patients with well documented Alzheimer’s disease [32].  The therapeutic approach, known as metabolic enhancement for neurodegeneration (MEND), is a multi-pronged protocol designed to promote metabolic enhancement that consists of dietary modifications, exercise, vitamin and herbal supplementation, stress reduction incorporation, exercise, and hormonal balancing [33].       

After 10 months on the program, patient 1 (a 66-year-old professional male with documented Alzheimer’s disease, a strongly positive amyloid PET scan, and abnormal neuropsychological studies) experienced an increase in hippocampal volume from the 17^th to the 75^th percentile and an absolute increase in hippocampal volume of 11.7% as measured via volumetric analyses by Neuroquant [32].  Interestingly, interruption of compliance to the protocol led to an episode of memory loss for the patient (failed to remember that he left the car in the driveway idling).  However, re-adherence to the protocol led to marked symptomatic improvement (memory improvement and “work came more easily to him”) in addition to a significant increase in hippocampal volume [32].

Patient 2, a 69-year-old professional male and entrepreneur, also had well-documented Alzheimer’s disease, with an FDG PET scan showing reduced glucose utilization in the parietotemporal cortices and the temporal lobes, a reduction in CVLT (California Verbal Learning Test), auditory delayed memory at the 13^th percentile, and a Stroop color test at the 16^th percentile. The patient also reported subjective instances of memory loss (difficulty recognizing faces at work) and declines in cognitive capacity (loss the ability to rapidly add columns of numbers in his head) [32]. After 6 months on the MEND program, the patient’s ability to recognize faces at work and to rapidly add columns of numbers in his head returned. Strikingly, quantitative neuropsychological testing after 22 months on the program revealed an increase from the 3^rd to the 84^th percentile for CVLT-IIB, reverse digit span from the 24^th to the 74^th percentile, auditory delayed memory from the 13^th to the 79^th percentile, and CVLT-II from the 54^th to the 96^th percentile [32].

Interestingly, the authors also noted that the improvement experienced by all 10 patients had been sustained and no patient exhibited the cognitive decline characteristic of Alzheimer’s disease, despite claims that Alzheimer’s disease can not be prevented, delayed, or reversed [32,34].

The details of the MEND protocol (reproduced and adapted below) clearly indicate that a significant number of disparate modalities and compounds that synergistically modulated metabolism, leading to a striking reversal of cognitive decline in patients diagnosed with early Alzheimer’s disease, are in fact inducers of a cellular stress response. The induction of cellular stress leads to the activation of the master metabolic regulator AMPK (see red notations for references).  Synergistic AMPK activation by this protocol is essentially a contextual redefinition of the “Shock and Live” approach that defines the process of oocyte activation, a mechanism that is responsible for the creation of all human life.

(Adapted from: Bredesen DE. Reversal of cognitive decline: a novel therapeutic program. Aging (Albany NY). 2014 Sep;6(9):707-17.

Therapeutic System 1.0

Goal	Approach	Rationale and References
Optimize diet: minimize simple CHO, minimize inflammation.	Patients given choice of several low glycemic, low inflammatory, low grain diets.  Glucose deprivation activates AMPK [1,2].	Minimize inflammation, minimize insulin resistance.
Enhance autophagy, ketogenesis	Fast 12 hr each night, including 3 hr prior to bedtime. Fasting and caloric restriction activates AMPK.  AMPK stimulates brain ketogenesis and authophagy [3-6].	Reduce insulin levels, reduce Aβ.
Reduce stress	Personalized—yoga or meditation or music, etc.  AMPK reduces cortiol levels [7].	Reduction of cortisol, CRF, stress axis.
Optimize sleep	8 hr sleep per night; melatonin 0.5mg po qhs; Trp 500mg po 3x/wk if awakening. Exclude sleep apnea.  Melatonin activates AMPK [8].	[36]
Exercise	30-60′ per day, 4-6 days/wk.  Aerobic exercise activates AMPK [9].	[37, 38]
Brain stimulation	Posit or related.  Brain stimulation via high frequency stimulation (HFS) activates AMPK [10].	[39]
Homocysteine <7	Me-B12, MTHF, P5P; TMG if necessary.  MTHF (Folic acid) activates AMPK [11].	[40]
Serum B12 >500	Me-B12	[41]
CRP <1.0; A/G >1.5	Anti-inflammatory diet; curcumin; DHA/EPA; optimize hygiene. EPA, DHA, and curcumin activate AMPK [12-14].	Critical role of inflammation in AD
Fasting insulin <7; HgbA1c <5.5	Diet as above	Type II diabetes-AD relationship
Hormone balance	Optimize fT3, fT4, E2, T, progesterone, pregnenolone, cortisol. fT3, E2, and T activate AMPK [15-17].	[5, 42]
GI health	Repair if needed; prebiotics and probiotics. Prebiotics and probiotics activate AMPK [18,19].	Avoid inflammation, autoimmunity
Reduction of A-beta	Curcumin, Ashwagandha.  Curcumin activates AMPK.  Ashwagandha likely activates AMPK [12,20].	43-45
Cognitive enhancement	Bacopa monniera, MgT.  MgT likely activates AMPK [21].	[46, 47]
25OH-D3 = 50-100ng/ml	Vitamins D3, K2.  Vitamin D3 activates AMPK [22].	[48]
Increase NGF	H. erinaceus or ALCAR.  ALCAR activates AMPK [23].	[49, 50]
Provide synaptic structural components	Citicoline, DHA. DHA activates AMPK [14].	[51].
Optimize antioxidants	Mixed tocopherols and tocotrienols, Se, blueberries, NAC, ascorbate, α-lipoic acid.  Tocotrienols, Se, blueberries, and α-lipoic acid activate AMPK [24-27].	[52]
Optimize Zn:fCu ratio	Depends on values obtained	[53]
Ensure nocturnal oxygenation	Exclude or treat sleep apnea	[54]
Optimize mitochondrial function	CoQ or ubiquinol, α-lipoic acid, PQQ, NAC, ALCAR, Se, Zn, resveratrol, ascorbate, thiamine.  CoQ10, α-lipoic acid, ALCAR, Se, and resvertrol activate AMPK.  PQQ likely activates AMPK [23,25-30].	[55]
Increase focus	Pantothenic acid	Acetylcholine synthesis requirement
Increase SirT1 function	Resveratrol. Resveratrol activates AMPK [26,29].	[32]
Exclude heavy metal toxicity	Evaluate Hg, Pb, Cd; chelate if indicated	CNS effects of heavy metals
MCT effects	Coconut oil or Axona.  MCT/Coconut oil likely activates AMPK [31].	[56]

CHO, carbohydrates; Hg, mercury; Pb, lead; Cd, cadmium; MCT, medium chain triglycerides; PQQ, polyquinoline quinone; NAC, N-acetyl cysteine; CoQ, coenzyme Q; ALCAR, acetyl-L-carnitine; DHA, docosahexaenoic acid; MgT, magnesium threonate; fT3, free triiodothyronine; fT4, free thyroxine; E2, estradiol; T, testosterone; Me-B12, methylcobalamin; MTHF, methyltetrahydrofolate; P5P, pyridoxal-5-phosphate; TMG, trimethylglycine; Trp, tryptophan

As initially proposed in my most recent publication, AMPK activation is likely critical, if not indispensable, for oocyte activation via the induction of a cellular stress response (mediated by an increase in intracellular calcium levels, an AMP/ATP ratio increase, or reactive oxygen species (ROS) generation) [35].  AMPK has been shown to be critical for the resumption and maturation of meiosis in oocytes, two processes that are critical for efficient sperm- or artificially-induced oocyte activation [35].  Interestingly, several distinct compounds and modalities that induce a cellular stress response have been used to artificially activate oocytes during in vitro fertilization procedures to produce healthy children, including electrical stimulation and the calcium (Ca²⁺) ionophores ionomycin and A23187 (increases intracellular Ca²⁺ levels similar to sperm-induced oocyte activation) [35-37]. 

The “Shock and Live” approach is also analogous to the “Shock and Kill” approach, a method currently being pursued by HIV-1 cure researchers to potentially eradicate HIV-1 [35].  The “shock and kill” approach involves reactivating (i.e. “shock”) a T cell that harbors dormant HIV-1, hence reactivating the virus itself and thus inducing destruction of the T cell along with the virus or enhancing recognition and destruction of the virus-infected T cell by the immune system (i.e. “kill”) [35].  AMPK is also critical for the activation of T cells and the mounting of an effective immune response to eliminate viruses, bacteria, and cancer cells [35,38,39].  Interestingly, the same compounds that have been used to induce a “shock” to initiate the creation of human life (i.e. ionomycin and A23187) have also been used in combination with other compounds to initiate a “shock” to facilitate T cell activation and thus reactivate dormant HIV-1  [35,40]. Ca²⁺ ionophores including ionomycin have also been used to induce a “shock” to activate cytotoxic CD8⁺ T cells, a T cell subset that is critical for the destruction of viruses such as HIV-1 and cancer cells. AMPK activation has also been shown to promote the formation of long-lived cytotoxic CD8⁺ memory T cells [38,39,41].

Unsurprisingly, AMPK activation has been shown to promote neurogenesis, increase the levels of BDNF (a protein essential for the growth and differentiation of new neurons and synapses), promote viability of neural stem cells, and enhance intracellular mechanisms that promote learning and memory formation [42-44].  As AMPK is activated as a result of the induction of cellular stress, many of the components of the MEND protocol likely activate AMPK by inducing a “shock”, thus enhancing and sustaining the viability of higher level brain functioning (i.e. “live”).  Indeed, as evident by the chart above and the associated references, glucose deprivation, fasting, caloric restriction, and exercise all induce varying levels of “shock” (mediated by increased levels of ROS, intracellular Ca^2+, or AMP/ATP ratio), leading to the activation of AMPK and AMPK-induced autophagy (“live”).  Several naturally-occurring compounds, including EPA, DHA, melatonin, folic acid, selenium, alpha-lipoic acid, and acetyl-l-carnitine also activate AMPK, likely via the induction of a cellular stress response.  Additionally, as also noted from the chart, brain stimulation via electrical pulses also leads to the activation of AMPK (and long-term potentiation—a process that underlies learning and memory), similar to oocyte activation induced by electrical stimulation.   

Interestingly, resveratrol, a polyphenol produced by several plants that activates AMPK, has been shown to not only promote long-term potentiation but also enhance reactivation of latent HIV-1 while an analog of resveratrol has been shown to promote meiotic resumption in mouse oocytes (a model for human oocytes), indicating that an appropriate “shock” or cellular stress induction characterizes beneficial physiological responses in oocytes, T cells, and brain cells [45-47]. Curcumin (a compound derived from the plant Curcuma longa) and butyrate (a short chain fatty acid produced by certain gut bacteria/probiotics) have also been shown to increase neural stem cell differentiation and enhance latent HIV-1 reactivation [48-51].

A particularly striking example of an AMPK-orchestrated “Shock and Live” approach is exemplified by 1α,25-dihydroxyvitamin D3 (vitamin D).  In addition to activating AMPK in vivo, vitamin D has recently been shown to profoundly improve nuclear morphology, significantly reduce DNA damage, improve cellular proliferation, delay premature cellular senescence, and dramatically reduce progerin production in patients diagnosed with the accelerated aging disorder Hutchinson-Gilford progeria syndrome (HGPS) [52].  As vitamin D has been shown to increase Ca²⁺ levels in the cell, HGPS cells treated with vitamin D initially experienced a slight decrease in proliferation (i.e. “shock”) followed by an increased improvement in growth rate compared to control cells, effectively delaying premature entry into cellular senescence (i.e. “live”) [52]. 

Vitamin D administered to HIV-1 patients also led to an increase in activated CD4⁺ T cells in a placebo-controlled randomized study [53].  The phorbol ester PMA/TPA (which has been shown to induce mouse oocyte activation when combined with Ca²⁺ ionophores) and vitamin D have also been shown to stimulate HIV-1 proviral activation to similar levels in a cell line latently-infected with a monocytotropic strain of HIV-1JR-FL [54,55].

Startlingly, vitamin D has also been shown to induce the acrosome reaction in human sperm, a process that is indispensable for sperm-induced fertilization by facilitating penetration of the oocyte plasma membrane [56].  Interestingly, similar to oocyte activation, an increase in intracellular Ca²⁺ levels (i.e. “shock”) is also critical for the induction of the acrosome reaction in sperm and the same compounds that have been used to activate human oocytes to produce healthy children (e.g. A23187) (i.e. “live”) have also been used to induce the acrosome reaction in human sperm (i.e. “live”), indicating that the acrosome reaction is also likely dependent on AMPK activation [57].

The induction of cellular stress and the activation of AMPK thus appear to be a central biological theme that is likely responsible for the creation of all human life, the promotion of lifespan and healthspan, and the potential amelioration or eradication of disease.  Just as the “Shock and Live” approach defines the beginnings of life, the activation of T cells, and the improvement or reversal of accelerated aging symptoms in HGPS, AMPK activation, via application of the “Shock and Live” approach, also likely represents a common mechanism of action through which distinct compounds and methodologies are able to ameliorate or reverse neurodegeneration.     

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