“Fasting, Food, Folatesand

the Sun”

Bernie Hendricks, R.Ph.CE Coordinator

South Dakota State University College of Pharmacyand Allied Health Professions

Brookings, SD

Disclosure:

I have no financial relationships to declare.

1.0 hr – ACPE credit

Pharmacists:#0063-9999-19-050-L04-P

Tecjnicians:#0063-9999-19-050-L04-T

September 13, 2019

Pharmacist Learning Objectives

1. Explain the triggering mechanisms for autophagy and mitophagy;

2. Describe the structural changes that occur during starch retrogradation, and explain the resulting nutritional benefits of following those changes;

3. Identify two major nutritional benefits of folates, and identify potential absorption problems;

4. Evaluate the potential benefits of chronic, low-intensity UVR exposure.

Technician Learning Objectives

1. Define the terms autophagy and mitophagy;

2. Describe the nutritional benefits of starch retrogradation;

3. Name three folate supplements, and identify major food groups that are high in folate nutritional value;

4. Explain the potential benefits of moderate daily sunshine.

Goal of this presentation

Improve the personal health profile of pharmacy professionals themselves.

Alternate title:

“Fun, Food (deprivation), Fast-Food, Folates

and the Sun”

Motivational Quotes…

“If I had known I was going to live this long, I would have taken better care of myself.”

-Unknown

“As for me, except for an occasional heart attack, I feel as young as I ever did.” - Robert Benchley

Food deprivation - “Fasting”…

IntroductionVideo - Hungry German Shepherd:https://www.youtube.com/watch?v=nGeKSiCQkPw

Glossary

Autophagy (self-devouring):Segregation and disposal of damaged organelles within a cell.

GlossaryMitophagy:Mitochondrial selective autophagy -surveils mitochondrial population, eliminating superfluous and/or impaired organelles and mediating cellular survival and viability in response to injury/trauma and infection. Front. Immunol., 05 June 2018 | https://doi.org/10.3389/fimmu.2018.01283 Accessed from: https://www.frontiersin.org/articles/10.3389/fimmu.2018.01283/full

Fasting – triggers autophagy and mitophagy Nutrient depletion, which is one of the physiological triggers of autophagy, results in the

depletion of intracellular acetyl coenzyme A (AcCoA) coupled to the deacetylation of cellular proteins. We surmise that there are 3 possibilities to mimic these effects, namely (i) the depletion of cytosolic AcCoA by interfering with its biosynthesis, (ii) the inhibition of acetyltransferases, which are enzymes that transfer acetyl groups from AcCoA to other molecules, mostly leucine residues in cellular proteins, or (iii) the stimulation of deacetylases, which catalyze the removal of acetyl groups from leucine residues.

There are several examples of rather nontoxic natural compounds that act as AcCoA depleting agents (e.g., hydroxycitrate), acetyltransferase inhibitors (e.g., anacardic acid, curcumin, epigallocatechin-3-gallate, garcinol, spermidine) or deacetylase activators (e.g., nicotinamide, resveratrol), and that are highly efficient inducers of autophagy in vitro and in vivo, in rodents. Another common characteristic of these agents is their capacity to reduce aging-associated diseases and to confer protective responses against ischemia-induced organ damage. Hence, we classify them as "caloric restriction mimetics" (CRM).

Here, we speculate that CRM may mediate their broad health-improving effects by triggering the same molecular pathways that usually are elicited by long-term caloric restriction or short-term starvation and that imply the induction of autophagy as an obligatory event conferring organismal, organ- or cytoprotection.

Autophagy. 2014;10(11):1879-82. doi: 10.4161/auto.36413. Caloric restriction mimetics: natural/physiological pharmacological autophagy inducers. Mariño G1, Pietrocola F, Madeo F, Kroemer G. https://www.ncbi.nlm.nih.gov/pubmed/25484097

Fasting – triggers autophagy and mitophagy

Nutrient depletion, which is one of the physiological triggers of autophagy, results in the depletion of intracellular acetyl coenzyme A (AcCoA) coupled to the deacetylation of cellular proteins.

Autophagy. 2014;10(11):1879-82. doi: 10.4161/auto.36413. Caloric restriction mimetics: natural/physiological pharmacological autophagy inducers. Mariño G1, Pietrocola F, Madeo F, Kroemer G. https://www.ncbi.nlm.nih.gov/pubmed/25484097

Fasting – triggers autophagy and mitophagy

There are several nontoxic natural compounds that are “highly efficient inducers of autophagy in vitro and invivo in rodents”:1. AcCoA depleting agents (e.g., hydroxycitrate), acetyltransferase inhibitors (e.g., anacardic acid, curcumin, epigallocatechin-3-gallate, garcinol, spermidine)2. deacetylase activators (e.g., nicotinamide, resveratrol), and that are highly efficient inducers of autophagy in vitro and in vivo, in rodents. Autophagy. 2014;10(11):1879-82. doi: 10.4161/auto.36413. Caloric restriction mimetics: natural/physiological pharmacological autophagy inducers. Mariño G1, Pietrocola F, Madeo F, Kroemer G. https://www.ncbi.nlm.nih.gov/pubmed/25484097

Fasting – triggers autophagy and mitrophagyAnother common characteristic of these agents is their capacity to reduce aging-associated diseases and to confer protective responses against ischemia-induced organ damage. Hence, we classify them as "caloric restriction mimetics" (CRM). Here, we speculate that CRM may mediate their broad health-improving effects by triggering the same molecular pathways that usually are elicited by long-term caloric restriction or short-term starvation and that imply the induction of autophagy as an obligatory event conferring organismal, organ- or cytoprotection.

Autophagy. 2014;10(11):1879-82. doi: 10.4161/auto.36413. Caloric restriction mimetics: natural/physiological pharmacological autophagy inducers. Mariño G1, Pietrocola F, Madeo F, Kroemer G. https://www.ncbi.nlm.nih.gov/pubmed/25484097

Autophagy - Exercise“Exercise and exercise training induced increased autophagy markers in human skeletal muscle”“…exercise increases markers of autophagy in human skeletal muscle within the first 2 h of recovery and 8 weeks of exercise training increases the capacity for autophagy and mitophagy regulation.”

Physiol Rep. 2018 Apr;6(7):e13651. doi: 10.14814/phy2.13651.Accessed: https://www.ncbi.nlm.nih.gov/pubmed/29626392

Mitophagy – Innate Immunity

“Defective removal of damaged mitochondria leads to hyperactivationof inflammatory signaling pathways and subsequently to chronic systemic inflammation and development of inflammatory diseases.”Mitophagy has a critical role in the “innate immune system homeostasis.”

Front. Immunol., 05 June 2018 | https://doi.org/10.3389/fimmu.2018.01283 Accessed from: https://www.frontiersin.org/articles/10.3389/fimmu.2018.01283/full

“System-wide benefits to intermealfasting by autophagy”“Our studies suggest that consuming two meals a day with complete food restriction in between the meals is sufficient to lower blood glucose and lipid levels. This simple dietary approach activates a cell “cleansing system” called autophagy in liver, fat, brain, and muscle that helps prevent obesity and diabetes.”

Accessed from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718973/

“The Fasting Cure is No Fad”

Wall Street Journal, Aug 1, 2019https://www.wsj.com/articles/the-fasting-cure-is-no-fad-11564676512

—Dr. Michalsen is a professor at Berlin’s Charité University Medical Center. This essay is adapted from his new book, “The Nature Cure: A Doctor’s Guide to the Science of Natural Medicine,” which Viking will publish on Aug. 6.

Michalsen:

“Scientific evidence for the glory of breakfast is scarce. Instead, we should skip it and eat lunch like kings.”

Michalsen:“At the Charité University Hospital in Berlin, I’ve employed what’s called intermittent fasting, or time-restricted eating, to help patients with an array of chronic conditions. These include diabetes, high blood pressure, rheumatism and bowel diseases, as well as pain syndromes such as migraines and osteoarthritis.

Michalsen:“… omit either dinner or breakfast..don’t ingest any food for at least 14 hours at a stretch. That makes lunch the most important meal of the day. It also reduces the time spent each day processing food and lengthens the period devoted to cleansing and restoring the body’s cells, both of which have positive health effects”

Michalsen:“Adopting this technique is not as difficult as it may seem. If you sleep from 11 p.m. to 7 a.m., you’ve already fasted for eight hours. Now you only need another six. It’s healthy to avoid eating late in the evening to let your body burn energy from food rather than store it, so if you eat dinner by 7 p.m., that’s another four hours. For breakfast, you can limit yourself to coffee or tea (maybe with a small piece of fruit) and make lunch your first proper meal. By that time, you’re clearly beyond the 14 hours and don’t need to restrain yourself: You can eat until you are full.

Michalsen:“There is a logic to it. When we eat, our body releases insulin. That disrupts the process of autophagy (from the Greek, meaning “self-devouring”), by which cells deconstruct old, damaged components in order to release energy and build new molecules. Autophagy helps to counteract the aging of cells and builds immunity. Fasts stimulate autophagy and allow the full molecular process to take place, as a team led by Frank Madeo at the University of Graz in Austria found in 2017.”

Michalsen:“Fasting also can contribute to brain health and happiness. The neurobiologist Mark Mattson, who retired this year from the National Institutes of Health, has demonstrated in experiments for two decades that nerve growth factors contribute significantly to brain health and positive mood. He also found that fasting, restricting calories and exercising spur distinct increases in the best-known nerve growth factor, BDNF.”

Part 2: Fast Food

Part 2: Fast Food

The ‘original’ Fast Food:“Left-overs”

Fast Food (the original fast food): “Left-overs”

Starch retrogradation:A process in which disaggregated amylose and amylopectin chains in a gelatinizedstarch paste reassociate to form more ordered structures.

Comprehensive Reviews in Food Science and Food Safety https://onlinelibrary.wiley.com/doi/pdf/10.1111/1541-4337.12143

Fast Food (the original fast food)

Dr Denise Robertson, University of Surrey:If you cook and cool pasta down, then your body will treat it much more like fibre, creating a smaller glucose peak and helping feed the good bacteria that reside down in your gut. You will also absorb fewer calories.

What happens if the starch-based food is then reheated?

Fast Food (the original fast food)

Question: What happens if the starch-based food is then reheated?

Starch Retrogradation - Research

Dr Chris van Tulleken: The volunteers had to undergo three days of testing in all,

spread out over several weeks. On each occasion they had to eat their pasta on an empty stomach. The volunteers were randomised to eating either hot, cold or

reheated pasta on different days. On one day they got to eat the pasta, freshly cooked, nice and

hot with a plain but delicious sauce of tomatoes and garlic. On another day they had to eat it cold, with the same sauce, but

after it had been chilled overnight. And on a third day they got to eat the pasta with sauce after it

had been chilled and then reheated. On each of the days they also had to give blood samples every

15 minutes for two hours, to see what happened to their blood glucose as the pasta was slowly digested.

Starch retrogradation - research

Eating cold pasta led to a smaller spike in blood glucose and insulin than eating freshly boiled pasta had.

Our leftovers could be healthier for us than the original meal. Also… cooking, cooling and then reheating the pasta had an even more dramatic effect. Or, to be precise, an even smaller effect on blood glucose.

In fact, it reduced the rise in blood glucose by 50%

Part 3: Folates

Areas of interest…

Part 3: Folates

Areas of interest…

DNA Is Not Destiny: The New Science of Epigenetics Discovery Magazine – Nov 22, 2006

Folates

National Institutes of Health Office of Dietary Supplements - Fact Sheet for Health Care Professionals:

“Folates” (vitamin B-9) – term covering folates from food, dietary supplements, fortified foods, folic acid.

Accessed: https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/

Folates - Food groupsBeef liverSpinachBlack-eyed peas (cowpeas)AsparagusBrussel sproutsRomaine lettuceAvacado

Accessed: https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/

Folates

Essential for proper cell division.

Folate functions as a coenzyme or cosubstrate in single-carbon transfers in the synthesis of nucleic acids (DNA and RNA) and metabolism of amino acids.

Accessed: https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/

Folate deficiency – causes:

Alcohol use disorderPregnant womenCertain medicationsMalabsorption disordersPeople with MTHFR polymorphisms

Accessed: https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/

Folates and Health

7 Diseases and Disorders in which folates might play a role:- Autism Spectrum Disorder (ASD)- Cancer- Cardiovascular disease and stroke- Dementia, cognitive function, Alzheimer’s- Depression- NTDs- Pre-term birth, congenital heart defects, other

congenital anamolies

Accessed: https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/

Folate status

Smoking depletes folatesAlcohol blocks folate uptakeAnti-seizure medications diminish folate uptakeAntineoplastics, Immunosuppressantsinhibit dihydrofolate reductaseChronic overexposure to UVR depleted folates in skin tissue

“Impact of Folate Deficiency on DNA Stability”ABSTRACT Convincing evidence links folate deficiency with colorectal

cancer incidence. Currently, it is believed that folate deficiency affects DNA stability principally through two potential pathways. 5,10-Methylenetetrahydrofolate donates a methyl group to uracil, converting it to thymine, which is used for DNA synthesis and repair. If folate is limited, imbalances in the DNA precursor pool

occur, and uracil may be misincorporated into DNA. Subsequent misincorporation and repair may lead to double strand breaks, chromosomal damage and cancer.

Oxford Academic – The Journal of Nutrition 2002 Accessed: https://academic.oup.com/jn/article/132/8/2444S/4687602

Folates – skin health “Photobiological implications of folate depletion and

repletion in cultured human keratinocytes”

Folate restriction leads to rapid depletion of intracellular reduced folates resulting in S-phase growth arrest, increased levels of inherent DNA damage, and increased uracil misincorporation into DNA, without a significant losses in overall cellular viability. Folate depleted keratinocytes were sensitized toward UVR induced apoptosis and displayed a diminished capacity to remove DNA breaks resulting from both photo and oxidative DNA damage. Thus, folate deficiency creates a permissive environment for genomic instability, an early event in the process of skin carcinogenesis. The effects of folate restriction, even in severely depleted, growth-arrested keratinocytes, were reversible by repletion with folic acid. Overall, these results indicate that skin health can be positively influenced by optimal folate nutriture.

J Photochem Photobiol B. 2010 Apr 2;99(1):49-61. doi: 10.1016/j.jphotobiol.2010.02.003. Epub 2010 Feb 6Accessed: https://www.ncbi.nlm.nih.gov/pubmed/20211567

Part 4: The Sun

The Sun

UVA: 320-400 nmUVB: 290-320 nmNarrow-band UVB: 311-312 nm

Narrow-band UVB“Reversal of Atopic Dermatitis with Narrow-Band UVB Phototherapy and Biomarkers for Therapeutic Response”

J Allergy Clin Immunol. 2011 Sep; 128(3): 583–93.e1-4. Published online 2011 Jul 16. doi: 10.1016/j.jaci.2011.05.042

Accessed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448950/

“How UV light touches the brain and endocrine system through skin, and why” “UV radiation can upregulate local neuroendocrine

axes, with UVB being markedly more efficient than UVA. The locally induced cytokines, corticotropin-releasing hormone, urocortins, proopiomelanocortin-peptides, enkephalins, or others can be released into circulation to exert systemic effects, including activation of the central hypothalamic-pituitary-adrenal axis, opioidogenic effects, and immunosuppression, independent of vitamin D synthesis.”

Endocrinology 2018 May: Accessed : https://www.ncbi.nlm.nih.gov/pubmed/29546369

“How UV light touches the brain and endocrine system through skin, and why” “Similar effects are seen after exposure of the

eyes and skin to UV, through which UVB activates hypothalamic paraventricular and arcuate nuclei and exerts very rapid stimulatory effects on the brain. Thus, UV touches the brain and central neuroendocrine system to reset body homeostasis. This invites multiple therapeutic applications of UV radiation, for example, in the management of autoimmune and mood disorders, addiction, and obesity.”

Endocrinology 2018 May: Accessed : https://www.ncbi.nlm.nih.gov/pubmed/29546369

“How UV light touches the brain and endocrine system through skin, and why”“Thus, UV touches the brain and central neuroendocrine system to reset body homeostasis. This invites multiple therapeutic applications of UV radiation, for example, in the management of autoimmune and mood disorders, addiction, and obesity.”

Endocrinology 2018 May: Accessed : https://www.ncbi.nlm.nih.gov/pubmed/29546369

Conclusion:

For optimal health and longevity…There are important factors that are deserving of continued research and consideration in the fields of intermittent fasting, starch retrogradation, folate status and ‘healthy’ UVR exposure.

Future Conventions:Deadwood….

Video - Slots in Room: https://www.youtube.com/watch?v=t3NxmKv4PHc