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Yogis and Cold exposure

The popularity of cold exposure has increased over the last few years. Whether it is through cryotherapy or cold water immersion more and more people practice and/or hashtag #coldexposure. What are the benefits of cold exposure for the modern yoga practitioner (yogi or yogini)?

 

Cold exposure as a meditation TECHNIQUE

Those that practice cold water immersions for some time report a sensation of stillness in mind (usually 30 seconds to a minute after the initial exposure). A friend of mine Luke Wills (founder of the Optimal Health Method) said he reached the same state of mind in his 2nd ice bath, with that on the 7th day in a vipassana meditation retreat. Anecdotal evidence like this were confirmed to be valid in a study published in May 2018 titled “Brain over Body” [1].  In this study participants with no previous experience in cold exposure and Wim Hof (a Dutch man with chronic practice in cold environments) were interchangeably exposed to cold and neutral temperatures. One of the most striking differences between the inexperienced subjects and Wim was the Dutchman’s ability to reduce activity in the insular cortex part of the brain during cold exposure. Insular cortex is an area involved in emotional attachment to external stimuli and self-reflection. Activity in this part of the brain has been shown to be linked with meditation and control in emotional eating.

 

Meditation is the 5th of the 8 limbs of yoga.

 

Cold exposure To overcome fears

Iyengar’s book “Light on Yoga” has the subtitle: “the yoga journey to wholeness, inner peace and ultimate freedom.” In our yogic journey (our journey to wholeness) we will have to ultimately face our fears. I believe that cold exposure offers a unique opportunity to learn how to do that.

Cold exposure is demanding on many levels; the adrenals, musculoskeletal system, circulation and the brown fat tissue (if existent) are activated at low temperatures. Aside though the multiple biochemical adaptations in the rest of the body, our brain also changes when we are exposed to cold. The initial response is that of: “fight or flight” [2]. A small area of the brain called amygdala (Greek word for almond) – by activating the HPA (Hypothalamic Pituitary Adrenal) axis – signals a Stress response to the rest of the body. While this initial stage is universal the way one deals with cold thereafter depends on her experience and ability to use her breath.

By training the body to deal with a stressful situation (ie. a cold immersion) in a controlled environment (such as a shower or a bath) we can reprogram our mind to deal with stressful situations which are out of our control. Our main tool in this process is our breath. Dealing with fear was the focus of a workshop I gave in 2017 to a group of actors. You can see footage from it in the video.

 

Cold exposure to improve Circulation / Cardiovascular Function

The benefits of an asana practice to physical health are far reaching. The improvement of respiratory function, the increase of muscle flexibility and joint mobility are just a few.  Depending though on the style of yoga one practices she may be getting more or less of a cardiovascular workout. Cold exposure is a unique way to strengthen one’s cardiovascular system.

Our cardiovascular system is surrounded by epithelial muscles which facilitate the circulation of the blood. At low temperatures the epithelial muscles surrounding the veins and arteries of our extremities constrict – preserving the blood and the nutrients carried in it for the more vital organs in the trunk and the head. When the body returns to higher temperatures the epithelial muscles in our extremities dilate again allowing for the blood to flow freely there. In a similar way that our biceps get stronger as they contract during chaturangas our cardiovascular system can get stronger through cold exposure.

 

 

Good circulation means no athletes foot, no cold extremities, better cognitive function, ability to heal/recover faster and perform better in sports.

 

Conclusion

The list above is not exhaustive of the benefits one can get from cold exposure; controlling pain perception [2], generation of Brown Far [3], strengthening of the immune system [4], improved tolerance to cold [5] are also good reasons for modern yogis and yoginis to practice cold exposure.

 

Future workshops are listed here.

 

References:

  1. Muzik, O., Reilly, K. T., & Diwadkar, V. A. (2018). “Brain over body”–A study on the willful regulation of autonomic function during cold exposure. NeuroImage172, 632-641.
  2. Kanosue, K., Sadato, N., Okada, T., Yoda, T., Nakai, S., Yoshida, K., … & Kobayashi, K. (2002). Brain activation during whole body cooling in humans studied with functional magnetic resonance imaging. Neuroscience letters329(2), 157-160.
  3. van der Lans, A. A., Hoeks, J., Brans, B., Vijgen, G. H., Visser, M. G., Vosselman, M. J., … & Schrauwen, P. (2013). Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. The Journal of clinical investigation123(8), 3395-3403.
  4. Buijze, G. A., Sierevelt, I. N., van der Heijden, B. C., Dijkgraaf, M. G., & Frings-Dresen, M. H. (2016). The Effect of Cold Showering on Health and Work: A Randomized Controlled Trial. PloS one11(9), e0161749.
  5. Vosselman, M. J., Vijgen, G. H., Kingma, B. R., Brans, B., & van Marken Lichtenbelt, W. D. (2014). Frequent extreme cold exposure and brown fat and cold-induced thermogenesis: a study in a monozygotic twin. PloS one9(7), e101653.

Fasting Diet: progressions

 

Updated: 26 Sep 2018

 

This article is written with deep respect in the process of fasting and consciousness that its epigenetic effects are far reaching. Fasting in my opinion is something we all need to be comfortable with. There are many disputes on what the healthiest diet is, with advocates of the different diets often trying to support their view using ethnological and ancestral data. It is clear though to everyone that our ancestors had to survive periods of fasting independent of their diet (whether the famine was caused due to lack of game or a disaster in the crops).

My Journey with the Fasting Diet

I have been following a Fasting Diet on and off since September 2009. In my first attempt to fast (after reading my first book on nutrition called: Food Governs your Destiny) I set x3 2hour slots in the day during which I allowed myself to eat. Outside these windows I would consume only liquids. I stayed on the diet for 6 months, during which I:

👉🏻 reduced my waist circumference from 34 to 29 inches.

👉🏻 lost 7.5 kilos.

👉🏻 achieved mental clarity I have never experienced before.

During a big part of these 6 months I was vegetarian.

In 2016 I decided that as a way of monitoring my metabolism I would like to measure the production of ketones in my body. Between October 2016 and February 2017 I monitored my Blood Glucose (BG) and Ketone Bodies (KB) – beta-hydroxybutyric acid on a daily basis. Monitoring can be useful:

👉🏻 as feedback for one’s response to food / exercise.

👉🏻 for compliance when BG & KB targets are set.

During this period there were weeks of following a vegetarian diet but most days I consumed meat.

Fast Diet: Progressions

Bellow I share what I consider to be a natural progression of fasting. Of course everyone’s starting point is different: not everyone starts with a: 3 meals and 2 snacks diet and neither do we all have the same tolerance to the changes each step requires. I imagine you have not been eating the same way all your life, after all. If you are not sure how quickly you should progress from one stage to the next I suggest you err on the safe side. Most people will find progressions comfortable if they spend 1-2 months on each stage. Those with a healthy relationship to food will evolve our fasting practice over our lifespan.

⏱ Time Restrict your Eating

I consider the 16-8h type-diet to be an easy one for most people to adopt. During this diet you restrict your caloric intake over an 8 hour window. The remaining 16 hours one is allowed to have non-caloric drinks such as water, coffee and tea. The easiest way to get into it, is to prolong the overnight fast. Assuming one sleeps for 8 hours and stops eating 4 hours prior to going to bed, she / he can achieve the 16/8h fast by eating 4 hours after waking up. If the idea still feels daunting here are a few tips to ease your way into it:

👉🏻 Start with a 12-12h diet and gradually increase the fasting window. The danger here is not to be consistent. Decide which window schedule suits you and stick to it for at least 1 week before increasing the fasting phase.

👉🏻 Take days off if you find the idea of doing it daily suffocating. However have the days scheduled before hand and do not change them. You know you are ready to proceed when you have completed 4 consecutive weeks with 5 days per week on your “Time Restricted Eating” schedule.

🌞 Eat while the Sun is up

While I acknowledge that many people working in offices have more physically active evenings than mornings; the body’s biological clock will not flip upside down because you signed up at the 20:30 CrossFit class. Neither your sleeping time can accommodate all the digestion you wish just because your gym class finishes at 22:00. As a next step to a “Time Restricted Eating” I consider to be the swift of the eating window earlier in the day. How early is early? – you decide. My suggestion is to finish eating prior to the sunset and ideally by midday. As you can see in the infographic from a 2018 paper [1], time restricting food to the earlier part of the day causes an number of beneficial effects:

Actions that helped me with this transition:

👉🏻 Exercise earlier in the day.

👉🏻 Make sure the quality of my sleep is not compromised. Supplements as well as breathing practices can support a good night sleep. Initially prolonged fasts can lead to elevated cortisol levels which will mess up with sleep. Poor sleep leads to tiredness and erratic appetite the next day.

⏰ Set your Eating Times

That stage could also be called: Stop snaking. Most of us (living a western lifestyle) have constant access to food and numerous stressors during our day. The combination of the two in many cases lead to binging / snaking. Whether you call it comfort food or not, every extra meal (and by meal let’s call anything containing more than 20 calories) requires the activation of the pancreas and the subsequent release of insulin. Insulin is a hormone with multiple roles in our biochemistry other than food metabolism. With that in mind I don’t find strange that hormonal imbalances are common in those with erratic eating patterns.

If one attempts to “Set her Eating Times” while she is eating during daytime only, I expect this transition not to be a big challenge. On the other hand shifting from a 16-8h fast to a “Set Eating Times” schedule can be a bigger step.

Setting the times when someone eats is a personal issue and can be scheduled around her lifestyle. My suggestion is to schedule no more than 3 meals a day and if for whatever reason a meal is lost not to be replaced.

☝🏻 Eat Once a Day

If you have been following the progression described above I would be surprised if you are eating more than twice a day by now. Eating once can be something you want to try occasionally based on your energy expenditure & mood.

😶 Eat only When Hungry & As much as you Need

Even when I eat once a day I sometimes find hard not to overeat. I consider our relationship with food complex and the addictive aspect of it multidimensional. We can be addicted to:

👉🏻 certain foods.

👉🏻 the sensation of fullness.

Whatever the addiction is it will always manifest to emotions which make it hard to break loose off. To that extent I would like to clarify that:

“I consider eating one of the big joys of life & fasting can only enhance this sensation.”

Fasting works as a challenge for the body. This doesn’t mean it makes it makes the body weaker. In the same way that you would not assume a runner to be doing harm to her body just because her legs are weak at the end of a training session, don’t be afraid of fasting.

Fast Diet: Considerations

Most people when they consider fasting, they are worried about their energy levels and muscle mass maintenance. The energy levels may fluctuate initially : that is due not to lack of energy but to poor hormone regulation. Even if you have 9% of body fat, there is enough energy stored in your body to keep you alive for days. Fluctuations in energy levels can be caused because your metabolism has no access to your fat. If you are concerned with maintaining muscle mass I suggest you keep your protein intake high when you eat (~x1.6 gr of protein per body weight in kg)

Those that depend on constant energy supply (ie. 3 meals a day + 2 snacks), are the ones that would benefit the most from fasting.

🔑  Things to consider

👉🏻 Always keep your (AME) Appetite, Mood and Energy levels in check. If one of them is not under control adjustments may be necessary. In most cases soon after one gets out of control the other 2 follow.

👉🏻 Our life changes constantly and so will our mood, circadian cycle, appetite, needs for nutrients etc. I hope this article works as a road map not an itinerary.

👉🏻 Food composition can affect your Blood Glucose and consequently your fasting phases. Fibre, fat, protein can slow down your meals’ metabolism which is necessary initially.

👉🏻 Metabolism is complex and its efficiency depends on many factors including: oxygen availability & insulin sensitivity. Practicing yoga, breathing exercise and cold exposure can be very useful towards improving metabolic efficiency and supporting a fasting practice.

Things to consume while fasting

In order to maintain the calories low during fasting my suggestion is to limit your liquid intake to coffee & teas. If stimulants play havoc in your metabolism & appetite you should avoid caffeinated drinks all together. I have been consuming them freely. Two things that can help a lot in extending your fasting periods are:
👉🏻 Water – in particular carbonated. I think it is easier if one takes sips during the day aiming for 1-3 litters as opposed to drinking 3 glasses when filling peckish.

👉🏻 Magnesium Citrate powder (I like the one from Designers for Health). Its sweet taste can help deal with a sweet tooth while the Magnesium supports the adrenals & promotes gut mobility.

👉🏻 Brushing teeth after eating. Making sure mouth hygiene is in check can help in 2 ways: 1. some associate a clean mouth with the end of eating 2. food leftovers will stop triggering taste buds receptors.

 

 

References:

1. Sutton, E. F., Beyl, R., Early, K. S., Cefalu, W. T., Ravussin, E., & Peterson, C. M. (2018). Early Time-Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, and Oxidative Stress Even without Weight Loss in Men with Prediabetes. Cell Metabolism.

The link between type 2 diabetes and Alzheimers Disease

The 1st case of Alzheimer’s Disease (AD) was reported in 1906 in Germany [53]. According to Alzheimer’s Association (www.alz.org) as of Oct 2016 there are more than 5 mil. Americans living with AD while in 2017 it is estimated to cost US $274 billion.

Over the last decade there has been a lot of research associating the development of Alzheimer’s Disease with Type 2 Diabetes.

There are 2 ways in which T2D influences the risk of AD:

1. by contributing to small vessel disease. T2D can disrupt the healthy function of brain vasculature and lead to dementia and AD [47]

2. by interacting with key proteins & pathways (such as Aβ and tau), T2D influences the development of AD.

In this article I will discuss the 2nd link.

 

 

1. The hallmarks of T2D and AD

Alzheimer’s Disease (AD) is a neurodegenerative disease characterised by selective neuronal cell death. Two hallmarks of AD are:

– the intracellular neurofibrillary tangles (NFTs)

– extracellular amyloid deposits forming senile plaques.

The accumulation of neurotoxin amyloid β peptide (Aβ) in the hippocampus and cerebral cortex appears to be a major pathological step in the progression of AD [1, 10]. Based on the tau hypothesis excess phosphorylation of tau proteins result in the transformation of normal tau proteins to NFTs.

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Diabetes mellitus is a metabolic disorder characterised by hyperglycaemia. In type 2 diabetes (T2D) the main effect is insulin resistance causing relative insulin deficiency. Pancreatic β-cells co-secrete insulin and amylin (also known as islet amyloid polypeptide IAPP). One of the hallmarks of T2D is:

– β-cell loss [11] due to amyloid deposits (composed primarily of amylin) [2].

Similar with AD in T2D degeneration of pancreatic islets has been associated with NFTs formation [12].

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2. Insulin’s implications in Aβ breakdown

Both Aβ peptide and insulin are amyloidogenic peptides sharing a common sequence recognition motif. Together with other amyloidogenic proteins (i.e. glucagon and amylin) they are degraded by Insulin Degrading Enzyme (IDE)* [3, 13]. IDE highest expression is in the liver, testes, muscles and brain [4]. Aβ is also broken down through Neprilysin (NEP) [5].

Both Aβ peptide and insulin compete with each other not only for their degeneration through IDE but also for binding to insulin receptors [6].

Insulin plays a key role in the healthy metabolism of Aβ peptides. It up regulates the transport of AβPP/Aβ from trans-Golgi to cellular membrane [13] promoting the transport of Aβ outside the cell [13] and has been shown through different mechanisms to contribute to the increase of extracellular Aβ levels and decrease of intracellular Aβ levels [13].

As I will discuss later insulin seems to counteract many of the toxic effects of Aβ in the mitochondria.

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In the only study so far that measured insulin levels in the brain** it was shown that insulin reduces with age in both healthy subjects and patients with AD [8] indicating that low brain insulin is not  direct cause of AD pathology. On the other hand though there is consistency in the findings of insulin resistance in AD patients [49].

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The following mechanism has been speculated to contribute to that:

1. IDE expression decreases with ageing [7] reducing the breakdown capacity of Aβ peptides; leading to higher intracellular Aβ levels.

2. Sequentially the relatively higher levels of Aβ 1-40 & Aβ 1-42 peptides by binding on insulin receptors reduce insulin’s binding capacity and promote insulin resistance [5].

The fact that insulin resistance is not specific to insulin in AD brain is supported by the fact that both insulin-like growth factor (IGF) I & II (50,51) and lectin (52) are reported to be lower.

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3. Other links through which insulin resistance can contribute to Alzheimer’s

Insulin also regulates the phosphorylation of tau proteins with insulin resistance been shown to cause [14] tau hyper-phosphorylation [15] and the formation of NFTs.

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4. Hypometabolism of glucose (in cerebral cortex)

In areas of the brain with high glucose demand and insulin resistance, AD patients have been shown to have compromised glucose metabolism [16]. 44% reduction in cerebral glucose metabolism has been reported in the early onset of AD [5].

Hypo metabolism of glucose leads to:

A. the inhibition of glutamine synthase, creatine kinase, aconitase, pyruvate dehydrogenase & α-ketoglutarate dehydrogenase [17,18,19] Sequentially the lower levels of pyruvate dehydrogenase lead to lower levels of acetyl-CoA, the compromised production of acetylcholine [20] and the decreased formation of intracellular cholesterol [21] (which is necessary for normal cell function).

B. reduced ATP production. In sporadic AD patients*** there is a 50% ATP decrease in the beginning of the disease [22]. Reduced ATP production leads to the activation of erk36 & erk40 [23] and subsequently tau hyperphosphorylation [24].

Glucose hypo metabolism of early onset AD was shown to be much more severe than in late onset patients [25].

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5. Impaired detoxification & compromised Ca2+ buffering (mitochondria)

Aβ42 protein was shown to inhibit cytochrome oxidase in human mitochondria in a dose depended manner [26]. The effect was dependent in the presence of Cu2+. Studies in cybrid cells demonstrated deficit of cytochrome oxidase in AD platelets as well as impaired intracellular calcium buffering and elevated basal cytosolic calcium concentration in AD [27,28]

Mitochondria serve as a high capacity Ca2+ sinks, supporting cellular Ca2+ homeostasis [33]. Excess Ca2+ uptake in the mitochondria has been shown to [34, 35, 36]:

1. Increase ROS production

2. inhibit ATP synthesis

3. release cytochrome c

4. induce mitochondrial permeability transition (MPT)****

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The maintenance of Ca2+ homeostasis represents a major expenditure within neutrons [40]. In high oxidative stress there is an increase in cytoplasmatic Ca2+ [37].  MTP is enhanced by increased Ca2+, oxidative stress, and low membrane potential, while Mg2+, ADP, high membrane potential [38, 39], CoQ10, vitamin E, reduced glutathione, melatonin and nicotine oppose that effect [41, 42].

Diabetes decreases the capacity of mitochondria to accumulate Ca2+ thus leading to MPT opening [31, 32]

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6. Insulin’s protective mechanism in the presence of Aβ (mitochondria)

Insulin has been shown to support mitochondrial function in skeletal muscles [43]. It seems to impact the function of neuronal mitochondria in multiple ways [40]:

1. prevents the depolarisation of mitochondrial inner membrane [44]

2. increases CoQ9 antioxidant  [44]

3. modulates glutathione redox cycle [127]

4. increases capacity of mitochondria to accumulate Ca2+ [40]

5. promotes clearance of Aβ [13]

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“ Although insulin does not affect basal mitochondria function, in the presence of Aβ  insulin prevents a drastic decline in mitochondrial OXPHOS efficiency and avoids an increase in the oxidative stress, improving and/or preserving the function of neurons under adverse conditions.” [40]

 

7. Conclusion

While genetics indisputably play a role in the development of AD; with 50% of patients been carriers of the APOE4 gene [1], there is enough research showing the link between T2D and AD. Non-APOE4 carriers have 535% (1.4 -> 7.5%) more chances of developing AD if their fasting blood insulin is > 89.4 pmol/l [54, 55].

The relationship between T2D and AD is intricate though if you consider the following:

1. One of the hallmarks of T2D is insulin resistance causing elevated insulin levels.

2. One of the hallmarks of AD is elevated Αβ peptides.

3. Insulin counteracts many of the toxic effects of the Aβ peptides in the brain of patients with AD.

3. Aβ peptides appear to contribute to the development of insulin resistance independent of insulin’s action, by binding on insulin receptors.

AD -> high Aβ peptides -> Insulin Resistance / T2D -> elevated insulin -> Protect from Aβ toxicity

Could T2D be a defence mechanism against brain’s degeneration in AD?

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* IDE is a zinc-metallopeptidase. It is also known as insulysin.

** It is not clear if insulin is produced in the brain or transferred there through the bloodstream [48]

*** Sporadic AD are the patients without genetic predisposition to develop AD

**** The mitochondrial permeability transition (MPT) is the sudden increase of inner mitochondrial membrane permeability to solutes with a molecular mass less than 1500 Da [29,30]

8. References

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2. Kahn SE, Andrikopoulos S, Verchere CB. Islet amyloid: a long-recognized but underappreciated pathological feature of type 2 diabetes. Diabetes 1999;48:241–53

3. Bennett RG, Duckworth WC, Hamel FG. Degradation of amylin by insulin-degrading enzyme Identification and isolation of a cytosolic proteolytic complex containing insulin degrading enzyme and the multicatalytic proteinase. J Biol Chem 2000;275:36621–5.

4. Runyan K, Duckworth WC, Kitabchi AE, Huff G. The effect of age on insulin-degrading activity in rat tissue. Diabetes 1979;28:324–5

5. Ling Y, Morgan K, Kalsheker N. Amyloid precursor protein (APP) and the biology of proteolytic processing: relevance to Alzheimer’s disease. Int J Biochem Cell Biol 2003;35:1505–35.

6. Xie L, Helmerhorst E, Taddei K, Plewright B, Van Bronswijk W, Martins R. Alzheimer’s beta-amyloid peptides compete for insulin binding to the insulin receptor. J Neurosci 2002;22:RC221.

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9. Gibson, G.E. Petersen, C. and Jenden, D.J. (1981) Brain acetylcholine synthesis decline with senescence. Science, 213, 674-676.

10. Selkoe DJ. Alzheimer’s disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein. J Alzheimers Dis 2001;3:75–80.

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16. Henneberg N, Hoyer S. Desensitization of the neuronal insulin receptor: a new approach in the etiopathogenesis of late-onset sporadic dementia of the Alzheimer type (SDAT)? Arch Gerontol Geriatr 1995;21:63–74

17. Sorbi S, Bird ED, Blass JP. Decreased pyruvate dehydrogenase complex activity in Huntington and Alzheimer brain. Ann Neurol 1983;13:72–8

18. Kish SJ. Brain energy metabolizing enzymes in Alzheimer’s disease: alpha-ketoglutarate dehydrogenase complex and cytochrome oxidase. Ann N Y Acad Sci 1997;826:218–28.

19. Gibson GE, Park LC, Sheu KF, Blass JP, Calingasan NY. The alphaketoglutarate dehydrogenase complex in neurodegeneration. Neurochem Int 2000;36:97–112.

20. Sims NR, Bowen DM, Allen SJ, Smith CCT, Neary D, Thomas DJ, et al. Presynaptic cholinergic dysfunction in patients with dementia. J Neurochem 1983;40:503–9.

21. Michikawa M, Yanagisawa K. Inhibition of cholesterol production but not of nonsterol isoprenoid products induces neuronal cell death. J Neurochem 1999;2:2278–85

22. Hoyer S. Oxidative energy metabolism in Alzheimer brain. Studies in early-onset and late-onset cases. Mol Chem Neuropathol 1992;16: 207–24.

23. Röder HM, Ingram VM. Two novel kinases phosphorylate tau and the KSP site of heavy neurofilament subunits in high stoichiometric ratios. J Neurosci 1991;11:3325–42

24. Bush ML, Miyashiro JS, Ingram VM. Activation of a neurofilament kinase, a tau kinase, and a tau phosphatase by decreased ATP levels in nerve growth factor-differentiated PC12 cells. Proc Natl Acad Sci U S A 1995;92:1962–5

25. Kim EJ, Cho SS, Jeong Y, Park KC, Kang SJ, Kang E, et al. Glucose metabolism in early onset versus late onset Alzheimer’s disease: an SPM analysis of 120 patients. Brain 2005;128:1790–801.

26. Crouch PJ, Blake R, Duce JA, Ciccotosto GD, Li QX, Barnham KJ, et al. Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-1-42. J Neurosci 2005;25:672–9

27. Davis RE, Miller S, Hermstadt C, Ghosh SS, Fahy E, Shinobu LA, et al. Mutations in mitochondrial cytochrome c oxidase genes segregate with late-onset Alzheimer’s disease. Proc Natl Acad Sci U S A 1997;94:4526–31

28. Swerdlow RH, Parks JK, Cassarino DS, Maguire DJ, Maguire RS, Bennett Jr JP. Cybrids in Alzheimer’s disease: a cellular model of the disease? Neurology 1997;49:918–25.

29. Bernardi P. The permeability transition pore. Control points of a cyclosporin A-sensitive mitochondrial channel involved in cell death. Biochim Biophys Acta 1996;1275:5–9.

30. Bernardi P, Broekemeier KM, Pfeiffer DR. Recent progress on regulation of the mitochondrial permeability transition pore; a cyclosporin-sensitive pore in the inner mitochondrial membrane. J Bioenerg Biomembr 1994;26:509–17

31. Moreira PI, Santos MS, Sena C, Seiça R, Oliveira CR. Insulin protects against amyloid β-peptide toxicity in brain mitochondria of diabetic rats. Neurobiol Dis 2005;18:628–37.

32. Moreira PI, Santos MS, Moreno AM, Seiça R, Oliveira CR. Increased vulnerability of brain mitochondria in diabetic (Goto-Kakizaki) rats with aging and amyloid-beta exposure. Diabetes 2003;52:1449–56.

33. Rizzuto R, Bernardi P, Pozzan T. Mitochondria as all-round players of the calcium game. J Physiol 2000;529:37–47.

34. Jiang D, Sullivan PG, Sensi SL, Steward O,Weiss JH. Zn(2+) induces permeability transition pore opening and release of pro-apoptotic peptides from neuronal mitochondria. J Biol Chem 2001;276: 47524–9.

35. Brustovetsky N, Brustovetsky T, Jemmerson R, Dubinsky JM. Calcium-induced cytochrome c release from CNS mitochondria is associated with the permeability transition and rupture of the outer membrane. J Neurochem 2002;80:207–18.

36. Sullivan PG, Rabchevsky AG, Keller JN, Lovell M, Sodhi A, Hart RP, et al. Intrinsic differences in brain and spinal cord mitochondria: implication for therapeutic interventions. J Comp Neurol 2004;474: 524–34.

37. Biessels GJ, ter Laak MP, Hamers FPT, Gispen WH. Neuronal Ca(2+) disregulation in diabetes mellitus. Eur J Pharmacol 2002;447:201–9.

38. Bernardi P, Broekemeier KM, Pfeiffer DR. Recent progress on regulation of the mitochondrial permeability transition pore; a cyclosporin-sensitive pore in the inner mitochondrial membrane. J Bioenerg Biomembr 1994;26:509–17.

39. Hansson MJ, Mansson R, Mattiasson G, Ohlsson J, Karlsson J, Keep MF, et al. Brain-derived respiring mitochondria exhibit homogeneous, complete and cyclosporin-sensitive permeability transition. J Neurochem 2004;89:715–29.

40. Moreira, P.I., Santos, M.S., Seiça, R. and Oliveira, C.R., 2007. Brain mitochondrial dysfunction as a link between Alzheimer’s disease and diabetes.Journal of the neurological sciences, 257(1), pp.206-214.

41. Cardoso SM, Santos S, Swerdlow RH, Oliveira CR. Functional mitochondria are required for amyloid beta-mediated neurotoxicity. FASEB J 2001;15:1439–41.

42.  Moreira PI, Santos MS, Sena C, Nunes E, Seica R, Oliveira CR. CoQ10 therapy attenuates amyloid beta-peptide toxicity in brain mitochondria isolated from aged diabetic rats. Exp Neurol 2005;196: 112–9.

43. Stump CS, Short KR, Bigelow ML, Schimke JM, Nair KS. Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts. Proc Natl Acad Sci U S A 2003;100:7996–8001.

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