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Fasting causes aging by energy depletion, vitamin B2 can stop it

haidut

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Well, if this title does not rile up the fasting crowd, I don't know what will:): Aside from that controversy, it is actually a great study that not only suggests a dirt cheap and widely available option for retarding aging, but once again demonstrates that stress (e.g. fasting) directly causes aging by depleting/blocking OXPHOS, and the key mechanism for stopping/reversing aging is by restoring energy production. The proposed "senolytic" in this study is the humble vitamin B2, also known as riboflavin. Vitamin B2 is the precursor for FAD - a key coenzyme, responsible for about 20% of the energy produced in the OXPHOS process. Btw, the other 80% are controlled by NAD - a molecule synthesized endogenously from the precursor niacinamide. There has been an explosion in publications over the last decade touting NAD as the cure to virtually every disease out there, and many of those claims are well-backed by evidence. While there are several companies selling proprietary NAD precursor such as nicotinamide riboside and nicotinamide mononucleotide, plain old niacinamide works just as well and is drastically cheaper. Niacin is another NAD precursor but is increases histamine and serotonin, and still has to be converted into niacinamide before it can end up as NAD. So, no reason to take anything else but niacinamide.
Doing so, raises the NAD/NADH ratio, shifts the cell redox state towards oxidation (as opposed to reduction), and the ample energy produced by the cell can be used for all types of maintenance "work" the cells needs to perform in order to stay healthy, prevent aging, etc.
Oh wait, this was a post about vitamin B2 (riboflavin), right? Ok, well, vitamin B2 has a similar metabolic role as well. It is a precursor to the co-factor FAD and taking B2 raises FAD and thus the FAD/FADH ratio, which facilitates electron flow through the electron chain complexes I&II. Conversely, having insufficient levels of FAD (and/or low FAD/FADH ratio) can effectively block the ETC. This crucial role of FAD in the ETC demonstrates why excessive fatty acid oxidation (FAO) is harmful. Namely, FAD is consumed in the process of beta-oxidation of fatty acids and as such excessive FAO can consume too much FAD, drop the FAD/FADH ratio, and thus block electron flow through ETC. This reduction/blockade of ETC is exactly what is seen in most chronic, degenerative diseases, but especially in conditions such as cancer, diabetes, Alzheimer's disease, autoimmune conditions, etc. Well, the study below found that this reduction of mitochondrial activity (ETC) is exactly what triggers the senescence process, and activating mitochondria (specifically ETC II) by supplementing vitamin B2 prevented cellular aging. Here is the actual explanation from the study authors.

"...Cells under stress produce SLC52A1, and increase their absorption of vitamin B2 from outside the cell. Once inside the cell, the vitamin B2 is converted into FAD and inreases mitochondrial energy production by becoming a coenzyme of mitochondrial respiratory chain complex II. As a result of the AMPK and p53 (which induce cellular senescence) are inactive, therefore stress-mediated cellular senescence is suppressed."

Now, I did mention that the study bashes fasting, right? Where in the study does it say so? Well, the study does not use the word "fasting" but refers to it through its chief biochemical mechanism. Namely, the study demonstrated that stress activates an enzyme known as AMPK. This enzyme is like a sensor for when the energy levels in the cell drop...as in during fasting. High mitochondrial activity apparently keeps AMPK suppressed, while reduced mitochondrial activity activates AMPK and that triggers the initiation of senescence processes. Well, fasting is well-known to activate AMPK and there is a multi-billion dollar industry out there trying to come up with "fasting-mimetic" drugs/supplements that activate AMPK.

Calorie restriction: is AMPK as a key sensor and effector?
Feast or famine - Nature Reviews Neuroscience

"...In the hypothalamus, AMPK is inhibited by leptin and stimulated by fasting, and manipulation of hypothalamic AMPK activity influences energy balance."

The study below is one of the few I have seen so far that directly implicate fasting as a stressor that directly causes aging. This is in direct contrast to what is being promoted on TV and by most public health officials - i.e. fasting is the only known mechanism through which aging can be delayed. As usual, the truth seems to be 180 degrees from what is being pushed on the public...

Molecular Biology of the Cell (MBoC)
A newly discovered anti-senescence function of vitamin B2

"...The research team discovered a phenomenon whereby resistance to cellular senescence occurred as a result of increasing the amount of SLC52A1 produced. SLC52A1 is the protein responsible for transporting vitamin B2 into cells (vitamin B2 transporter). When SLC52A1 production was increased, cellular senescence did not occur immediately even under stress conditions (where human cells were treated with a drug to injure the DNA and induce aging). Following on from this, the researchers conducted an experiment where they exposed the cells to stress and then increased the amount of vitamin B2 in the culture solution. They found that resistance to senescence increased in accordance with the amount of vitamin B2 in the solution. Inside the cell, vitamin B2 is converted into a substance called Flavin Adenine Dinucleotide (FAD), a coenzyme that promotes the chemical reactions necessary for biological activities such as energy production. In fact, the amount of FAD in cells exposed to stress increased, which resulted in the vitamin B2 that had been transported into the cells to be converted into FAD, thus suppressing senescence."

"...Next, the research team focused on the mitochondria to investigate the mechanism behind FAD's suppression of cellular senescence. It is known that functional decline in mitochondria causes cellular senescence, and that FAD is essential for energy production in mitochondria as it functions as a respiratory chain complex II coenzyme. When the researchers investigated the response of the mitochondria, they were surprised to find that mitochondrial activity temporarily increased in cells subjected to stress, with the subsequent decline in [mitochondrial] activity resulting in senescence. Furthermore, the researchers were able to maintain the high level of stress-mediated mitochondrial activity by increasing the amount of vitamin B2 in the culture solution, which also allowed a high level of anti-aging to be maintained."

"...Finally, the researchers sought to illuminate how mitochondrial activity and anti-aging are connected. To do this, they investigated the activity of the enzyme AMPK, which detects when there is insufficient energy inside a cell, and discovered that AMPK activity is suppressed by mitochondrial activity. Conversely, suppressing mitochondrial activity with a drug caused AMPK to be activated, and sends signals to the protein p53 (that induces cellular senescence) to stop cell division thus resulting in an aged state. The above results reveal that Vitamin B2 increases mitochondrial activity in cells exposed to stress and prevents aging by suppressing the functions of AMPK and p53."
 

Mauritio

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Namely, the study demonstrated that stress activates an enzyme known as AMPK. This enzyme is like a sensor for when the energy levels in the cell drop...as in during fasting. High mitochondrial activity apparently keeps AMPK suppressed, while reduced mitochondrial activity activates AMPK and that triggers the initiation of senescence processes. Well, fasting is well-known to activate AMPK and there is a multi-billion dollar industry out there trying to come up with "fasting-mimetic" drugs/supplements that activate AMPK.
If that is so then it doesn't make sense that many peaty molecules like salt, aspirin or biotin increase AMPK! I've also read studies showing very beneficial effect on fatty liver and insulin sensitivity and AMPK, so something doesn't add up here ...

It also increases mitochondrial biogenesis:
(Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis - PubMed)

(Aspirin Activates AMPK ,reduces Liver Fat)

(Biotin Decreases Serum Free Fatty Acids)
 

youngsinatra

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E226AA23-9BCB-4D87-BB7E-55498C49C75B.png
If someone wants a good overview of nutrients that are needed in energy metabolism.
The only ones that they missed (from my perspective) were copper, iron and biotin that are vitally important for the ETC.

Source:
 

LeeLemonoil

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If that is so then it doesn't make sense that many peaty molecules like salt, aspirin or biotin increase AMPK! I've also read studies showing very beneficial effect on fatty liver and insulin sensitivity and AMPK, so something doesn't add up here ...

It also increases mitochondrial biogenesis:
(Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis - PubMed)

(Aspirin Activates AMPK ,reduces Liver Fat)

(Biotin Decreases Serum Free Fatty Acids)
Yep. The concepts of the study are in part against conventional anti-acting / Health Knowledge.
Highly intriguing.
Will circulate it a bit among AA-folks
 

haidut

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Any word on the dosage of B2 ?

Can't get access to the full study. Once it becomes available, I will edit the post and include the dosage.
 

opethfeldt

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A lot of people feel they have higher energy when they fast. I used to as well. The problem is that it's the jittery/stressed energy that is akin to taking money from your future to pay for expenses now. Sure, you can get away with it for a while but eventually, you have to pay up, with interest.
 

aliml

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AMPK: The Energy Enzyme​

AMPK (5′ AMP-activated protein kinase) is an enzyme that plays a key role in energy balance. All creatures from yeast to humans have this enzyme [1].

AMPK can detect the level of energy (number of ATP molecules) in a cell and helps regulate responses when it gets too low or high.

AMPK is produced in a number of tissues, including the liver, brain, fat cells and muscle [1].

While much of AMPK activity is dependent on external factors such as diet and exercise we all have a genetic disposition inherited from our parents.

Health Effects of AMPK Activation

1) Increases Metabolism

AMPK in the hypothalamus senses our level of energy production in the body (in the form of ATP). It increases energy expenditure and can also increase appetite (when it is activated in the hypothalamus) [2].

When cellular energy is low, AMPK is activated and targets a range of processes, the net response of which is an increase in energy production and a coordinated decrease in energy (ATP) usage [3].

Hypothalamic AMPK increases appetite, increases glucose production and uptake, reduces heat production, and decreases energy output [2].

2) Produces and Burns Sugars

Glucose is the main source of energy for the body and is particularly essential for normal brain activity. Hypoglycemia, a condition in which the blood glucose drops below normal levels, poses a great danger to the stability and functioning of the brain and therefore activates AMPK [2].

Hypothalamic AMPK activation promotes glucose production from the liver [2] and glucose uptake into the muscles [4].

AMPK inhibits glucose storage (glycogen synthesis), resulting in more glucose being available for energy production [4].

In various cells, AMPK stimulates the breakdown of glucose for energy (in the form of ATP) [4].

3) Burns Fat

AMPK inhibits the production of fatty acids, cholesterol, and triglycerides, and instead stimulates the breakdown and burning of existing fat for energy [4].

4) Inhibits Protein Production

Protein production is a high-energy process that is inhibited during low energy states to conserve energy. Therefore, it is not surprising that AMPK inhibits protein production [4].

Inhibiting excessive protein production results in a much more energy-efficient and less wasteful cell.

5) Promotes Cellular Recycling (Autophagy)

Autophagy is the process of recycling cellular components. This process promotes molecular and cell subunit quality control by degrading damaged or misfolded proteins and even damaged mitochondria [3].

Autophagy can contribute to energy generation by providing fuel for mitochondrial metabolism, and AMPK promotes this process [4].

6) Regulates the Mitochondria

AMPK is capable of both acute and long-term improvement of mitochondrial activity [3].

AMPK also regulates the production and turnover of mitochondria. Loss of AMPK in mice reduces mitochondrial activity and greatly diminishes muscle performance [3].

7) Acts as an Antioxidant

AMPK has a crucial role in increasing antioxidant defense during oxidative stress [4].

AMPK increases the production of several antioxidant proteins, such as NRF2, superoxide dismutase and uncoupling protein 2 (UCP2) [4].

8) Helps With Oxygen Delivery

Upon hypoxia (low oxygen) at altitude or during sleep, activation of AMPK may protect against acute breathing instability. Loss of AMPK was shown to cause breathing dysfunction during hypoxia in mice [5].

Variations of gene components of AMPK has been found in high-altitude Andean populations, presumably in order to improve survival in low oxygen conditions [5, 6].

9) Important for Fertility

In several animal species, AMPK increases the production of sex hormones [7].

The absence of AMPK leads to reduced fertility in both sexes [7].

10) Increases Blood Flow

AMPK plays a critical role in increasing blood flow through vasodilation (widening of the blood vessels), by stimulating nitric oxide release in blood vessels [8].

11) May Promote Healthy Weight

AMPK outside of the brain increases fat burning, and this pathway can result in weight loss [9].

By contrast, AMPK activation in the brain increases appetite. In mice, when the activity of brain/hypothalamic AMPK was inhibited, the mice ate less and lost weight. When AMPK activity was raised the mice ate more and gained weight [10].

Ghrelin, the hunger hormone, stimulates AMPK in the hypothalamus [11].

12) May Promote Longevity

AMPK activation gradually declines during aging. Some researchers believe that the age-related increase in chronic inflammation levels is responsible for the suppression of AMPK activity [4].

Activating AMPK may help multiple longevity pathways and promote healthy aging [3].

Many studies have shown that AMPK plays a crucial role in increasing longevity and calorie restriction-induced lifespan extension in worms, fruit flies, and rodents [4].

In worms, AMPK activation can increase lifespan by as much as 15% [12].

AMPK increases longevity by reducing protein production [3] and enhancing autophagy [3].

Longevity Pathways of AMPK

  • AMPK activates longevity FOXO proteins [3]
  • AMPK activates the master antioxidant regulator NRF2 [4]
  • AMPK inhibits the ‘master regulator’ of lipogenesis SREBPc [3]
  • AMPK inhibits mTOR indirectly [3]
Longevity research is a contentious and controversial field, and the precise role of AMPK in determining lifespan is unknown. Much more research is required to determine this enzyme’s role in aging and longevity.

14) Helps Decrease Inflammation

AMPK can both decrease inflammation and be decreased by inflammation.

AMPK also exerts potent anti-inflammatory effects. AMPK inhibits inflammation by indirectly inhibiting NFκB, a key activator of inflammation [4].

While AMPK could have many beneficial effects in chronic inflammation, it is typically reduced in such states.

15) Improves Diabetes

AMPK activation improves insulin sensitivity [4].

AMPK deficient mice showed impaired glucose tolerance [13].

Metformin, an activator of AMPK, is the most frequently prescribed antidiabetic drug for type-2 diabetic patients [4].

16) Benefits the Heart

The activation of AMPK also performs a protective role in cardiovascular diseases [14].

17) Increases Testosterone

AMPK can increase male hormones/androgens in human cells [15]. However, metformin (AMPK activator) is commonly given to women with PCOS to a good effect (PCOS is a condition with higher male hormones); much more research is required to determine AMPK’s role in testosterone production.

Activating AMPK (outside of the brain)

Healthy diet and exercise are the necessary first steps to a healthy lifestyle, and they’re also the most reliable bet for weight loss. Before adopting any other strategies, talk to your doctor about the best ones for you.

Best AMPK Activators

1) Exercise

Exercise uses energy (in the form of ATP), and the resulting lack of energy stimulates AMPK [2].

AMPK is stimulated by muscle contraction. High-intensity exercise significantly increases the activity of AMPK in healthy humans [2].

Many beneficial effects of exercise are carried out through AMPK, such as the insulin-sensitizing effect [4].

2) Calorie Restriction

Calorie restriction has been associated with many beneficial effects on aging, diabetes, and cancer. Some of these effects are mediated by AMPK. It was shown that calorie restriction activates AMPK through multiple mechanisms [4].

Overeating inhibits AMPK, and AMPK activity is decreased in obese individuals [4].

High glucose levels, high levels of amino acids, especially branched-chain amino acids, and excess saturated fat inhibit AMPK. Elevated insulin also inhibits AMPK [4].

Calorie restriction stimulates adiponectin secretion from fat cells. Adiponectin activates AMPK in multiple tissues, including skeletal muscles [4].

Adiponectin secretion is significantly reduced in obese individuals, which partially explains reduced AMPK activity in these individuals [4].

3) Decrease Inflammation

AMPK can both decrease inflammation and be decreased by inflammation, so it’s important to address any underlying inflammatory conditions.

Anti-inflammatory cytokines activate AMPK, while pro-inflammatory cytokines suppress it [3].

AMPK suppression in chronic inflammation contributes to insulin resistance. Reduced AMPK activity was associated with increased inflammation in the organ fat tissue and insulin resistance in morbidly obese individuals [4].

4) Cold Exposure

In rats, exposure to cold increased AMPK activation in the hypothalamus and stimulates food intake. This effect has not been reproduced in humans [18].

5) Lipoic acid

α-Lipoic acid (ALA) may activate AMPK in muscles and other tissues, though its precise mechanism and effects have not been sufficiently investigated. Some studies have suggested that ALA may decrease hypothalamic AMPK, which could help reduce appetite and food intake [19, 13].

Natural Supplements

Hormone Pathways

1) Adiponectin

Fat cells produce adiponectin [13], which serves as a starvation signal [2].

In fasting, adiponectin increases and stimulates AMPK, leading to the induction of food intake and reduction of energy expenditure. After refeeding, a decrease in adiponectin level is accompanied by blunted AMPK activity [2].

2) Leptin

Leptin, the satiety hormone secreted by fat cells in the presence of insulin, prevents overeating by inhibiting AMPK in the hypothalamus to suppress appetite [4]. It also activates AMPK in muscle [4].

3) Thyroid hormone T3

The thyroid hormone T3 increases cellular oxygen consumption and activates AMPK in the muscles [50].

4) Nitric Oxide

Nitric oxide activates AMPK [51, 52].

Drugs

1) Metformin

Metformin is a blood-sugar-lowering agent. It is widely used for the treatment of type 2 diabetes [13].

AMPK mediates many of the antidiabetic actions of metformin: stimulation of fat burning and glucose uptake, and decreased fat production and liver glucose production [19].

2) Aspirin

Salicylate is a direct activator of AMPK [19].

Aspirin reduces circulating free fatty acids and TG levels in obese patients with type-2 diabetes and increases fat breakdown during fasting in healthy humans, which can be explained by the direct effect of aspirin on AMPK activation [4].

 

Vesi

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Thank you @haidut

My blood pressure was roughly 180/100 just over week ago, consistently. I went to lab, and also had fasting blood glucose in diabetic values, liver enzymes too high. Basically metabolic syndrome. Coincidentally, i went to optician few weeks ago, who said that my eye pressure is way too high (27 and 23), basically leading to glaucoma.

So, from last friday to yesterday morning i fasted with only water, 3.5 days. Yesterday morning my blood pressure was 115/75. After a day of refeeding, it has now been avg 140/85. I presume that it will continue to rise somewhat, but i hope that not to where it was before fasting. Also, i went to eye doctor yesterday evening, and my eye pressure was normal (16 and 15).

Anyway, i took one B50 during my fast. Because of this thread, will take it (or just B1,2,3) next time every day.
 

cupofcoffee

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AMPK activation always seemed to be a good thing, especially since it drives autophagy, mitochondrial biogenesis and a whole lot of other mechanisms. Perhaps having it activated all time (metformin, intermittent) is bad but having it activated acutely (maybe a fast every once in a while, some exercise) might still yield some benefits?

This is only kinda related to this topic, but do you have any strong opinion on autophagy? @haidut
 

cupofcoffee

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A lot of people feel they have higher energy when they fast. I used to as well. The problem is that it's the jittery/stressed energy that is akin to taking money from your future to pay for expenses now. Sure, you can get away with it for a while but eventually, you have to pay up, with interest.
i've never fasted, do you think there is a sweet spot where you don't burn out your thyroid and adrenals too much but can still get some benefits? I recall reading someone saying that a 3 days fast detoxes most PUFAs from the cells
 

youngsinatra

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Thank you @haidut

My blood pressure was roughly 180/100 just over week ago, consistently. I went to lab, and also had fasting blood glucose in diabetic values, liver enzymes too high. Basically metabolic syndrome. Coincidentally, i went to optician few weeks ago, who said that my eye pressure is way too high (27 and 23), basically leading to glaucoma.

So, from last friday to yesterday morning i fasted with only water, 3.5 days. Yesterday morning my blood pressure was 115/75. After a day of refeeding, it has now been avg 140/85. I presume that it will continue to rise somewhat, but i hope that not to where it was before fasting. Also, i went to eye doctor yesterday evening, and my eye pressure was normal (16 and 15).

Anyway, i took one B50 during my fast. Because of this thread, will take it (or just B1,2,3) next time every day.
How old are you?
 

Momado965

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AMPK activation always seemed to be a good thing, especially since it drives autophagy, mitochondrial biogenesis and a whole lot of other mechanisms. Perhaps having it activated all time (metformin, intermittent) is bad but having it activated acutely (maybe a fast every once in a while, some exercise) might still yield some benefits?

This is only kinda related to this topic, but do you have any strong opinion on autophagy? @haidut

Sucrose induces autophagy.
 

LeeLemonoil

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AMPK activation always seemed to be a good thing, especially since it drives autophagy, mitochondrial biogenesis and a whole lot of other mechanisms. Perhaps having it activated all time (metformin, intermittent) is bad but having it activated acutely (maybe a fast every once in a while, some exercise) might still yield some benefits?

This is only kinda related to this topic, but do you have any strong opinion on autophagy? @haidut

This is accepted knowledge. Fasting and AMPK activation is beneficial and regenerating in cycles. Not permanently.

Same goes for mTOR activation.
 

Ritchie

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i've never fasted, do you think there is a sweet spot where you don't burn out your thyroid and adrenals too much but can still get some benefits? I recall reading someone saying that a 3 days fast detoxes most PUFAs from the cells
I'd say the sweet spot is intermittent fasting. Assuming when one is eating they are eating high sugar, high carb, good quality protein and everything else, then I would say intermittent fasting would be that sweet spot you are asking about.
 

Elie

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mostlylurking

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"...Finally, the researchers sought to illuminate how mitochondrial activity and anti-aging are connected. To do this, they investigated the activity of the enzyme AMPK, which detects when there is insufficient energy inside a cell, and discovered that AMPK activity is suppressed by mitochondrial activity. Conversely, suppressing mitochondrial activity with a drug caused AMPK to be activated, and sends signals to the protein p53 (that induces cellular senescence) to stop cell division thus resulting in an aged state. The above results reveal that Vitamin B2 increases mitochondrial activity in cells exposed to stress and prevents aging by suppressing the functions of AMPK and p53."
"and discovered that AMPK activity is suppressed by mitochondrial activity. Conversely, suppressing mitochondrial activity with a drug caused AMPK to be activated...."

Thiamine deficiency damages mitochondrial activity because it is a required cofactor for several enzymes in the Krebs cycle. This would reduce mitochondrial successful activity which should increase AMPK. However, if the mitochondrial activity is suppressed by thiamine deficiency, there's another issue:

Quote: "TD (thiamine deficiency) inhibited the phosphorylation of AMPK in the arcuate nucleus (ARN) and paraventricular nucleus (PVN) of the hypothalamus without affecting its expression."

So evidently, even if the AMPK is being expressed, it cannot be used if the phosphorylation of AMPK is inhibited?

Metformin, an activator of AMPK, is the most frequently prescribed antidiabetic drug for type-2 diabetic patients [4].
Metformin is known to cause problems by blocking thiamine function. Blocked thiamine function could also block the phosphorylation of AMPK.
 
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