Following a calorie-restricted diet has been shown to improve health in later life and extend lifespan in a number of animals, ranging from the simple worm to rhesus monkeys. The type 2 diabetes drug metformin has been found to have similar effects in animals but until now it was not clear exactly how the drug delays the aging process.
...
"Overall, treatment with metformin adds up to 6 days of life for the worm which is equivalent to around a third of its normal lifespan."
...
They found that treatment with metformin disrupted the bacteria's ability to metabolise folate, a type of B-vitamin, and methionine, one of the building blocks of proteins. This limits the nutrients that are available to the worm and mimics the effects of dietary restriction to enable the worms to live longer.
...
However, when they added an excess of sugar to the diet, the team found that the life-extending effects of metformin were cancelled out.
Exercise improves health by evoking 'recycling'
-
- Posts: 1238
- https://cutt.ly/meble-kuchenne-wroclaw
- Joined: Mon 14 Feb 2011 09:24
Re: Exercise improves health by evoking 'recycling'
How Diabetes Drug Delays Aging in Worms
Re: Exercise improves health by evoking 'recycling'
Of all amino acids, methionine by far inhibits autophagy the most.dime wrote:"metformin disrupted the bacteria's ability to metabolise ... methionine, ... mimics the effects of dietary restriction to enable the worms to live longer.... However, when they added an excess of sugar to the diet, the team found that the life-extending effects of metformin were cancelled out".RRM wrote:Its both.dime wrote:I think the effects of caloric restriction on autophagy are mainly due to protein restriction, not calories.
Insulin is triggered by both protein and sugars, and is a very potent autophagy inhibitor.
Methionine (protein) restriction induces autophagy.
Its very interesting that excess carbs eliminates methionine restriction-induced autophagy.
So, methionine restriction (to induce autophagy) may be useless when excessive carbs are consumed.
It would be interesting to know at what level of intake (insulin level) carbs start to significantly inhibit methionine restriction-induced autophagy.
That drug Metformin is displayed in the overview Kasper posted, influencing AMPK (and indirectly MTOR). Equally so, also upstream of MTOR in that overview, is AKT. AKT is an insulin-signaling molecule, which participates in the regulation of glucose homeostasis.Zhang Y et al
Re: Exercise improves health by evoking 'recycling'
How about intentionally emptying liver glycogen reserves, then during the day eat fat and small amounts of sugar (often and short of what you need), and in the evening before sleep "bulk up" with protein and sugar. This protein and sugar will be used up by the time you awake, and you're again back with empty liver and blood with minimum amino acids. I guess in the end it turns out to the same pattern you're doing now.
In the evening you'd eat let's say 50g protein, 100g sugar and 50g fat; half calories during the day, half in the evening.
In the evening you'd eat let's say 50g protein, 100g sugar and 50g fat; half calories during the day, half in the evening.
Re: Exercise improves health by evoking 'recycling'
Yes, thats kind of intermittent 'fasting', but instead of fasting, you have a low intake of energy.
Thats what im trying right now, indeed.
Thats what im trying right now, indeed.
Re: Exercise improves health by evoking 'recycling'
Here's some useful stuff
http://en.wikipedia.org/wiki/Chaperone- ... ons_of_CMA
Also important, but I guess nothing we can do about it
http://en.wikipedia.org/wiki/Chaperone- ... ons_of_CMA
The last sentence may explain why sugar cancels out the effects of methionine restriction (viewtopic.php?f=36&t=3363&start=45#p37299), because it activates glycolysis?CMA contributes to the maintenance of cellular homeostasis by facilitating recycling of amino acids of the degraded proteins (contribution to energetic cellular balance) and by eliminating abnormal or damaged proteins (contribution to cellular quality control).[2]
CMA is active at all times in different tissues (liver, kidney, brain), and almost all cell types in culture studied. However, it is maximally activated in response to stressors and changes in the cellular nutritional status. When nutrient supply is limited, the cells respond by activating autophagy, in order to degrade intracellular components to provide energy and building blocks, which the cell can utilize in this dire state.[11] Macroautophagy is activated as early as 30 minutes into starvation and remains at high activity for at least 4–8 hours into starvation. If the starvation state persists for more than 10 hours, the cells switch to the selective form of autophagy, namely CMA, which is known to reach a plateau of maximal activation ~36 hours into fasting and remains at these levels until ~3 days. The selectivity of CMA for individual cytosolic proteins permits cells to degrade only those proteins that might not be required in these starvation conditions in order to generate amino acids for the synthesis of essential proteins. For example, some of the best-characterized CMA substrates are enzymes involved in glycolysis, a pathway known to be less active in fasting conditions.[12]
Also important, but I guess nothing we can do about it
CMA activity declines with age in many cell types of old rodents and in cells of older humans.[18][19][20] This impairment of CMA in aging is mainly due to a decrease in the levels of LAMP-2A at the lysosomal membrane, because of reduced stability of the CMA receptor and not due to decreased de novo synthesis. Studies in a transgenic mouse model in which normal levels of LAMP-2A are maintained throughout life, showed that these animals had ‘cleaner’ cells, better response to stress – and overall, a better health-span.[20] These studies support the possible contribution of declined CMA activity to poor cellular homeostasis and inefficient response to stress characteristic of old organisms.
Re: Exercise improves health by evoking 'recycling'
Glycolysis is the conversion of glucose (or glycogen) > glucose-6-phosphate > ... > ... > pyruvate (releasing energy; ATP)dime wrote:CMA ...facilitates recycling of amino acids ...and eliminating damaged proteins...
... some of the best-characterized CMA substrates are enzymes involved in glycolysis, a pathway known to be less active in fasting conditions.
...
The last sentence may explain why sugar cancels out the effects of methionine restriction, ... because it activates glycolysis?
In the opposite direction, excess protein > glucose-6-phosphate (> glycogen)
In fasting conditions, there is relatively little glucose available for glycolysis.
During fasting, the energy mainly comes from glucose-6-phosphate.
During autophagy, catabolism of amino acids to glucose-6-phosphate is elevated.
During fasting, liver glycogen is depleted, so that any excess glucose-6-phosphate may be further converted to glycogen.
So that excess sugar might only affect autophagy after glycogen repletion.
The effects of insulin, however, are way faster.
Excess sugar increases insulin, directly inhibiting autophagy (thus directly cancelling out the effects of methionine restriction).
Re: Exercise improves health by evoking 'recycling'
Signaling Molecule May Help Stem Cells Focus On Making Bone Despite Age
This is some good research to follow, they plan to look for ways to enhance autophagy and delay the issues that come up with messed up autophagy, whether it's because of mutated proteins (link to Parkinson's desease) or decreased effectiveness due to aging.
Unique Peptide Has Therapeutic Potential Against Cancers, Neurological Disorders, and Infectious Diseases
Not sure if this has been already posted here, but it's really exciting! Also PubMed link
Scientists Identify 'Clean-Up' Snafu That Kills Brain Cells in Parkinson's DiseaseThey've found that inside the usual, oxygen-poor niche of mesenchymal stem cells, stromal cell-derived factor-1, or SDF-1, turns on a survival pathway called autophagy that helps the cells stay in place and focused on making bone
...
Unfortunately with age or disease, SDF-1 appears to change its tune, instead reducing stem cells' ability to survive and stay in the bone marrow. Additionally cells that do stay put may be less likely to make bone and more likely to turn into fat cells in the marrow.
...
"Your cells normally have a reminder to take out the trash," said Dr. Carlos Isales, MCG endocrinologist and Clinical Director of the GRU Institute of Regenerative and Reparative Medicine. "That reminder, SDF-1, becomes inconsistent as you get older, so rather than being an activator of the trash signal, it becomes an inhibitor."
Herberg led efforts to genetically modify stem cells from mice to overexpress SDF-1 -- in fact the researchers were in the enviable position of being able to adjust expression up or down -- and control autophagy in their novel cells. They found that while SDF-1 didn't increase stem cell numbers, it protected stem cells hazards related to low oxygen and more by increasing autophagy while decreasing its antithesis, programmed cell death, or apoptosis.
This is some good research to follow, they plan to look for ways to enhance autophagy and delay the issues that come up with messed up autophagy, whether it's because of mutated proteins (link to Parkinson's desease) or decreased effectiveness due to aging.
Unique Peptide Has Therapeutic Potential Against Cancers, Neurological Disorders, and Infectious Diseases
Not sure if this has been already posted here, but it's really exciting! Also PubMed link
researchers were able to synthesize a peptide called Tat-beclin 1, which induces the autophagy process. Mice treated with Tat-beclin-1 were resistant to several infectious diseases, including West Nile virus and another mosquito-borne virus called chikungunya that is common to Asia, Africa, and India. In additional experiments, the team demonstrated that human cells treated with the peptide were resistant to HIV infection in a laboratory setting.
...
The Tat-beclin 1 peptide was derived from sequences in beclin 1, one of the first known proteins in mammals found to be essential for autophagy, a finding that was made by Dr. Levine's laboratory. Her research has since demonstrated that defects in beclin 1 contribute to many types of disease. Conversely, beclin 1 activity and the autophagy pathway appear to be important for protection against breast, lung, and ovarian cancers, as well as for fighting off viral and bacterial infections, and for protecting individuals from neurodegenerative diseases and aging.
Autophagy
Can't you simply substitute sugar and protein with fat in the fasting period? Fat will anyway be used up from adipose tissue, so why not change this to dietary fat? Unless the body can figure that the fat (still calories) are coming in from diet, i.e. we are not starving. Have there been any studies on whether dietary fat inhibits autophagy?
Some related reading
Lipophagy: Connecting Autophagy and Lipid Metabolism (review of the literature on lipophagy)
Effect of Short- and Long-Term High-Fat Feeding on Autophagy Flux and Lysosomal Activity in Rat Liver
Some related reading
Lipophagy: Connecting Autophagy and Lipid Metabolism (review of the literature on lipophagy)
Effect of Short- and Long-Term High-Fat Feeding on Autophagy Flux and Lysosomal Activity in Rat Liver
Re: Exercise improves health by evoking 'recycling'
That totally depends on the fats you use. For example, lauric acid has a slight insulin raising effect and will therefore inhibit autophagy to a certain extent.
Re: Autophagy
We utilize bodyfat 24/7, at a basic level.dime wrote:Can't you simply substitute sugar and protein with fat in the fasting period? Fat will anyway be used up from adipose tissue, so why not change this to dietary fat?
Substituting sugar and protein for fat, will increase the level of fatty acids in the blood.
This (in combination with low blood sugar) will evoke gluconeogenesis. That newly created glucose will inhibit autophagy.
Correct. Similar to capric acid and linoleic acid.Garfinkel M et al,overkees wrote:lauric acid has a slight insulin raising effect and will therefore inhibit autophagy to a certain extent.
but the main point is that elevated serum fatty acids (saturated or not) will increase gluconeogenesis, inhibiting autophagy.
Re: Exercise improves health by evoking 'recycling'
Can't it be that insulin has a protein sparing effect and therefore inhibits autophagy?
Re: Exercise improves health by evoking 'recycling'
Insulin stimulates the uptake of amino acids (eg tryptophan) in the brain (for conversion into serotonin),
and of amino acids in other tissues, such as muscles, for the construction of protein.
Leaving all those amino acids in the blood instead, would have yielded a greater use of amino acids for energy.
So, yes, insulin has a protein sparing effect.
But how is that related to autophagy?
Insulin is elevated in response to a (high) protein and sugar influx.
Autophagy is a survival mechanism, in responding to low protein and sugar levels in cells.
When much protein and sugar is coming in, there is no need for this survival mode.
Hence insulin (as a hormone) directly signals at cells to stop autophagy.
If autophagy would not be stopped, it would go on and on,
also breaking down normal functioning organelles, eventually leading to cell death;
the results of real and ongoing starvation.
Again, autophagy is a survival mechanism, only needed in case of an acute lack of nutrients.
and of amino acids in other tissues, such as muscles, for the construction of protein.
Leaving all those amino acids in the blood instead, would have yielded a greater use of amino acids for energy.
So, yes, insulin has a protein sparing effect.
But how is that related to autophagy?
Insulin is elevated in response to a (high) protein and sugar influx.
Autophagy is a survival mechanism, in responding to low protein and sugar levels in cells.
When much protein and sugar is coming in, there is no need for this survival mode.
Hence insulin (as a hormone) directly signals at cells to stop autophagy.
If autophagy would not be stopped, it would go on and on,
also breaking down normal functioning organelles, eventually leading to cell death;
the results of real and ongoing starvation.
Again, autophagy is a survival mechanism, only needed in case of an acute lack of nutrients.
autophagy
For someone who work out in the morning, on a regular Wai diet, is there any benefit to train in a fasted state?
In terms of fat burning, muscle growth, insulin sensitivity, autophagy, etc.
In terms of fat burning, muscle growth, insulin sensitivity, autophagy, etc.
Re: autophagy
In general, the work out has little effect on fat burning.fred wrote:For someone who work out in the morning, on a regular Wai diet, is there any benefit to train in a fasted state?
In terms of fat burning, muscle growth, insulin sensitivity, autophagy, etc.
I dont think it would make any difference regarding muscle growth, insulin sensitivity or autophagy either.
The only difference i noticed is that there is no digestion going on at all (feeling 'lean and mean'),
so that no energy is lost on digestion, so that you may perform better. (and more intense training will have a positive effect, of course).
That, btw, may be the actual cause of my 'increased strength'.
Re: Exercise improves health by evoking 'recycling'
This is quite interesting: http://www.sciencedaily.com/releases/20 ... 131011.htm
Two groups of obese women consumed moderate-carbohydrate, moderate-fat diet of total 1400kcal for three months.
Group 1 had - 700 calories at breakfast, 500 at lunch, and 200 at dinner
Group 2 had - 200 calories at breakfast, 500 at lunch, and 700 at dinner
The 700kcal breakfast and dinner were same.
Two groups of obese women consumed moderate-carbohydrate, moderate-fat diet of total 1400kcal for three months.
Group 1 had - 700 calories at breakfast, 500 at lunch, and 200 at dinner
Group 2 had - 200 calories at breakfast, 500 at lunch, and 700 at dinner
The 700kcal breakfast and dinner were same.
Does this mean that the "big dinner" lost less weight because of more efficient autophagy, compared to the big breakfast? Either way, it's convincing that the best way to do "wai warrior" for me would be to eat in the evening, as I want to minimize weight loss and maximize efficiency in energy utilization. On the other hand the "big breakfast" people had lower levels of insulin, glucose, triglycerides. Confusing.By the end of the study, participants in the "big breakfast" group had lost an average of 17.8 pounds each and three inches off their waist line, compared to a 7.3 pound and 1.4 inch loss for participants in the "big dinner" group.
The big breakfast group also showed a more significant decrease in insulin, glucose, and triglyceride levels than those in the big dinner group. More important, they did not experience the high spikes in blood glucose levels that typically occur after a meal. Peaks in blood sugar levels are considered even more harmful than sustained high blood glucose levels, leading to high blood pressure and greater strain on the heart.