Hormesis is evolutionarily conserved stress response. No other anti aging therapy has shown beneficial results in humans so far except Hormetic interventions like Calorie Restriction, prolonged fasting, intermittent low dose rapamycin and metformin.
We come across all kinds of stress on a daily basis like UV radiation, very hot or cold exposure, prolonged hunger, high intensity exercise, etc. Our body has adaptive genes that activate boosters to cope with these minor stress events and minimize damage to the system. At a sweet spot of the amount of stress Hormesis leads to house cleaning with activation of autophagy and mitophagy. This recycles senescent cells and leads to mitogenesis. It also activates Nrf2 which releases enzymes that reduce the burden of reactive oxygen species ROS amongst 200 other beneficial gene expressions. It protects against age related chronic disorders including diabetes, middle aged obesity, cardiovascular disease, cancer and neurodegenerative diseases (Mattson, 2008). This post is not a detailed study of hormesis but a layman's update about benefits of hormesis and how one can take advantage today. So there are many other beneficial hormetic actions but the above examples illustrate their purpose. It launches a cascade of renewal including stem cell renewal, release of beneficial enzymes and hormones (for example an oxytocin bath) and clean up of wastes which allows the system to use it's full resources to recover from the stress. For a more comprehensive understanding of hormesis please read posts on the blog 'Anti Aging Firewalls' by Vincent Giuliano. You can also read 'Hormesis, Adaptive Epigenetic Reorganization, And Implications For Human Health and Longevity' by Alexander Vaiserman published in 2010 in Dose Response. Hormetic response is only available against stress up to a certain threshold with regards to intensity and time. It has a sweet spot or narrow range where it leads to an over compensation. The beneficial cascade not only helps recover from the stress but also then goes ahead and delivers system wide improvements. This over compensation is what provides all the anti aging benefits of hormesis. Hormesis can also be seen in plants. For example when we boil raw peanuts or tomatoes their nutritive value increases in multiples. Although limited the benefits can be potent. All system wide anti aging successes seen so far in humans use hormesis. For example Calorie Restriction at identified levels creates a stress which triggers a hormetic response leading to all its studied benefits. Valter Longo director of University of Southern California Longevity Institute has published an amazing study which concludes that prolonged fasting of 7 days triggers a stem cell based repair and regeneration of our hematopoietic system. Similarly rapamycin is a poison which targets mTOR. Its inhibition due to a low intermittent dose leads to partial reversal of the damage caused by aging. mTOR is inversely related to many pathways involved in renewal and repair like Nrf2, AMPK, etc. From a different path Metformin also generates hormetic benefits. Diabetic patients on Metformin it has been found in large studies tend to outlive patients on other medicines and also non diabetics. Even the most popular health intervention exercise provides it's most powerful benefits due to hormesis.
So can hormesis stop aging and increase lifespan. No. As we age our repair and renewal machinery begins to lose its efficiency gradually in a progressive manner. Hormesis provides boost to the repair and renewal systems. Regular use of it would slow down the loss of efficiency thereby reducing unrepaired damage and build up of senescent cells, cancer causing mutations and protein aggregates. This has shown to improve healthspan and help prevent diseases like middle age obesity, metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer, neurodegenerative disease, etc. This in turn may lead to reaching longer lifespan.
I have started on rapamycin (Sirolimus) thanks to Dr. Alan Green (please web search for his name and rapamycin and it will lead to his website). On his website he has given his experience with rapamycin along with some very useful information about dosage, half life, strategy to avoid side effects, etc. He suggests 2 options conservative could be 3mg per 10 days. Aggressive would be 6mg per week. FDA states a elimination half life of 62 hours +/- 16 hours. So in a week it would be 2.7 half lives. If we take a shorter interval than it may lead to accumulation of the toxin which is not a good idea. Dr. Green as he says on his website ran a marathon in 4 hours at age 40 but by the time he reached 70 his physical activity was restricted to walking his dog. At age 72 he experienced angina and shortness of breath - his fasting blood sugar was high, creatinine was high and he could not fit in any of his pants. He discovered rapamycin and Koschei through Blagosklonny. He decided to take the aggressive approach. He shared that the results in 4 months were miraculous: he lost 20 pounds, his waist line went from 38 to 33 inches. He could walk 5 miles a day and ride bike over hills without angina. His blood sugar and creatinine went back to normal. He reported no side effects (no mouth sores). He felt from feeling old to feeling young. He has called rapamycin the world's greatest medicine. I have had a few exchange of messages with Dr. Green on an anti aging forum and can vouch that he is skeptical of all science unless it has shown replicable evidence. Someone younger may want to consider the conservative approach. Of course rapamycin and metformin both are prescription drugs and must be taken only after consulting your doctor. I personally started with 1mg and after 9 days taken 2mg and have now stabilized at 3mg. Also space weights training and other heavy exercise away from rapamycin days. It is important to do exercise as that too produces hormesis and allows us to make the most of taking rapamycin. Let me give you an example. In our middle age rogue macrophages block signal from our brain to our visceral fat cells to burn fat when we need energy for example during exercise. But when rapamycin benefits reconnect the signal it will not do any good unless we create an energy demand by doing intense exercise. With regards to Metformin one can create a hormetic effect every day whereas in the case of rapamycin there would be a tapering off between doses as part of the cycle. Not yet come across a study comparing the hormetic benefits between the two. Life Extension foundation has a good web page discussing metformin dosage for non diabetics at:
http://www.lifeextension.com/Featured%20Articles/2003/8/Metformin%20Dosage/Page%2001
They mention 500 mg twice a day for anti aging benefits for non diabetics but some scientists believe such benefits start only at 1,500 mg a day divided in 3 doses. To be noted that anyone having liver, kidney or congestive heart failure should not take this. One must also consider that no human trials have been done in either specifically for their anti aging benefits. That doesn't mean hormetic benefits are speculative but it leaves a gap with regards to ideal dosage for optimum benefits and safety. My personal opinion is not to take both rapamycin and metformin as too much of mTOR inhibition too is not good. When one does weights training one needs the growth with an activated mTOR. An article by Blagosklonny published in Aging 2010 cites two studies that show that inhibition of mTOR beyond a certain level causes depletion of male hormones which would adversely affect ones sex life. Therefore it may be better to have a cyclic intervention like rapamycin with a 10 day interval rather daily dose of metformin. One can investigate whether cyclic dosing of metformin provides similar benefits. I do take DHEA about 4 days away from rapamycin to make up for any deficiency in testosterone. People as young as 35 are starting on one of the two to protect their future from age related diseases but one must avoid such mTOR inhibition in younger than 35. Many scientists wrongly believe that chronic inhibition of mTOR during aging leads to sustained anti aging benefits. Even when we are young mTOR swings between activation and inhibition based on its role as an important sensor. Insulin, cytokines, nutrients, and tesosterone stimulate cellular growth in part by activating the mTOR pathway. At puberty there seems to be optimum balance between mTOR activation for growth and mTOR inhibition for repair. As we age due to falling levels of repair the balance is lost which leads to over activation of mTOR. All we need is either intermittent activation of repair (a strategy my venture is pursuing) or intermittent inhibition of mTOR. Either action should lead to reduction of their imbalance. Which in turn should slow down the epigenetic drift - and in turn aging itself.
With regards to hormesis what is exciting though is that for the aging this system wide benefit is available today! One could begin to benefit immediately.
This is not a cure for aging or death but is still the most significant recourse available today for humans to improve old age. If we can slow down aging we may be alive when the cure for aging is discovered. In the future people will see old movies just to find out about the disease of old age and gasp at how horrible it made us look and feel. My venture to hunt for the cure just progressed further - We have a CTO who is a Professor of Natural Sciences from 23 years of a highly reputed USA University and we just signed a research collaboration agreement with a very highly reputed University for pre-clinical trials - 14 in all. We are awaiting Ethical Committee approval and hope to launch by first week of December. Wish us luck. We are developing nature or endogenous derived interventions that also inhibit mTOR like rapamycin and metformin but indirectly by upregulating or activating key repair pathways. It seems that Repair and activated mTOR are inversely related. Our interventions are expected to have amongst the highest upregulation of beneficial gene expressions available. On a separate note I was asked what will you look for if you were able to live longer. I said: Purity. The most prized human trait after unsolicited acts of kindness.
We come across all kinds of stress on a daily basis like UV radiation, very hot or cold exposure, prolonged hunger, high intensity exercise, etc. Our body has adaptive genes that activate boosters to cope with these minor stress events and minimize damage to the system. At a sweet spot of the amount of stress Hormesis leads to house cleaning with activation of autophagy and mitophagy. This recycles senescent cells and leads to mitogenesis. It also activates Nrf2 which releases enzymes that reduce the burden of reactive oxygen species ROS amongst 200 other beneficial gene expressions. It protects against age related chronic disorders including diabetes, middle aged obesity, cardiovascular disease, cancer and neurodegenerative diseases (Mattson, 2008). This post is not a detailed study of hormesis but a layman's update about benefits of hormesis and how one can take advantage today. So there are many other beneficial hormetic actions but the above examples illustrate their purpose. It launches a cascade of renewal including stem cell renewal, release of beneficial enzymes and hormones (for example an oxytocin bath) and clean up of wastes which allows the system to use it's full resources to recover from the stress. For a more comprehensive understanding of hormesis please read posts on the blog 'Anti Aging Firewalls' by Vincent Giuliano. You can also read 'Hormesis, Adaptive Epigenetic Reorganization, And Implications For Human Health and Longevity' by Alexander Vaiserman published in 2010 in Dose Response. Hormetic response is only available against stress up to a certain threshold with regards to intensity and time. It has a sweet spot or narrow range where it leads to an over compensation. The beneficial cascade not only helps recover from the stress but also then goes ahead and delivers system wide improvements. This over compensation is what provides all the anti aging benefits of hormesis. Hormesis can also be seen in plants. For example when we boil raw peanuts or tomatoes their nutritive value increases in multiples. Although limited the benefits can be potent. All system wide anti aging successes seen so far in humans use hormesis. For example Calorie Restriction at identified levels creates a stress which triggers a hormetic response leading to all its studied benefits. Valter Longo director of University of Southern California Longevity Institute has published an amazing study which concludes that prolonged fasting of 7 days triggers a stem cell based repair and regeneration of our hematopoietic system. Similarly rapamycin is a poison which targets mTOR. Its inhibition due to a low intermittent dose leads to partial reversal of the damage caused by aging. mTOR is inversely related to many pathways involved in renewal and repair like Nrf2, AMPK, etc. From a different path Metformin also generates hormetic benefits. Diabetic patients on Metformin it has been found in large studies tend to outlive patients on other medicines and also non diabetics. Even the most popular health intervention exercise provides it's most powerful benefits due to hormesis.
So can hormesis stop aging and increase lifespan. No. As we age our repair and renewal machinery begins to lose its efficiency gradually in a progressive manner. Hormesis provides boost to the repair and renewal systems. Regular use of it would slow down the loss of efficiency thereby reducing unrepaired damage and build up of senescent cells, cancer causing mutations and protein aggregates. This has shown to improve healthspan and help prevent diseases like middle age obesity, metabolic syndrome, type 2 diabetes, cardiovascular disease, cancer, neurodegenerative disease, etc. This in turn may lead to reaching longer lifespan.
I have started on rapamycin (Sirolimus) thanks to Dr. Alan Green (please web search for his name and rapamycin and it will lead to his website). On his website he has given his experience with rapamycin along with some very useful information about dosage, half life, strategy to avoid side effects, etc. He suggests 2 options conservative could be 3mg per 10 days. Aggressive would be 6mg per week. FDA states a elimination half life of 62 hours +/- 16 hours. So in a week it would be 2.7 half lives. If we take a shorter interval than it may lead to accumulation of the toxin which is not a good idea. Dr. Green as he says on his website ran a marathon in 4 hours at age 40 but by the time he reached 70 his physical activity was restricted to walking his dog. At age 72 he experienced angina and shortness of breath - his fasting blood sugar was high, creatinine was high and he could not fit in any of his pants. He discovered rapamycin and Koschei through Blagosklonny. He decided to take the aggressive approach. He shared that the results in 4 months were miraculous: he lost 20 pounds, his waist line went from 38 to 33 inches. He could walk 5 miles a day and ride bike over hills without angina. His blood sugar and creatinine went back to normal. He reported no side effects (no mouth sores). He felt from feeling old to feeling young. He has called rapamycin the world's greatest medicine. I have had a few exchange of messages with Dr. Green on an anti aging forum and can vouch that he is skeptical of all science unless it has shown replicable evidence. Someone younger may want to consider the conservative approach. Of course rapamycin and metformin both are prescription drugs and must be taken only after consulting your doctor. I personally started with 1mg and after 9 days taken 2mg and have now stabilized at 3mg. Also space weights training and other heavy exercise away from rapamycin days. It is important to do exercise as that too produces hormesis and allows us to make the most of taking rapamycin. Let me give you an example. In our middle age rogue macrophages block signal from our brain to our visceral fat cells to burn fat when we need energy for example during exercise. But when rapamycin benefits reconnect the signal it will not do any good unless we create an energy demand by doing intense exercise. With regards to Metformin one can create a hormetic effect every day whereas in the case of rapamycin there would be a tapering off between doses as part of the cycle. Not yet come across a study comparing the hormetic benefits between the two. Life Extension foundation has a good web page discussing metformin dosage for non diabetics at:
http://www.lifeextension.com/Featured%20Articles/2003/8/Metformin%20Dosage/Page%2001
They mention 500 mg twice a day for anti aging benefits for non diabetics but some scientists believe such benefits start only at 1,500 mg a day divided in 3 doses. To be noted that anyone having liver, kidney or congestive heart failure should not take this. One must also consider that no human trials have been done in either specifically for their anti aging benefits. That doesn't mean hormetic benefits are speculative but it leaves a gap with regards to ideal dosage for optimum benefits and safety. My personal opinion is not to take both rapamycin and metformin as too much of mTOR inhibition too is not good. When one does weights training one needs the growth with an activated mTOR. An article by Blagosklonny published in Aging 2010 cites two studies that show that inhibition of mTOR beyond a certain level causes depletion of male hormones which would adversely affect ones sex life. Therefore it may be better to have a cyclic intervention like rapamycin with a 10 day interval rather daily dose of metformin. One can investigate whether cyclic dosing of metformin provides similar benefits. I do take DHEA about 4 days away from rapamycin to make up for any deficiency in testosterone. People as young as 35 are starting on one of the two to protect their future from age related diseases but one must avoid such mTOR inhibition in younger than 35. Many scientists wrongly believe that chronic inhibition of mTOR during aging leads to sustained anti aging benefits. Even when we are young mTOR swings between activation and inhibition based on its role as an important sensor. Insulin, cytokines, nutrients, and tesosterone stimulate cellular growth in part by activating the mTOR pathway. At puberty there seems to be optimum balance between mTOR activation for growth and mTOR inhibition for repair. As we age due to falling levels of repair the balance is lost which leads to over activation of mTOR. All we need is either intermittent activation of repair (a strategy my venture is pursuing) or intermittent inhibition of mTOR. Either action should lead to reduction of their imbalance. Which in turn should slow down the epigenetic drift - and in turn aging itself.
With regards to hormesis what is exciting though is that for the aging this system wide benefit is available today! One could begin to benefit immediately.
This is not a cure for aging or death but is still the most significant recourse available today for humans to improve old age. If we can slow down aging we may be alive when the cure for aging is discovered. In the future people will see old movies just to find out about the disease of old age and gasp at how horrible it made us look and feel. My venture to hunt for the cure just progressed further - We have a CTO who is a Professor of Natural Sciences from 23 years of a highly reputed USA University and we just signed a research collaboration agreement with a very highly reputed University for pre-clinical trials - 14 in all. We are awaiting Ethical Committee approval and hope to launch by first week of December. Wish us luck. We are developing nature or endogenous derived interventions that also inhibit mTOR like rapamycin and metformin but indirectly by upregulating or activating key repair pathways. It seems that Repair and activated mTOR are inversely related. Our interventions are expected to have amongst the highest upregulation of beneficial gene expressions available. On a separate note I was asked what will you look for if you were able to live longer. I said: Purity. The most prized human trait after unsolicited acts of kindness.
