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Announcement: April 1, 2024.
An avalanche of cancellations just prior to consult is destroying the viability of my practice. This requires radical changes. The initial consult is $500. Follow-up consults are $250.
The entire fee must now be paid PRIOR to consult with non-refundable deposit. Deposit paid for with Zelle or mailed check.
This change has no effect on patients who were planning on keeping scheduled appointment. It only effects patients who wait until a few hours before appointment and then decide they have other things to do that day.
Consult must be paid for prior to being put on calendar.
Today 4 consults were scheduled. 3 out of 4 cancelled.
Can't have practice if majority of patients cancel just prior to consult. Reviewing labs, medical history, setting up Zoom consult takes a lot of time
5 New Podcasts by Dr Alan Green MD posted on YouTube:
https://www.youtube.com/@RapTORAntiAging-pz1uy
With the extraordinary assistance of two of my friends and patients, Elizabeth Zurcher and Michele Vacanti, we made 5 podcasts. Before this endeavor, neither had any such experience. They were very quick learners. This is a list of the 5 podcasts.
Podcast 1, 2016. Nobody had taken Rapamycin as a long-term anti-aging. Every paper about rapamycin concluded that too toxic to take and nobody had a protocol. I came up with the protocol of 6 mg once a week. I took Rapamycin for 12 months. I had zero side-effects. I had great results. After 12 months, I started the world's first rapamycin anti-aging practice.
Prior to my experience there were just mouse studies. Mouse studies tell you almost nothing about how humans will respond. This was a great adventure as everything was new and no idea of what would happen. 4 years later a very few other physicians started to prescribe rapamycin. 99% of what is known about the use of Rapamycin in humans comes from the clinical physicians treating patients and their experience. If you have not treated humans; you may present yourself as an expert; but you don't know about rapamycin in humans
Podcast 2: Modern Aging Theory. The 150 year old "Evolutionary theory that 99% of Aging"spcialists "promote is false. Mammals have programmed aging. They intentionally kill old animals. Why? Because it allows them to evolve much faster. This is the reason mammals rule the Earth, not reptiles. You need to kill old animals so the new generation with new and improved genes will dominate the breedinng; not thee old animals.
Podcast 3: Discussion of prevention of Alzheimer's disease. The new Chapter 1.2.3 is much more detail.
Podcast 4: Rapamycin has powerful effect in prevention of coronary artery disease, atherosclerosis, heart attacks.
Podcast 5: The Disease of Aging. Aging and age-related diseases are two very different processes. The statement: "Nobody dies of Aging, they only die from age-related disease" is complete crap. Middle-aged people suffer and die from age-related diseases. The very old die from the disease of Aging. Rapamycin dramatically prevents age-related disease but has only a small effect on the disease of Aging. Understanding the difference is critical.
ASG Guest Speaker at Baylor University :
On October 26, 2021, I did a 50 minute presentation on Aging I did at Baylor University as a guest speaker on Rapamycin and Anti-Aging Practice https://www.youtube.com/OZhOhu3HyNQ?t=1
The presentation is attached using a you-tube link.[Need to clean out the garbage which jumps into U-tube links) It includes a large number of slides which provide a very good summary. There were two parts of the presentation. The first part is a summary of rapamycin-based anti-aging medicine and the very large number of age-related diseases and conditions in which mTOR plays a major role in the pathogenesis. This includes a discussion how of how the reduction of mTOR with rapamycin prevents AD. The second part is a theoretical discussion of the new evidence that aging is programmed.
>>> Alan Green MD : Rapamycin for Longevity in CLINICAL PRACTICE :
https://www.youtube.com/watch?v=JiyJ_X3YBew
ASG Interview with Robert Lufkin; 2022
Evaluation of off‑label Rapamycin in Clinical Practice of Dr Alan S. Green MD
in 333 adult patients; Green, Kaeberlein et al.
In Jan 2022, Matt Kaeberline wanted to study the use of Rapamycin in clinical Anti-Aging Practice. At that time, I was the only physician with a large group of patients. Matt Kaeberline is a PhD and has never treated a human being. I gave him a computer list of 900 of my patients and asked them to answer his questionaire. Kaeberline prepared the questions, mailed the questionnaire to my patients and tabulated the results. About 300 of my patients responded. This paper is the most important paper in the clinical treatment of Aging at that time. Rapamycin is the most important anti-aging drug. There is a huge amount of speculation; but prior to this paper, no data. This paper is almost entirely about the experience of my patients.
In April 2017, I started the first rapamycin-based anti-aging medical practice in the world. In the first year, I had a small number of adventurous and extremely well-informed patients. This was by intent a sub rosa medical practice. There was no promotion. All there was was this website. If somebody did a huge amount of study in the field of Aging and rapamycin they might find my website. Everybody was told they must come to my office in Little Neck, N.Y.
People did come to Little Neck. A few people from N.Y. but mostly people came from almost every state. People came from over a dozen countries. Peopple came from places from places I didn't even know were places; like the Yukon, Wyoming, and Bonaire.
This is a one person medical practice .. Everybody sends an e-mail to make an appointment.
Gradually after 5 years; word started to slowly leak out. People taking Rapamycin stopped complaining about Aging. Aging was so slow it was not apparent on a yearly basis.
All of my patients are prescribed rapamycin once a week. Some take a little less interval and some a little longer. What is most important is NONE OF MY PATIENTS TAKE RAPAMYCIN DAILY.
Rapamycin was approved to be used DAILY in transplant medicine. A few clinical studies have been done by University associated researchers. In these studies, they always use rapamycin once a day. It doesn't appear to matter to them that rapamycin was approved to be a biological poison. It was approved to be used once a day and they use it once a day. All their studies are a TOTAL FAILURE.
In this study, 3 people used Rapamycin daily. In the data, I would have separated those 3 from everybody else. However, this was just 3; so not enough to screw up the overall results.
One extraordinary thing that was confirmed by this study was Rapamycin and Covid. In the Spring of 2020, when the world was in a Covid panic; I had 500 middle age patients who did a lot of world traveling. Based on my research, I advised all my patients to continue taking Rapamycin. This went against conventional thinking. My analysis was people got sick due to cytokine storm. Rapamycin stops overstimulation of the innate immune system. All my patients got Covid at the expected rate. None of my patients got very sick, none went to the hospital, none died, and none got Long Haul Covid.
The reason this study is so important is that this questionnaire reflects the result when middle-aged people take Rapamycin once a week instead of daily.
The results SPEAK FOR THEMSELVES. They are almost entirely my patients and the results are an excellent reflection of what my patients tell me every day.
SEE BELOW FOR NEW SECTION ON PREVENTION OF ALZHEIMER'S DISEASE
Chapter 1, Section 2 - Section 12; Chapter 2, Chapter 3.
I consider this topic so important, it was moved to the front of the website.
Chapter 4 resumes usual discussion of Rapamycin.
Rapamycin, used weekly, is extremely effective for the prevention of Alzheimer's disease in ApoE4 carriers, both homozygous (2 genes) and heterozygous (1 gene); But must be started before memory impairment and cognitive decline. The primary focus of my practice is the prevention of AD in ApoE4 carriers. This is the most neglected group in the world of traditional medicine.
This paper includes the most important papers regarding prevention in ApoE4 studies.
It also includes my observations, since 2017, treating ApoE4 carriers, based upon these preclinical studies. I have over 700 ApoE4 patients. This includes about 140 double ApoE4 carriers (homozygous), the very high-risk group with my results consistent with pre-clinical studies. If started before cognitive decline and memory impairment; the results are excellent for delaying or indefinitely preventing the onset of AD.
Each year the U.S. is projected to have 500,000 new cases of AD. This number will only increase. Pre-clinical studies presented here suggest that the incidence of AD could be dramatically reduced. What is lacking is the desire of the medical world to prevent AD as AD is a booming trillion-dollar industry. Prevention of AD, with a generic drug like Rapamycin; is the last thing the medical world wants. They prefer to promote the pipe dream that a "cure" is possible. However, once the underlying cerebral microcirculation is damaged, and synapsis are lost and electrical circuits are lost; the changes become irreversible. There is as much chance to "cure" Alzheimer's disease as to bring the dead back to life. However, Alzheimer's disease can be prevented. Prevention is best started decades before the onset of clinical AD; when the underlying deterioration of the brain microcirculation is happening. The problem is there is no money in this approach. Rather than making money; prevention would be a trillion-dollar loss to the Alzheimer's Disease Industry. The only one who benefits from prevention is the patient and who never DEVELOPS dementia and their family.
Pathogenesis:The pathogenesis of Alzheimer's disease regarding the 99.9% of cases not having autosomal dominant defective genes can be split into two parts:A. Concepts from 1990s to 2011.B. Concepts from 2011 to present. In this discussion, the entire focus is on new papers and concepts starting in 2011 to the present. The ideas which were developed prior to 2011 (amyloid hypothesis) are rejected as obsolete.
Prevention is based upon the understanding of the pathogenesis of AD. 0.1% of cases are caused by autosomal dominant AD (FAD). This presents as "early-onset" AD. This variant of AD is caused by defective autosomal genes which cause the accumulation of amyloid.The other 99.9% do not have these genes. In the general understanding of AD, however the 0.1 % swallowed the 99.9%. In the case of autosomal dominant, the early initiating pathology is the accumulation of amyloid. This is consistent with the amyloid hypothesis in which the accumulation of amyloid is the cause of the disease. To support this theory, the proponents use mouse models with genes from autosomal dominant AD. These mouse models represent the pathology in autosomal dominant AD.
There is another school of understanding of the pathogenesis of AD in which the focus is on what happens in the 99.9% of cases that do not have abnormal dominant genes.
In these 99.9 of cases the early changes are deterioration of the cerebral microvascular system. In the 25% percent with the APOE4 gene, the issue is that E4 does not suppress CypA which leads to deterioration of the Blood-brain barrier. The deterioration of the cerebral microcirculation and BBB then causes failure of myelination maintenance by oligodendrocytes.
In the 99.9% which is the focus of this discussion, there is a two-stage process. The first stage is deterioration the of the cerebral microcirculation. The second stage is the failure to maintain myelination.
Here deterioration is discussed in Part 1 and myelination is discussed in Part 2.
The amyloid hypothesis and the theories that arise from the study of abnormal autosomal genes are rejected as not relevant to 99.9% of cases
The pathogenesis of AD is divided into two totally different concepts. of the pathogenesis. In my opinion, the understanding of the pathogenesis of AD has been severely impaired by two widespread concepts, which I consider "junk science." One such junk science theory is the amyloid hypothesis, a 40-year-old theory that proclaims accumulation of amyloid is the cause of AD. In reality, accumulation of amyloid occurs late in the disease development and is the RESULT of upstream events, not the CAUSE. The other equally false junk science concept lumps the very rare autosomal dominant Alzheimer's disease as the same process of the garden variety Alzheimer's disease which constitutes 99.9% of cases. Along with this false notion of the pathogenesis of Alzheimer's disease, there is the widespread use of mouse models that feature genes from autosomal dominant AD are used as mouse models of AD. In this discussion, we focus on two mouse/rat models of Alzheimer's disease. We focus on transgenic APOE4 mice and wild-type mice as a model of early vascular changes in wild-type mice and rats. Furthermore, the focus is on the response to lowering mTOR with Rapamycin. This focus on Apoe4 transgenic mice and wild-type rats provides a very different perspective on the pathogenesis of AD and PREVENTION from what is widely accepted.
The use of rapamycin is made possible by 8 years of use of WEEKLY rapamycin use by my office which has shown in nearly 1500 patients, that weekly rapamycin is very safe; as opposed to daily rapamycin as used in transplant patients, which is poisonous.
The studies presented here are based on the work of some of the world's best scientists. It presents very few papers out of the 250,000 papers about AD. The trick in understanding AD is being able to separate the wheat from the chaff; brilliant research from junk science.
mmm
>>> Alzheimer's disease can be seen as a domino effect. Each domino causes the next domino to fall.
Prevention is based on the prevention of the first few dominoes. Attacking the last few dominoes does not affect prevention. If we consider the pathogenesis as 10 dominoes:
Dominoes 1-3 is the deterioration of the Blood-Brain barrier and deterioration of the cerebral microvascular system.
Dominoes 4,5,6,7 is the failure to maintain myelination in the frontal cortex and associated areas, discussed by Professor George Bartzokis, discussed in his Masterpiece 2011 paper. Bartzokis tragically died in 2014.
Dominoes 8,9,10 is the accumulation of beta-amyloid and hyperphosphorylated Tau. This is a secondary byproduct of failure to maintain myelination. This is the amyloid cascade hypothesis of AD.
Accumulation of amyloid is the result, not the cause of AD. Treatment of dominoes, 8,9,10; has no role in prevention. Dominoes 8,9,10 represent the end-stage pathology of dementia. This is the stage of irreversible brain damage.
Prevention of AD in ApoE4 carriers with rapamycin is the prevention of dominoes 1,2,3 to fall.>>>
There are three risk factors for AD.
1: Being human. Humans are the only animal that gets Alzheimer's disease.
2. Age: The risk of AD doubles every 5 years starting at age 65. By age 95, the risk is 25% each year. By age 100, the incidence is about 40% a year.
3. ApoE4 carriers: Each year, there are 500,000 new cases of AD in the United States. Half of these cases will be in ApoE4 carriers.
AD frequently presents as a disease of middle age in ApoE4 carriers. However, in non-ApoE4 carriers, AD presents after age 80.
ApoE4 carriers are about 25% of the population; however, they get the great majority of AD cases prior to age 80.
Double ApoE4 carriers are 2-3 of the population but represent 10% of cases of AD.
Furthermore, they represent the most tragic cases with median age of onset at 70 years old,
Therefore, it is essential that everybody know their ApoE type. Once someone is aware that they are ApoE4 carriers, can they start prevention with weekly rapamycin; before cognitive decline
and memory impairment develop.
Bell, Zlokovic, 2012
This is the first great breakthrough by Zlokovic.
[CypA -->nuclear factor-->kb-->matrix metalloproteinase-9 (MMP9) ---> breakdown of BBB.]
Abstract: Apolipoprotein E controls cerebrovascular integrity via cyclophilin A (CypA)
"Human apolipoprotein E has three isoforms: APOE2, APOE3, and ApoE4. ApoE4 is a major genetic risk factor for Alzheimer's disease and is associated with Down's syndrome dementia and poor neurological outcomes after traumatic brain injury and hemorrhage. Neurovascular dysfunction is present in normal APOE4 carriers and individuals with ApoE4-associated disorders. In mice, lack of ApoE leads to blood-brain-barrier (BBB) breakdown, whereas APOE4 increases BBB susceptibility to injury. How APOE genotype affects brain microcirculation remains elusive. Using different APOE transgenic mice, including mice with ablation and/or inhibition of cyclophilin (CypA), here we show that expression of APOE4 and lack of murine Apoe, but not APOE2 and APOE3, leads to BBB breakdown by activating a proinflammatory CypA-nuclear factor-kb-MMP-9 pathway (breakdown in pericytes.) This, in turn, leads to neuronal uptake of multiple blood-derived neurotoxic proteins, and microvascular and cerebral blood flow reductions. We show that the vascular defects in Apoe-defined APOE4-expression mice precede neuronal dysfunction and can initiate neurodegenerative changes. Astrocyte-secreted ApoE3, but not APOE4, suppresses the CypA-nuclear facto-kb pathway
in pericytes. Astrocyte-secreted APOE3, but not APOE, suppresses the CypA-nuclear factor kb-MMP-9 pathway in pericytes through a lipoprotein receptor. Our data suggests that CypA is a key target for treating APOE-4 mediated neurovascular injury and the resulting neuronal dysfunction and degeneration."
Abstract: "Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease", Haliday, Zlokovic, 2015.
"The blood-brain barrier (BBB) limits the entry of neurotoxic blood-derived products and cells into the brain that is required for normal neuronal functioning and information processing. Pericytes maintain the integrity of the BBB and degeneration in Alzheimer's disease (AD). The BBB is damaged in AD, particularly in individuals carrying the apolipoprotein E4(APOE4) gene, which is a major risk factor for late-onset AD. The mechanism underlying the BBB breakdown in AD remains, however, elusive. Here we show accelerated pericyte degeneration in AD ApoE4 carriers >AD ApoE3 carriers> non-AD controls, which correlates with the magnitude of BBB breakdown to immunoglobulin G and fibrin. We also show accumulation of the proinflammatory cytokine cyclophilin A (CypA)and matrix metalloproteinase-9 (MMP-9) in pericytes and endothelial cells in AD(ApoE4 > ApoE3), previously shown to lead to BBB breakdown in transgenic Apoe4 mice. The levels of the apoE lipoprotein receptor, low-density lipoprotein receptor-related protein-1 (LRp1), were similarly reduced in AD ApoE4 and ApoE3 carriers. Our data suggests that APOE4 leads to accelerated pericyte loss and enhanced activation of LRP1-dependent CypA--MMP-9 BBB-degrading pathway in pericytes and endothelial cells, which can mediate a greater BBB damage in AD ApoE4 compared with AD ApoE3 carriers. "
The groundbreaking work of Zlokovic started about 2011. It starts the focus on the role of the cerebrovascular system. Zlokovic follows with a series of papers. The series of papers are:
1. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A", 2012, Bell.. Zlokovic.
2. Cerebrovasclar Effects of Apolipoprotein E: Implications for Alzheimer's disease. 2013.
3. The Pericyte: a Forgotten cell type with important Implications for Alzheimer's Disease ?"; Winkler, Zlokovic, 2014.
4. "Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease', Halliday...Zlokovic, 2015
5. Blood-brain barrier breakdown in Alzheimer's disease and other neurodegenerative disorders, Sweeney...Zlokovic 2019.
The major breakthrough was the first paper, Bell, Zlokovic; "Apolipoprotein E control cerebrovascular integrity via cyclophilin A" (CypA)
The following are important concepts and quotes from the 5 Zlokovic papers:
Reference 5:
"The human brain contains 644 Km of blood vessels that supply the brain cells with oxygen, energy metabolites, and nutrients and remove carbon dioxide and other waste products from the brain to the systemic circulation. Although representing only 2% of total body mass, the brain consumes 20% of the body's glucose and oxygen, and can rapidly increase blood flow and oxygen delivery in its activated regions, a process known as neurovascular coupling. Capillaries are the smallest cerebral vessels, they account for approximately 85% of cerebral vessel length and are a major site of the blood-brain barrier."
Reference 5:
"The blood-brain barrier (BBB) is a continuous endothelial membrane within brain microvessels. The endothelial BBB has tightly sealed cell-to-cell contact that results in low permeability. The endothelial monolayer is sheathed by mural cells called pericytes."
Figure 1 from Reference 2:
"A schematic showing that astrocyte secreted ApoE2 and ApoE3, but not ApoE4... suppress the CypA-NF-kb-MMMP-9 pro-inflammatory pathway that causes BBB breakdown by MMP-9 degradation of tight junction and basement membranes and BBB proteins".
(ASG note: ApoE4 does not suppress CypA pro-inflammatory pathway leading to the breakdown of BBB. )
[Note: This entire discussion never mentioned the amyloid cascade hypothesis which plays zero role in the deterioration of the BBB and cerebral microcirculation or the increased risk of APOE4 carrier to develop AD.]
CypA combines with ApoE2 and ApoE3; but not with ApoE4. This is the most important defect of ApoE4 and a major part of the ApoE4 risk.
"Rapamycin rescues vascular, metabolic and learning deficits in apolipoprotein E4 transgenic mice with pre-symptomatic Alzheimer's disease.", Ai-ling Lin, Veronica Galvan; 2015.
This was the most informative mouse study ever done regarding ApoE4 humans.
The reason for the extreme importance of this study is the mouse model uses mice with human ApoE4, transgenic mice.
ASG note: It would seem to be common sense; to have a representative transgenic mouse model of ApoE4 in humans need mice with the human ApoE4, to be a representative model.
Almost all mouse models of AD use genes from the very rare autosomal dominant AD. These models are representative of human autosomal AD; not the garden-variety of AD seen in 99.9 percent of human cases of AD. I consider a transgenic ApoE4 mouse as more than 100 times more informative than the models using the abnormal genes from autosomal dominant AD. Also, this study was of extreme importance as the focus was "pre-symptomatic" Alzheimer's disease. This is what I refer to as domino stages 1,2 and 3; the stage when PREVENTION is possible.
Abstract:
"Apolipoprotein E e4 allele is a common susceptibility gene for late-onset Alzheimer's disease. Brain vascular and metabolic deficits can occur in cognitively normal apolipoprotein E e4 carriers decades before the onset of Alzheimer's disease. The goal of this study was to determine whether early intervention using rapamycin could restore neurovascular and neurometabolic functions, and thus impede pathological progression of Alzheimer's disease-like symptoms in pre-symptomatic Apolipoprotein E e4 transgenic mice. Using in vivo, multimodal neuroimaging, we found that apolipoprotein E e4 mice treated with rapamycin had restored cerebral blood flow, blood-brain barrier integrity, and glucose metabolism, compared to age-and gender wild-type controls. The preserved vasculature and metabolism were associated with amelioration of incipient learning deficits. We also found that rapamycin restored the levels of the proinflammatory cyclophilin A in the vasculature, which may contribute to the preservation of cerebrovascular function in the apolipoprotein E e4 transgenics. Our results show that rapamycin improves functional outcomes in this mouse model and may have the potential as an effective intervention to block the progression of vascular, metabolic, and early cognitive deficits in human Apolipoprotein E e4 carriers. As rapamycin is FDA-approved and neuroimaging is readily available in humans, the results of this study may provide the basis of future Alzheimer's disease intervention studies in human subjects."
Introduction:
"The Apolipoprotein E4 allele (APOE4) is the major genetic risk factor for Alzheimer's disease (AD). Individuals who possess one or two alleles have a 4-to 8-fold increased risk of developing AD, with age of onset of AD occurring 7-15 years earlier compared to non-carriers. Cross-sectional studies of healthy young APOE4 carriers, who have intact memory and are free of amyloid beta (AB) or tau pathology, show deterioration of the cerebrovascular system decades before the possible onset of symptoms. Longitudinal studies further showed that regional cerebral blood flow (CBF) is reduced in an accelerated manner in cognitively healthy APOE4 carriers years before clinical markets as AB, tau pathology and memory deficits appear.
[ASG note: ApoE4 carriers show deterioration of the cerebral microvascular system decades before the accumulation of amyloid and tau proving amyloid is not the cause; but the result.]
Cerebrovascular impairments were proposed to be an initiating event that leads to neuronal activity alteration, proinflammatory cytokine production, AB/tau deposition, and memory loss. Therefore, preserving cerebrovascular function early in life in ApoE4 carriers. may be critical for preserving metabolic and cognitive functions, slowing AD progression, and even preventing the onset of AD. The therapeutic and preventative potential of preserving cerebrovascular function was highlighted by our recent studies. We showed that rapamycin, a drug that extends lifespan by delaying aging, restored cerebrovascular functions, including CBF and vascular density in mice modeling AD. We also showed that vascular restoration was associated with reduced AB and improved spatial learning and memory in AD transgenic mice. These results suggest that rapamycin could be an effective treatment to restore cerebrovascular function and block or attenuate the progression of established AD-like deficits in mice modeling AD
In his study, our goal was to determine whether rapamycin administered early in disease progression would restore vascular and metabolic functions in the young mice expressing human APOE4 genes. Particularly we wanted to identify if we could rescue these functions in AD pre-symptomatic mice. We hypothesize that declines in CBF and CMR-glucose, in addition to increased blood-brain barrier (BBB) leakage, will precede cognitive impairments, and rapamycin can rescue the vascular and metabolic deficits in the young APOE4 carriers.
Material and method:
ApoE4 transgenic mice. These mice express human ApoE4.
ApoE4 transgenic mice have vascular defects as early as two weeks, metabolic/synaptic dysfunction at four months and memory decline at 12 months. rapamycin diet was started at 1 month of age and was continuously supplied for 6 months. The endpoint was 7 months of age.
Results:
1. Rapamycin restored brain vasculature functions of ApoE4 mice.
At 1 month of age, ApoE4 mice had a 20% reduction in global blood flow. After one month of rapamycin treatment increases global blood flow. After 6 months of rapamycin treatment, there was no significant difference between rapamycin-treated ApoE4 mice and wild-type mice. The ApoE4-control group had dramatically decreased global blood flow: 33% cerebral cortex, 25% hippocampus, and 38% temporal lobe. This reduction in global blood flow was not found in the APOE4-Rapa mice.
2. Rapamycin restored brain metabolic functions of APOE4 mice.
Metabolic function was measured by cerebral glucose metabolism.
ApoE4-control mice had a loss of BBB integrity at seven months of age. BBB leakage and BBB integrity were significantly improved in ApoE4-Rapa mice.
3. Rapamycin attenuated incipient spatial learning deficits of APOE4 mice.
4. Rapamycin restored CypA levels in cerebrovasculature of APOE4 mice.
Discussion:
We demonstrated that cerebrovascular deficits occur early in mice with the APOE4 genotype. At one month of age, the APOE4 mice already show significant reductions in the whole brain and regions involved in higher-order cognitive functions, including the hippocampus and temporal lobe. BBB impairments were also found in the temporal lobe. This is consistent with human studies, which suggest that AD pathology evolves early in the temporal lobe. We also found significantly decreased glucose metabolism in the APOE4 carrier's mitochondrial dysfunction and an overall reduction of glucose metabolism in the brain. As glucose metabolism is highly associated with neuronal activity, our results indicate that the APOE4 mice displayed both neuronal and synaptic dysfunctions, consistent with previous reports. Neuronal integrity is critical for cognitive functions, including memory and learning ability.
We further demonstrate that rapamycin was sufficient to restore brain vascular functions in young APOE4 mice The APOE4-Rapa group had restored CBF and BBB integrity after six months of treatment. These vascular restorations were associated with the reduced CypA levels in the vasculature. CypA is a proinflammatory cytokine that has previously been shown to have deleterious effects on the vascular system in mice lacking murine APOE with aortic aneurysm and atherosclerosis. CypA causes BBB breakdown by activating the NF--kb-matrix metalloproteinase (MMP9) pathway.
'Our results suggest that down-regulating CypA activity in cerebrovasculature. alone has significant effects on vascular integrity and these changes may be sufficient to improve cognitive outcomes.
Our findings indicate that rapamycin was able to inhibit CypA and restore its distribution between brain tissue and the vasculature.
In addition to endothelial CypA inhibition, we previously showed rapamycin restores vascular functions via the mTOR pathway.
Cerebrovascular integrity is highly coupled with brain glucose metabolism....We found that preserved cognition was reflected by the preservation of both CBF and glucose metabolism in the APOE4-Rapa mice.
Taken together, our results suggest that rapamycin may delay or even block events early in the progression of physiological and cognitive deficits in APOE4 mice
In summary, our findings indicate that abnormal vascular and metabolic functions precede irreversible cognitive decline in Apoe4 carriers.... The studies herein suggest rapamycin may be effective at mitigating the early vascular deficits associated with AD...As rapamycin is FDA-approved..., the study may have tremendous translational potential. "
ASG comment:
This study is of extreme importance. It provides the pre-clinical studies on Apoe4 transgenic mice that provide the basis of my approach to prevent AD in human APOE4 carriers. It shows that rapamycin is highly effective in the pre-symptomatic stage. Memory deficits are a LATE development and preventive treatment must be started early; before memory and cognitive decline.
There have been approximately 250,000 papers about Alzheimer's disease. This is the most
important paper as regards to human APOE4 carriers. Alzheimer's disease should be viewed as similar to rabies. Treatment is required PRIOR to the onset of symptoms.
The prevention of AD in non-ApoE4 is somewhat outside the scope of this discussion. In
my practice, I don' target th prevention of AD in non-ApoE4 carriers. I just treat non-ApoE44 carriers for age-related diseases in general. However, in certain pre-clinical studies, there is the suggestion that Rapamycin will prevent AD in non-ApoE4 carriers.
The best model of Alzheimer's for non-ApoE4 carriers is wild-type rats. Rats do not go on to later stages of AD, but they have cognitive decline due to vascular deterioration.
The a very interesting paper by Candice Van Skike,.Veronica Galvan is entitled:
"mTOR drives cerebrovascular, synaptic and cognitive dysfunction in normative aging."
In this study, they observed the effect of Rapamycin on rats from 16 months to 34-month-old rats (very old aged rats),
The difference in the treated rats and non-rapamycin treated rats was very dramatic as relates to cognitive function and function of the cerebral microvascular system. They called it the normative aging model. I consider it an excellent model for AD in non-ApoE4 humans. I would say this represents what I call: dominoes 1,2,3. This is how far things go in wild-type rats.
[ASG note: I consider AD models using genes from autosomal dominant Alzheimer's disease as a very poor model for the 99.9% of cases of AD; in which autosomal dominant are not present.
My impression is consistent with this wild-type rat study that suggests Rapamycin will decrease the risk of AD in non-apoE4 carriers, but I don't have enough 90-year-olds, non-ApoE4 carriers, to offer a real opinion, based upon my practice. I have about 700 non--Apoe4 patients; but very few are in the 90+ age group.
Abstract:
Cerebrovascular dysfunction and cognitive decline are highly prevalent in aging, but the mechanisms underlying this impairment are unclear. Cerebral blood flow decreases with aging and is one of the earliest events in the pathogenesis of Alzheimer's disease (AD). We have previously shown that the target of rapamycin (mTOR) drives disease progression in mouse models of AD and in models of cognitive impairment associated with atherosclerosis, closely recapitulating vascular cognitive impairment.
In the present studies, we sought to determine whether mTOR plays a role in cerebrovascular dysfunction and cognitive decline during normative aging in rats, Using behavioral tools and MRI--based functional imaging, together with biochemical and immunohistochemical approaches, we demonstrate that chronic mTOR attenuation with rapamycin ameliorates deficits in learning and memory, prevents neurovascular uncoupling, and restores cerebral perfusion in aged rats Additionally, morphometric and biochemical analysis cognitive of hippocampus and cortex revealed that mTOR drives cerebrovascular, neuronal, and cognitive deficits associated with normative aging.
Thus, inhibitors of mTOR may have the potential to treat age-related cerebrovascular dysfunction and cognitive decline. Since treatment of age-related cerebrovascular dysfunction in older adults is expected to prevent further deterioration of cerebral perfusion, recently identified as a biomarker for the early (preclinical) stages of AD, mTOR attenuation may potentially block the initiation and progression of AD."
Introduction:
"Normal brain aging predisposes vulnerable neurons to degeneration and is associated with cognitive decline and increased likelihood of developing a neurodegenerative disorder. The prevalence of Alzheimer's disease (AD), the most common cause of dementia in the elderly, is expected to double approximately every 20 years, with 131.5 million cases worldwide by 2050. The prevalence of AD is increasing rapidly, yet there are no disease-modifying treatments currently available. Although age is a primary risk factor for AD, very little is known about the molecular mechanism that links the regulation of brain aging to neurodegenerative diseases of advanced age."
Cerebrovascular dysfunction is a universal feature of aging (Zlokovic, 2011, ) that includes impaired endothelium-dependent vasodilation and global and regional decreases in cerebral blood flow. While decreased CBF is associated with impaired cognitive and decreased neuronal plasticity....
Because cerebrovascular plays a critical role in the pathogenesis of age-related neurodegenerative disorder, including AD, and manifests early in the disease progression, it is important to investigate the mechanisms underlying cognitive vascular deterioration decline and brain vascular deterioration driven by nonpathological aging."
The mTOR pathway regulates aging in mammals. mTOR is also expressed throughout the brain, where it is linked to synaptic plasticity and learning and memory through the regulation of protein synthesis and autophagy. In the aging brain, autophagy is reduced, contributing to the accumulation of aggregated proteins and neurodegeneration. Thus, dysregulation of the mTOR pathway during nonpathological aging may contribute to cognitive decline, cerebrovascular dysfunction, and a predisposition towards developing neurodegenerative diseases associated with advanced age,"
"We have previously shown that mTOR inhibition attenuates cognitive dysfunction in aged mice in aged mice. We and others have also shown that chronic mTOR attenuation with rapamycin can prevent and reverse cognitive and cerebrovascular deficits in several independent mouse models of AD and vascular cognitive impairment leading to improved cerebrovascular function and and preserved cognitive outcomes in these models of age-related disease. The contribution of mTOR to cerebrovascular deficit is associated with normative aging, though its impact on cognitive outcomes remains unknown. The goal of this study was to test the hypothesis that mTOR drives cerebrovascular and synaptic dysfunction during aging and that chronic mTOR inhibition with rapamycin mitigates nonpathological age-related deterioration of cognition and cerebrovascular function in aged rats without underlying disease."
Results:
1. Age-related decline in hippocampal-dependent learning and memory is driven by mTOR.
2. mTOR drives sensory-evoked functional hyperemia impairment in rays of advanced age.
3. mTOR contributes to decreased presynaptic density with age.
4. Attenuation of mTOR restores cerebral flow and sensory-evoked functional hyperemia in aged rats.
Discussion:
Increased age is the greatest risk factor for AD. Impaired cerebrovascular function during aging is, in turn, a biomarker for increased risk of AD (Zlokovc,2011) and is one of the earliest detectable changes in the disease pathogenesis. Consistent with prior reports showing that mTOR inhibition improves learning and memory in aged mice, our data indicate that chronic mTOR inhibition reduces age-dependent impairment in spatial learning and memory and that the improved cognitive outcomes are associated with the preservation of synaptic integrity, neuronal network activation, microvascular integrity, and cerebrovascular function during aging."
"Presynaptic synaptophysin expression decreases naturally with nonpathologic aging. Further, lack of functional synaptic protein expression, including synaptophysin, is associated with hippocampal-dependent memory impairment. Consistent with these data, we found that mTOR activity decreased synaptophysin quantity and density in the hippocampus, suggesting that age-related synaptic loss may underlie impairments in neuronal network activation and may contribute to spatial learning and memory deficits in aged rats."
"The regulation of CBF during neuronal network activation is a tightly coupled process that depends on the complex interaction between neurons, astrocytes, and vasculature in a process known as neurovascular coupling. Neurovascular coupling reflects both the neuronal activity and the corresponding hemodynamic response that ensures the delivery of critical substrates, largely glucose and oxygen, to active neuronal networks. Chronic mTOR inhibition prevented age-related declines in global and regional resting CBF, an early biomarker of brain aging in humans. Age-related cerebral hypoperfusion could be partially explained by microvascular rarefaction since we found a profound decrease in microvascular density in the cortex and hippocampus of aged rats. Microvascular density loss during aging, however, was negated by chronic mTOR attenuation, suggesting that preservation of microvascular density by mTOR attenuation, suggesting that preservation of microvasculature density by mTOR attenuation may underlie the protection of CBF in rapamycin-treated aged rats. These data strongly implicate mTOR as a driver of microvascular rarefaction and dysfunction during aging, and reveal mTOR attenuation as a potentially useful approach to diminish early age-related CBF loss.
"In summary, we show that mTOR drives cerebrovascular and neuronal dysfunction associated with cognitive decline during normative aging in the rat. In aged rats, chronic mTOR inhibition with rapamycin, an intervention that extends lifespan, ameliorated mTOR-dependent decline in learning and memory in aging at least partly through the restoration of cerebrovascular function and synaptic structure. Together with our previous studies, these data indicate that mTOR drives cerebrovascular dysfunction both in normative aging and in age-associated disease states, including AD and cognitive impairment associated with vascular disease, and thereby suggests that the brain microvascular dysfunction may link aging to an increased risk of AD. Therefore, mTOR attenuation provides a strategy to preserve synaptic and cerebrovascular function during aging and may help to reduce the risk of AD."
(ASG not: The sharp distinction implied between normative aging and Alzheimer's disease seems contrived and artificial.
When AD develops fast at age 75 in ApoE4 carriers; it is called Alzheimer's disease, something pathological. When cognitive decline develops slowly at age 95; it is called "normative aging. There is no bright line between the two conditions. They each result in dementia. They each represent the age-related decline of the human brain. Furthermore, from these studies, it appears that both are ameliorated by Rapamycin and reduction of mTOR.
George Bartzokis, was probably the greatest science of the last 50 years in the world of Medicine. He was to Alzheimer's disease in the same way Albert Einstein was to theoretical physics. His 2011 masterpiece, Alzheimer's disease as homeostatic responses to age-related myelin breakdown," defined the fundamental disease process of Alzheimer's disease. In one of the greatest tragedies in the history of science; the paper was almost entirely ignored, by researchers in the field of Alzheimer's disease who had less than 1% of the genius of Bartzokis. The paper was not supportive of the amyloid hypothesis and that was all they needed to know.
Karl Herrup, one of the current leading scientists in the pathogenesis of Alzheimer's, wrote this in a major 2017 paper:
"Dedicated to the memory of Dr. George Bartzokis. We who have come late to this field may not have known him, but we recognize the strength of the conceptual foundation he laid, and upon which many of the ideas of this review are built. We mourn his untimely passing in August, 2014 [pancreatic cancer].
Readers are advised to study this paper and a dozen other papers he published prior to 2011.
Unfortunately, this section does not come close to fully explaining his ideas.
This 2011 paper preceded the papers discussed in Part 1; but the two parts are intimately connected.
The paper presents the myelin model of the human brain. We will start with translating the title: "Alzheimer's disease as homeostatic responses to age-related myelin breakdown. By "homeostatic responses" he means failure to maintain myelination by Oligodendrocytes. The mechanism of maintenance is Fast Axon Transport (FAT). Therefore, FAT is the fundamental process in understanding Alzheimer's disease. "Age-related" includes the age-related breakdown of the BBB and cerebral microcirculation discussed in Part 1. "Myelin breakdown" means Alzheimer's disease is due to the failure of FAT to maintain myelination. In Section 8 we will discuss Fast Axon transport (FAT). In the following major section will present Figure 1, Myelin Repair. Taken together, Part 1 on Cerebral microcirculation and Part 2 on The myelin model presents the current best understanding of the pathogenesis of Alzheimer's Disease.
Oligodendrocytes are uniquely vulnerable to deterioration of the cerebral microcirculation and the breakdown of the BBB discussed in Part 1. Therefore any deterioration of the cerebral microcirculation and the BBB will very adversely affect the ability of oligodendrocytes to maintain myelination. Oligodendrocytes are the hardest-working cell type in the human body. Oligodendrocytes are also the weakest link. Myelination is presented as the unique part of the human brain. Failure to maintain myelination is the fundamental cause of AD.
The human brain is a super computer. A super computer requires billions of electrical connections and SPEED of transmission. Myelination is the secret sauce of the human brain. Myelination increases the speed of transmission 20-fold. Without the myelination of the grey matter in the frontal and temporal lobes, the human brain would not be a supercomputer. However, it is one thing to build a supercomputer and another thing to maintain it. To understand Alzheimer's disease requires an understanding of the brain's electrical circuits.
Abstract:
The amyloid hypothesis (AH) of Alzheimer's disease (AD) posits that the fundamental cause of AD is the accumulation of the peptide amyloid beta (AB) in the brain. This hypothesis has been supported by observations that genetic defects in amyloid precursor protein(APP) and presenilin increase AB production and cause familial AD (FAD). The AH is widely accepted but does not account for important phenomena including the recent failure of clinical trials to impact dementia in humans even after successfully reducing AB deposits."
Here in, the AH is viewed from the broader overarching perspective of the myelin model of the human brain that focuses on functioning brain circuits and encompasses white matter and myelin in addition to neurons and synapses. The model proposes that the recently evolved and extensive myelination of the human brain underlies both our unique abilities and susceptibility to highly prevalent age-related disorders such as late-onset AD (LOAD) it regards oligodendrocytes and the myelin they produce as being both critical for circuit function and uniquely vulnerable to damage. This perspective reframes key observations such as axonal transport disruptions, formation of axonal swelling/spheroids and neuritic plaques, and proteinaceous deposits such as AB, and tau as byproducts of homeostatic myelin repair processes.
Fast axon transport is the core idea of the Bartzokis, 2011 paper
Start by dropping to major section 2 to see full page figure of Fast Axon Transport,
Chapter 2, Figure 2
Myelin Repair, Figures A and B.
Chapter 3, Figure 3 "Progressive Age-related Cognitive Decline into AD with Early Loss of Memory Encoding".
Consequences of anterograde FAT disruptions:
FAT anterograde disruption can interfere with synaptic long-term potentiation (LTP) of synaptic transmission that may be the basis of memory encoding. Like most other synaptic needs, the molecular component underlying LTP depend on anterograde FAT. It is therefore quite possible that memory impairment in aging, MCI and AD may be related to myelin breakdown. Myelin breakdown would degrade the ability of circuits to support the high action potential frequencies needed to trigger LTP and memory storage. support. In addition, FAT reductions could impair/delay the arrival of necessary proteins to promote the establishment of LTP. Such powerful consequences of myelin repair could explain why memory impairments are the key and persistent manifestation of AD, years before the diagnosis can be made."
Consequences of retograde FAT disruptions:
"Hyperphosphorylating tau and disrupting microtubule tracts, during the myelin repair process could also stop retrograde FAT that uses the same microtubule tracts. When FAT stops retrograde transport of neurotrophins also stops. Neurotrophins signal the cell body that it is part of a functioning circuit, and their absence may cause neuron loss and permanent disability."
The amyloid hypothesis went from a promising idea in 1992 to an unmitigated disaster 30 years later. The fundamental understanding of the pathogenesis of Alzheimer's disease comes some twenty years later. Unfortunately, by that time the amyloid hypothesis had gone from theory to established dogma.; supported by extremely powerful financial interests.
The amyloid hypothesis of Alzheimer's Disease posit that the fundamental cause of AD is the accumulation of the peptide amyloid beta (AB) i the brain. The myelin model of Alzheimer's sees proteinaceous the deposits such as amyloid-beta and tau as by-products of failed homeostatic myelin repair processes.
Accumulation of amyloid is the result of disease process; not the cause.
A major cause of the lack of understanding of the pathogenesis of AD is lumping all AB cases as the same thing.
In reality, there are three diseases:
The very rare autosomal dominant disease with abnormal genes. This accounts for about 1 out of 1000 cases. The other 99.9% of AD cases do not have these abnormal defective genes. Of this, 99.9% are the 25% who are ApoE4 carriers and the other 75% who are non-ApoE4 carriers.
This is not to say that accumulation of beta-amyloid and hyperphosphorylated tau are not highly destructive and don't accelerate the path to end-stage dementia.
However, here they are seen as dominoes 8,9,10. They are a late development. Removal of amyloid play no role in the prevention of Alzheimer's disease.
Since this discussion is about PREVENTION, there will be no additional discussion about the amyloid hypothesis.
My practice has been treating patients with weekly Rapamycin since 2017. Weekly rapamycin is a very safe drug with dramatically less side-effects than statins. I have close to 1500. There are are 700 Apoe4 carriers, which includes over 140 double ApoE4/E4 carriers.
Most apoE4 carriers range from ages 40 to 85.
My observation is that if E4 carriers (single or double E4) start rapamycin PRIOR to memory impairment and prior to cognitive decline; they do perfectly well with no difference in E4 and non-E4 patients. the key is starting early. If treatment is delayed until onset of early symptomatic changes of AD; prognosis is very guarded. All bets are off if rapamycin treatment started after the onset of early symptoms of AD.
For this reason, any person with any at risk family history (any relatives with dementia or early heart attacks (coronary artery disease) needs genetic testing for ApoE4.
If you wait until you have memory impairment, it is too late for total prevention of AD.
Each year there will be 250,000 new cases of AD in ApoE4 carriers. My goal is to reach 1 percent, 2500 ApoE4 carriers. I realize I can't reach the other 99%. They believe in traditional medicine, what their primary doctor tells them; what 99.8% of neurologist tell them. There are 5000 Neurologist in the US. One Neurologist, a Harvard Medical school graduated contacted me. He was a total supporter of use of Rapamycin to prevent AD. The other 4999 Neurologists reject Rapamycin as being beneficial and are complete supporters of the amyloid theory of AD and whatever drugs big pharma is promoting.
However, preventing 2500 ApoE4 carriers from getting AD would be a great achievement for my office. .
I try to promote these ideas through my free-access website. However, I also try to stay under the radar. Considering that what I am saying is 100% opposite of Big Pharma and traditional medicine; publishing a book not trying to keep a low profile would seem to be not prudent. Things have never gone well for heretics. I am a very small fish in a very big ocean.
I rely on the grassroots approach. Word of mouth from patient to patient, from family member to family member. Individuals who are part of APOE4 support groups play a big role in informing those looking for information.
The goal is APOE4 carriers will find other open-minded physicians, part of "alternative medicine" and convince them to study the role of Rapamycin in the prevention of AD.
The Alzheimer's disease war is between very unequal forces. On one side you have a small number of the world's best scientists looking for truth and trying to understand a very complex disease; without regard to the commercial value of their work.
On the other hand, there is a trillion-dollar industry in alliance with traditional Medicine.
The problem is money doesn't just talk, it swears. It is a very unequal war for the handful of great scientists looking for truth to go up against a trillion-dollar industry. Big Pharma together with Traditional Medicine represents one of the most powerful industries in the US and the world.
It is the people who would like to avoid Alzheimer's disease who are the big losers in the Alzheimer's disease wars.
In the world of Rapamycin, victory is not measured in billions of dollars in revenue; but in a single human life rescued from the loss of one's brain and maintained in good cognitive condition, able to live a happy and productive life.
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Figure 2 (A). Myelin is "cut to reveal normal fast axonal transport (FAT)
Figure 2 (B) Myelin damage, FAT is disruption and axonal swelling phenotype of repair process.
Within the center of the axon are Microtubule tracts. Tau stabilizes the microtubule. Little motor cars move up and down the tracks carrying everything the axons and synapses require. The axons and synapses lack protein synthesis. Almost everything must be manufactured in the Neuron cell body and transported down the axon to the synapses. This is done by energy-requiring motors (kinesins for anterograde (Neuron body to synapses) and dynesis for retrograde transport (synapses to neuron cell body. This renders neuronal cells extremely dependent on fast axon transport. a bidirectional process. Almost everything from mitochondria (for energy) to neurotransmitter vesicles must be anterogradely transported down the axons to synapses. Conversely, damages mitochondria destined for destruction, and products such as neurorophin signaling molecule that are essential for neuronal survival, need to be retrogradely transported from synapses back to the neuron body.
All molecules to be transported must be attached to the motor cars. The attachment system, the "scotch tape" attaching the molecules to the motor cars is APP (amyloid precursor protein). All the defective molecules (B-site APP cleavage enzyme 1, BACE1, a-secretase. which are defective in FAD (familial autosomal dominant AD) are, in reality part of the Fast Axonal transport system. The problem in FAD was not the "accumulation of these molecules, BUT THAT THE DEFECTIVE MOLECULES COULD NOT DO THEIR JOB. The result was a failure of Fast Axon Transport, failure to repair neurons, and resulting accumulation of beta-amyloid.
In diagram A we see normal FAT. healthy mitochondria and endosomes carrying molecules are transported anterograde from the Neuron cell body to synapses. Damaged mitochondria and endosomes headed for degradation by neuronal lysosomes are transported retrograde from synapse to neuron cell body.
In diagram (B)"Myelin damage, FAT disruption, and axonal swelling phenotype of repair process" FAT is stopped for repair. Hyperphosphorylated tau breaks up the tracks and FAT stops. There is an accumulation of APP, BACE1, gamma secretase and amyloid-beta which are part of the FAT repair process. An axonan Seliing appears at the repair site. Starved synapses retract. All retrograde transport stops until repair is successful. The attempt is to repair the myelin breaks.
The initiating event is Myelin breakdown. This results in hyperphosphorylated tau which breaks up the tracts and stops FAT. The next step is Axonal swelling to develop at the repair site. In the axonal swelling there is accumulation of APP, BACE1, gamma secretase which is part f the repair process.
If repair is successful, FAT Resumes. Synapses are resupplied and Neurotropin is transported retrograde to the neuron cell body.
If repair fails the swelling bursts. Amyloid-beta, hyperphasphorylated tau are are deposited into the surrounding brain tisue.. This is the junk left over from failed repair. The Amyloid beta form Neuitic Plaques. The hyperphosphorylated tau form neuofibrillary tangle. This results in the AD markers and cause Neuronal Death and permanent disability and dementia.
The Myelin breakdown results in increase refractory time. Synapses are "starved leading to synapse loss. This results in decrease of long term potentiation (reduced LTP). This results in decreased memory encoding.
Myelin breakdown is promoted by Age, hypoperfusion, free radicals, Iron, Toxin, traumatic brain injury, suboptimal genes.
Factors favoring successful repair:
ApoE2 & ApoE3,
Adequate cholesterol and Sulfatide Recycling/Removal
Low Iron, low free radical, low inflammation.
Factor favoring failed Repair:
ApoE4,
Poor cholesterol and Sulfatide Recyling/Removal,
Increase Inflammation, Increase Iron, Increase Free Radicals.
Mutated gamma secretase, APP, mutated FAD (familial AD) genes.
After study Figure 2, Figure 3, to to Chapter 1, Section 8.
COVID-19 is not deadly early in life, but mortality increases exponentially with age, which is the strongest predictor of mortality. Mortality is higher in men than in women, because men age faster, and it is especially high in patients with age-related diseases, such as diabetes and hypertension, because these diseases are manifestations of aging and a measure of biological age. At its deepest level, aging (a program-like continuation of developmental growth) is driven by inappropriately high cellular functioning. The hyperfunction theory of quasi-programmed aging explains why COVID-19 vulnerability (lethality) is an age-dependent syndrome, linking it to other age-related diseases. It also explains inflammaging and immunosenescence, hyperinflammation, hyperthrombosis, and cytokine storms, all of which are associated with COVID-19 vulnerability. Anti-aging interventions, such as rapamycin, may slow aging and age-related diseases, potentially decreasing COVID-19 vulnerability.
COVID-19 is not deadly early in life, but mortality increases exponentially with age, which is the strongest predictor of mortality. Mortality is higher in men than in women, because men age faster, and it is especially high in patients with age-related diseases, such as diabetes and hypertension, because these diseases are manifestations of aging and a measure of biological age. At its deepest level, aging (a program-like continuation of developmental growth) is driven by inappropriately high cellular functioning. The hyperfunction theory of quasi-programmed aging explains why COVID-19 vulnerability (lethality) is an age-dependent syndrome, linking it to other age-related diseases. It also explains inflammaging and immunosenescence, hyperinflammation, hyperthrombosis, and cytokine storms, all of which are associated with COVID-19 vulnerability. Anti-aging interventions, such as rapamycin, may slow aging and age-related diseases, potentially decreasing COVID-19 vulnerability.
In March 2020, it was very clear COVID was going to be a very deadly disease. As we approach Thanksgiving 2021, the USA death toll approaches 800,000.
However, for people taking Rapamycin, COVID turned out to be just a novel viral infection. As a 77 y/o with a cardiomyopathy, I was very concerned in March 2020. I had COVID in October 2020 and it was nothing more than a mild viral syndrome lasting a few days. My experience seems to be very consistent with my patients.
Rapamycin has a very dramatic effect decreasing the activity of the innate immune system. It also has effect on T-cells. This had combined effect to block intense cytokine reaction and ameliorates reaction to COVID. The above paper by Blagosklonny is excellent discussion. In short, Rapamycin seems to give middle-aged persons a young person like reaction to COVID.
At this point, everybody is advised to follow CDC recommendations regarding Covid vaccination.
From Mikhail Blagosklonny:
The three major criteria for potential anti-aging drugs are:
These criteria overlap each other. If an intervention extends life span, it must delay age-related diseases. Animals die from age-related diseases. For example, caloric restriction (CR) delays all diseases of aging and extends life span. One may say that CR extends life span by delaying disease. One may say that CR delays diseases by slowing down aging, Both interpretations are correct. CR deactivates the nutrient-sensing pathway, know as TOR (Target of Rapamycin). [2]
Rapamycin is essentially CR in a pill. They each target the exact same pathway, TOR.
Of all the known chemical substances in the universe, a Rapamycin has emerged as the most robust in extending lifespan. Rapamycin has extended the lifespan of every living thing tested in the laboratory: yeast, worms, flies, and even middle-aged mice. In a recent 2014 paper, it was reported rapamycin extended the median lifespan 23% in male mice and 26% in female mice.
From Matt Kaeberlein: "The drug rapamycin is currently the most effective and reproducible pharmacological approach for directly targeting the aging process to increase life span and health span in laboratory animals. Rapamycin positively impacts most hallmarks of aging and it has been shown to increase lifespan in each major invertebrate model organism and in rodents. Rapamycin increases life span by 10 to 30% in multiple strains of mice." [4]
Blagosklonny and Kaeberlein are the two foremost experts on the theory and practice of rapamycin.
3. Blagosklonny, From rapalogs to anti-aging formula, Oncotarget. 2017 May 30; 8(22): 35492–35507.
4. Kaeberlein, Rapamycin and Alzheimer's disease: Time for a clinical trial?, Sci Transl Med. 2019 Jan 23;11(476).
From Blagosklonny: "Rapalogs prevent age-related diseases in mice as well as in other mammals including non-human primates and humans. As examples: rapamycin prevents atherosclerosis, neurodegeneration and retinopathy and cardiomyopathy in rodents. Rapalogs prevent cancer in mice and humans. Rapamycin decreases obesity in mice and humans. As predicted, rapalogs rejuvenate immunity, improve immune response in mice and humans." [3]
From Kaeberlein: "Not only does rapamycin treatment increase life span but it also delays, or even reverses, nearly every age-related disease or decline in function in which tested in mice, rats and companion dogs, including cancer, cardiac dysfunction, kidney disease, obesity, cognitive decline, peridontal disease, macular degeneration, muscle loss, stem cell function, and immune senescence" [4]
The above statements regarding Life span extension and prevention of age-related disease might seem fanciful, overimaginative and unrealistic. However, the quotes come from a 2017 and a 2019 paper prepared by the worlds leading authorities. Furthermore, a review of these two papers will show multiple references to support and document each and every statement.
Not mentioned in above was a very large body of evidence that rapamycin is the leading drug to prevent Alzheimer's disease. Alzheimer's disease is discussed in following section.
Rapamycin also prevents insulin resistance, metabolic syndrome, osteoarthritis, osteoporosis and age related chronic lung disease.
Criteria (3) above for potential anti-aging drug was suppressing formation of senescent cells.
In a 2018 paper Blagosklonny states, "It has been calculated than rapamycin slows geroconversion by approximately 3-fold". This means rapamycin slows formation of senescent cells three-fold. [5]
The Blagosklony theory of aging is that aging is hyperfunctional.
From Blagosklonny: "Killing senescent cells is beneficial because senescent cells are hyperfunctional. The hypersecretory phenotype or Senescence-Associated Secretory Pheontype (SASP) is the best known example of universal hyperfunction. Most hyperfunctions are tissue-specific. For example, senescent beta cells overproduce insulin and this activate TOR in hepatocytes, adipocytes, and other cells, causing their hyperfunction, which in turn leads to metabolic syndrome (obesity, hypertension, hyperlidemia, and hyperglycemia) and is also a risk factor for cancer. SASP, hyperinsulinemia, obesity, hypertension, hyperlipidemia and hyperglycemia are all examples of absolute hyperfunction (an increase in functionality)." [6]
"Killing senescent cells is beneficial because senescent cells are hyperfunctional." [6]
"Senolytics are drugs that extend life span and delay some age-related diseases by killing senescent cells. Targeting senescent cells have been shown in animal models to prevent age-related pathologies such as emphysema, lung fibrosis, atherosclerosis, osteoporosis, osteoarthritis, renal disease, intervetebral disc pathology, hepatic steatosis (fatty liver) and other age-related conditions." [6]
The above list of age-related disease shows why preventing the formation of senescent cells is so important. Senescent cells are extremely harmful and the harm causes by senescent cells can be lowered by preventing their formation in the first place (rapamycin) or killing senescent cells by drugs called senolytics.
These three sections show how rapamycin fulfills the criteria for potential anti-aging drugs.
Nothing in the entire universe of drugs comes close to rapamycin and other rapalogs in fulfilling these three criteria of potential anti-aging drugs.
5. Blagosklonny, Does rapamycin slow down time?, Oncotarget. 2018 Jul 13; 9(54): 30210–30212.
6. Blagosklonny, Paradoxes of senolytics,. Aging (Albany NY). 2018 Dec; 10(12): 4289–4293.
A recent paper by Blagosklonny has the provocative title: "Disease or not, aging is easily treatable". The first sentence is: "For decades, one of the most debated questions in gerontology was whether aging is a disease or the norm."(7)
In my opinion, this entire debate is obsolete, archaic and medieval. Galen, a philosopher in ancient Greece put forth the idea that aging was not a disease, because everybody got aging and therefore aging was natural. Galen also originated the miasma theory which held that diseases such as cholera and epidemics like the Black Death were due to "bad air." In the second half of 19th century the germ theory of infectious disease exploded Galen's miasma theory. It is also time for Galen's theory of aging to be consigned to the "ash heap of history"
The answer provided by Blagosklonny is: "It does not matter because aging is already treated using a combination of several clinically-available drugs, including rapamycin...For treatment purposes, aging is a deadly disease (or more generally, predisease), despite being a normal continuation of normal organismal growth. It must and, importantly, can be successfully treated thereby delaying classic age-related diseases such as cancer, cardiovascular and metabolic diseases, and neurodegeneration." (7)
In my practice, I have treated over 380 patients (Oct 2019) and the one question nobody ever asked was whether aging was a disease or was natural.
Aging should be considered a "term of art". In my practice aging can have TWO meanings:
A. "Aging is the sum of all age-related disease." This means aging is the sum of pre-disease and clinical disease.
B. Aging is also used as being short for TOR-driven aging as in the title: "TOR -driven aging, Speeding car without brakes" (Blagosklonny, 2009 [2]
Aging mechanisms which is not TOR-driven aging is put in category "post aging syndrome.
Aging must be connected to pre-disease or clinical disease. Aging is not an abstract concept. Aging is pathology.
"In pre-disease, abnormalities have not reached the arbitrary diagnostic criteria of the disease. So, aging consists of progression from (pre)-pre-disease (early aging) to disease (late aging associated with functional decline). Aging is NOT a risk factor for these diseases, as aging consists of these diseases: aging and disease are inseparable. [7]
In this paper, Blagosklonny has a very instructive diagram: GROWTH-->AGING. Initially aging is Hyper-functions in the pre-pre-disease and the Pre-disease stages, then aging ends in loss of function and Death.
Caption: Relationship between aging and disease, "When growth is completed. growth-promoting pathways increase cellular and systemic functions and thus drive aging. This is a pre-pre-disease stage, slowly progressing to a pre-disease stage. Eventually, alterations reach clinical disease definitions, associated with organ damage, loss of function (functional decline), rapid deterioration and death."
NORMATIVE AGING
The concept of "normative aging" is where the Blagosklonny concept of aging splits entirely from conventionally thinking. In conventional thinking normative changes, that which is the norm, is not a disease at all. In the Blagosklonny concept of aging, NORMATIVE AGING is the quintessential disease of aging. Unrelated humans share 99.5% genetic similarity. Therefore, it makes complete sense that something as fundamental as TOR-driven aging should effect everybody. Those changes that effect everybody are the bed rock of the disease. In an extremely important paper discussed below under the topic of normative brain aging; it was shown that rapamycin prevents deterioration of cognitive and vascular decline in the aging rat brain. That paper is the complete vindication of the concept of TOR-driven aging and prevention of pre-disease.
Healthspan. This term refers to the subclinical disease period. "In theory, a treatment that slows aging increases both healthspan (subclinical period) and lifespan. The goal of both anti-aging therapies and preventive medicine is to extend healthspan (by preventing disease), and thus extending total lifespan.
Preventive Medicine vs Anti-aging medicine
The goal of preventive medicine is to present disease by treating pre-disease. This is the same goal as anti-aging medicine. The difference between classic preventive medicine and anti-aging medicine is the cornerstone of anti-aging medicine is slowing aging.
When you start with preventive medicine and add rapamycin to slow aging, you have transformed preventive medicine into anti-aging medicine.
Conclusion: "Anti-aging drugs such as rapamycin delay age-relate diseases. In order to extend life span, an anti-aging drug must delay age-related disease...
"And this approach is actually being used now to treat aging at Alan Green's clinic in Little Neck, NY."(7)
7. Blagosklonny, Disease or not, aging is easily treatable, Aging (Albany NY). 2018 Nov; 10(11): 3067–3078..
Recent paper by Steve Horvath shows rapamycin suppresses the progression of aging as shown by the Horvath epigenetic clock. (8)
The Horvath clock is a major achievement in aging research. The Horvath DNA methylation epigenetic clock is an objective way to measure biologic age independently of time.
In this study Horvath showed that rapamycin reduced biologic aging of growing skin cells in culture. Rapamycin is now the first drug and so far the only drug shown to slow epigenetic aging.
Rapamycin reduced cellular proliferation rate, reduced somatic cell differentiation, REDUCED NUMBER OF SENESCENT CELLS and preserved proliferative capacity, however these specific effects were separate and distinct from slowing of the epigenetic clock.
The paper concluded: "In summary, the observations above represent the first biologic connection between epigenetic ageing and rapamycin.
These results for human cells add to the evidence that extension of life, at least by rapamycin, is indeed accompanied by retardation of ageing.
These observations also suggest that the life-extending property of rapamycin may be a resultant of its multiple actions which include, but not necessarily limited to SUPPRESSION OF CELLULAR SENESCENCE AND EPIGENETIC AGING, WITH THE POSSIBILITY OF AUGMENTATION OF CELLULAR PROLIFERATION POTENTIAL." [8]
This paper is huge. Prior to this paper the evidence that Rapamycin slows aging was the indirect evidence of extension of mouse and other lifespans.
This study is direct evidence on human cells of rapamycin slowing aging.
8. Horvath. Rapamycin retards epigenetic ageing of keratinocyts independently of its effects on replicative senescence, proliferation and differentiation, Aging (Albany NY). 2019 May 31; 11(10): 3238–3249.
TOR has two components, TOR1 and TOR2. Rapamycin has only one action, it blocks TOR. TOR1 is very sensitive to a single dose of rapamycin and TOR2 is very resistant. Therefore, intermittent use as weekly rapamycin can be used to block TOR1 and not block TOR2.
Rapamycin anti-aging preventive medicine is a combination of Anti-aging Medicine and Preventive Medicine as regards prevention of age-related disease.
Both seek to prevent disease and thus extend health span and prolong life span. Both treat pre-disease to prevent clinical disease. The difference is Preventive medicine uses classic methods to prevent specific age-related diseases. Anti-aging medicine seeks to slow down aging and thus delay all age-related disease. The cornerstone of slowing aging that this office uses is rapamycin. The target is TOR1. The basic concept is TOR1 is driving age-related disease.
The special expertise of this office is knowing how to use rapamycin to lower TOR1; but not lower TOR2
There are no published studies on how to use rapamycin to lower TOR1 and not TOR2 and get a satisfactory result. Knowing how to properly use rapamycin as an anti-aging drug is based upon experience and the art of medicine.
At this time (Sept 2019), the office has been treating patients with intermittent rapamycin for over 2 1/2 years and has treated over 350 patients. I have also taken rapamycin myself for close to 4 years.
The medical literature lists many side-effects from use of rapamycin. Many experts say that rapamycin has too many side-effects to be used for anti-aging medicine. It is true that rapamycin is a potent prescription drug and as is true for all prescription drugs; people who do not know what they are doing should not use or prescribe them. Rapamycin is not for the uninitiated or for those health care providers who lack sufficient expertise required to use rapamycin in a knowing manner.
COME FOR THE FUTURE, STAY FOR THE PRESENT
The ever expanding evidence in the scientific literature is that rapamycin slows aging, extends life span and delays and decreases risk of a large number of age-related diseases.
What is not clear from the literature is the effect in the present, not the future. Ameliorating pre-pre disease and pre-disease can have a dramatic impact on quality of life in three to six month from onset of treatment. One of most noticeable effects is on the brain. Overall mood and feeling of well-being is frequently improved.
Rapamycin treatment is not about waiting till you are 100 years old and noting all the diseases you dodged; or about a clinical study that follows people for 10 years and does calculations about "Odds ratio" [OR].
For many of my patients, slowing aging is about feeling better now [in the present] with life span extension and disease prevention something in the distant future rapamycin provides to boot.
However, not all patients have pre-clinical disease. Many have serious disease in the present.
In basic science, rapamycin has emerged as the silver bullet for the treatment of a large number of age-related diseases. However, rapamycin is a generic drug. In the United States, we are not Communists and nobody is expected to spend millions of dollars on clinical studies for which they can not receive any monetary benefit. Therefore, no human clinical studies are anticipated for rapamycin. However, the basic science research suggests that rapamycin is the greatest new drug to emerge since Penicillin, some ninety years ago. This office seeks to accommodate those persons who seek protection from age-related disease in their own lifetime. For this purpose, this office relies heavily upon animal models and basic research.. The premise underlying treatment is that those of us who need geroprotection now, would most likely be dead before appropriate clinical trials are initiated, completed, evaluated and the results incorporated into clinical practice.
This office practices Rapamycin Medicine. Rapamycin Medicine is the application of the theory and research of Mikhail Blagosklonny to clinical medicine. The Blagosklonny theory of aging and age-related disease is presented below in the following section, Blagosklonny Literature. In short, the theory is elevated TOR causes TOR driven aging and TOR driven aging causes age-related disease. Age-related disease and death is a late manifestation of the damage caused on a cellular and molecular level by elevated TOR.
Rapamycin Medicine is the "off-label" use of rapamycin for prevention and amelioration of these diseases.
This website attempts to present a very large amount of science-based information based upon quoted scientific papers. Almost all papers quoted are "open-label" and readers are encouraged to download and study all references.
CAVEAT: While I have been on weekly rapamycin for close to 4 years and I am very pleased with the results, and Mikhail Blagosklonny predicts rapamycin will become the standard of care in our lifetime for anti-aging protection; nevertheless, to the best of my knowledge, NO OTHER PHYSICIAN IN THE UNITED STATES HAS A SIMILAR PRACTICE USING WEEKLY RAPAMYCIN AS THE CORNERSTONE OF AN ANTI-AGING/ PREVENTIVE MEDICINE PROGRAM as regards age-related disease. Furthermore, the majority of physicians do not believe there is a common underlying cause for diseases of aging or that lowering TOR can prevent such disease.
Use of weekly Rapamycin as the cornerstone of an anti-aging formula has not been proven by human clinical trials. Such treatment is not recognized by the FDA. There is not the safety of many physicians having used a similar weekly rapamycin treatment for many years.
Consequently, a careful analysis is necessary to make a proper informed decision regarding use of weekly rapamycin.
Disease A:
Disease B:
Neurodegeneration:
In the drop-down section the evidence is primarily from basic science and animal studies.
Disease A has more evidence and studies than Disease B
APOE4 carriers should consult linked website Alzheimer-prevention.com
In "Koschei the Immortal and Anti-aging Drugs", 2014, Blogosklonny, sets forth an anti-aging formula. Rapamycin is the cornerstone of that formula. Rapamycin was approved in 2009 for use in transplant medicine. For that purpose it has been used in over a million people with good results with foreign organ retention for many years. Rapamycin is generally well tolerated with only mild to moderate side-effects. I stipulate that the dose and manner of use of Rapamycin in transplant medicine is hazardous to your health and certainly that manner of use is in no way suitable for anti-aging medicine.
In transplant medicine they start with somebody with a normal level of mTOR function and use rapamycin to knock mTOR activity down to almost zero level of activity. Then they keep mTOR at this very low level. The goal is to totally disrupt normal mTOR function and signaling. This complete disruption of normal mTOR function causes a severe disruption of lymphocyte function. The net result is you can put a foreign organ into a person and not get an immediate violent rejection and infarction of the transplanted organ. This is how the body is supposed to react. However, as long as mTOR is kept continuously depressed, the immune system will not function properly and orchestrate rejection of the foreign organ. This is great medicine and saves lives. The extraordinary thing is the "experts" who ascribe the same side-effects seen in transplant medicine to the effects they claim would be seen if rapamycin was used in anti-aging medicine.
It was well known in medicine 500 years ago that whether a drug is poison or safe is a matter of dose. Indeed, consuming 4 liters of water quickly is fatal 50% of time [LD 50] due to sudden hyponatremia and brain swelling and edema. Nobody says water is too dangerous to drink.
In anti-aging medicine, Blagosklonny recommends intermittent or pulse treatment and also suggested weakly dosage.Rapamycin has a half-life of @ 62 hours. That means daily use is once every 0.4 half-lives while weekly use is once every 2.7 half lives. For that reason, only data regarding using rapamycin once a week is applicable to side-effects expected from once a week use and side-effects from daily use are not applicable.
In my practice, I consider the proper anti-aging dose of rapamycin to be 2-6 mg, and the proper interval 1-3 weeks. So the most conservative anti-aging dose would be 2 mg once every 3 weeks.
I would certainly welcome formal research studies on the best dose and best interval and I expect to see those results in about 50 years from now.
Caloric restriction is major component of Koschei formula. Caloric restriction has been known to extend life span in numerous species from worms to mice for 100 years. Caloric restriction prevents age-related diseases including cancer and atherosclerotic heart disease. Interestingly, caloric restriction ameliorates sarcopenia. While caloric restriction increases insulin sensitivity, severe caloric restriction produces a glucose intolerance picture which is benign in significance. A 2015 study in mice showed mechanism of action of caloric restriction was inhibition or TOR and increase in SIRT1. Thus caloric restriction is different from rapamycin alone which only inhibits TOR.
In a very important study in humans, there was 25% caloric restriction in one group and 12.5% caloric restriction in another group combined with 12.5% increase in energy use through exercise. Compared to control group the caloric restriction group and the caloric restriction group plus exercise had similar results. There was a 20 pound weight loss, mostly body fat. Fasting glucose remained about the same; but fasting insulin levels went down 33%. Adiponectin showed 17% increase. SIRT1 level increase 3 fold. There was indication of decease in oxygen free radicals in muscle by 22%. Most important was the effect on mitochondria. Mitochondria increased in number and became more efficient. The increased efficiency of mitochondria was shown by reduced basal energy use at rest and less production of free radicals.
The best natural experiment showing what caloric restriction can do to a human population is the traditional Okinawan diet in the years 1950 to 1995. These people were farmers who worked very hard and as a matter of culture consumed less food. Studies calculated that they took in 8% less calories than their requirements. They had a remarkable decrease in age-related disease. Compared with Americans, men had 17% incidence of coronary heart disease and women 8%. Men had 50% incidence of colon cancer and women 30%. Men had 14% incidence of prostate cancer and women 9% incidence of breast cancer. As regards average life span, it was 5 years longer than Americans. The oldest 1% lived to 105 compared to 101 for oldest 1% of Americans. For the last 20 years, Okinawans have switched to a more traditional Japanese caloric intake and they no longer show any health benefits.
The Okinawan experience shows that an 8% caloric restriction less than required can achieve excellent results.
Most people notice that after a period of time on a caloric restriction diet they stop losing weight. They then get discouraged and go off the diet. In the Koschei formula, the purpose of a diet is not to lose weight; but rather maintain weight on less calories. It is not the weight loss; but the caloric restriction itself which results in the health benefits.
Physical activity is a very important part of the Koschei formula. Blagosklonny states, "chronic physical exercise inhibits mTOR and increases insulin sensitivity."
For an excellent study on the cellular mechanisms and signaling pathways through which physical activity decreases insulin resistance, see 2008 paper by Erin Glynn entitled, "A chronic increase in physical activity inhibits the fed-state mTOR/S6K1 signaling and reduced IRS-1 serine phosphorylation in rat skeletal muscle." The very short explanation is physical activity causes activation of AMPK energy sensing pathway, which leads to a decrease in insulin resistance in skeletal muscle. Muscle is the major regulator of insulin resistance as skeletal muscle is responsible for up to 75% of insulin dependent glucose disposal in humans.
In the book, "Autobiography of Geronimo", it was stated that Apaches could travel 70 miles a day on foot. There are ultra-marathon runners who train for runs of 50-100 miles. If they ever see a doctor, it is about running related injuries as they have very low level of age-related disease. The major negative effect of civilization on human health is that civilization caused a decrease use of leg muscles. Humans are by nature, the greatest long-distance runners of the animal world.
The question is: "what is the minimum level of physical activity needed"? The minimum requirement seems to be burning 1000 calories a week; the equivalent to walking 10 miles. One study showed that moderate physical activity is associated with 50% reduction in cardiovascular disease in over-65s. Another study had shown that moderate physical activity of walking 4 hours a week had a 54% reduction in cardiovascular mortality and a high level which was described as jogging 3 hours a week, had a 66% reduction.Note that the difference between moderate and high was small; but the difference between moderate and low activity was dramatic.The conclusion of the study was that older adults who are physically active have a lower risk of coronary heart disease, stroke, and death from cardiovascular disease.
The main point is that physical activity, like walking or jogging, causes a decrease in insulin resistance in leg muscles. A decrease in insulin resistance causes a decrease in insulin levels which causes a decrease in mTOR.
Metformin is part of our anti-aging formula. In a 2014 UK paper metformin monotherapy had a 15% longer survival than non-diabetic control subjects. Survival of diabetic patients not on Metformin had a survival 23% lower than non-diabetic subjects, which reflects expected results.
In a NIA (National Institute of Aging) 2016 study, metformin used alone had a modest increase in life spanbut only in male mice.When metformin was combined with rapamycin there was a very dramatic increase in one of two strains of mice. Male and female mice had a 24% increase in median life span and 10% and 17% increase in maximum life span. This was an impressive increase over rapamycin alone.
Metformin has been shown to reduce cancer in a great majority of animal studies and many human studies, especially liver and pancreas. Metformin acts through very interesting pathways which include activation of LKB1 (a tumor suppressor) and then stimulation of AMPK pathway which inhibits TOR.
For such an excellent drug, the question is why Metformin doesn't get more attention. A leading researcher on Metformin, explained, "The problem with Metformin is it's cheap, it's widely available, it has a great safety profile, and anyone can use it."
Metformin is also excellent to combine with rapamycin as the two agents have many opposite side effects, which can cancel each other's negative side effects.
Angiotensin II disruption is an extremely important part of the anti-aging formula. In clinical medicine today, there are two ways to disrupt angiotensin II, angiotensin-converting enzyme inhibitors (ACEIs, [Lisinopril, enalapril] and angiotensin II receptor blackers (ARBs, (Losartan, Candesartan). [We only use those that cross the blood-brain barrier]. These drugs are the most popular drugs used for the therapy for hypertension and are used by millions for that purpose. However, angiotensin II is involved in far more than just hypertension.
Two great parallel systems on the cellular level are the TOR system and the angiotensin system. The TOR system is 2 billion years old and the angiotensin system is 500 million years old. The evolution of the angiotensin system was essential for the development of a circulatory system, which was required for animals to get bigger than a few millimeters, the distance for effective diffusion.
There are two main theories of aging. The hyperactive TOR theory first presented in 2006, and the ROS theory (reactive oxygen species) first presented in 1956. The hyperactive TOR theory is about early aging and diseases of aging related to hyperactive TOR, and the ROS theory relates more to late aging. [see first section Blagosklonny Medicine] The current major focus of the ROS theory is on mitochondria, the major source of oxygen free radicals. Angiotensin is intimately involved with mitochondria and oxygen free radicals. While TOR is strictly organic chemistry, in the angiotensin system, the most important components are small molecules, superoxide and Nitric oxide.
Disruption of angiotensin II, prolongs lifespan of mammals. In hypertensive rats, treatment with angiotensin II inhibition with ACEIs or ARBs ameliorated the harmful vascular effects of hypertension and doubled the rats lifespan. In a study of normal rats without hypertension, Enalapril, an ACEi prolonged lifespan by 21.4% and Losartan, an ARB, increased lifespan 12.5%.
In an extremely important study by Begnigni, 2009, "Disruption of the Ang II type 1 receptor promotes longevity in mice", they created homozygous mice with knock-out of the Ang type 1 receptor. The knock-out mice lived a remarkable 26% longer than the controls. The knock-out mice showed protection from atherosclerosis and vascular damage. The knock-out mice also showed reduced age-induced mitochondrial loss. The conclusion was that reduction in oxidative stress ameliorated mitochondrial loss. They also showed an increase in genes for Nampt and SIRT3. Caloric restriction also has this effect, but not rapamycin, which only extends lifespan by inhibition of TOR. This study showed that knock-out Ang II receptor increased lifespan dramatically, but it seemed through a separate system than inhibition of TOR. Caloric restriction appears to have one foot in each system.
In a separate study of genes associated with extreme human longevity, Begnigni showed that genes with variations in angiotensin II receptor, which decreased function, were associated with extreme longevity.
Another study in humans showed treatment with angiotensin II inhibitors reduced risk of cancer, hazard ratio of 0.66.
For an understanding of the extraordinary roles of angiotensin II on age-related disease, I recommend reading, "Angiotensin II revisited: new roles in inflammation, immunology and aging", by Ariela Benigni, 2010. For the role of angiotensin II regarding mitochondria, I recommend "Renin-angiotensin system inhibitors protect against age-related changes in rat liver mitochondrial DNA content and gene expression", Elena de Cavanagh, 2008.
Aspirin is the only "anti-aging" drug recommended by the US Preventive Task force. The recommendation is for men 45-79 and women 55-79 to prevent cardiovascular disease and colorectal cancer. They did not specify 81 mg or 325 mg. I recommend 81 mg to decrease risk of upper gastrointestinal bleed.
I agree with evidence showing aspirin has a very beneficial effect on health of endothelial cells. The effect is mediated through both inhibition of platelets and decrease in chronic inflammation of endothelial cells. Part of the protective effect of Aspirin on endothelial cells is through blocking an inhibitor of NO synthase and increasing production of Nitric oxide. The increase in Nitric oxide causes a decrease in vasoconstriction and is similar to pathway of Ang II inhibitors who's main action is to increase Nitric Oxide.
I also agree with data that aspirin decreases risk of colon cancer.
One important study (Wan, 2013), established aspirin as a true anti-aging drug. The study was "Aspirin extends the lifespan of C.elegans via AMPK and DAF-16/FOXO in dietary restriction pathway." In this study aspirin was shown to activate LKB1. LKB1 is a very important tumor suppressor. LKBI then activates AMPK which in addition to many other beneficial effects also inhibits mTOR. This puts aspirin in same pathway as metformin with activation of LKB1 and AMPK. In contrast to Rapamycin, which has a single action; the direct inhibition of mTOR; Aspirin and Metformin are indirect inhibitors of mTOR and also involved in many other pathways.
Statins are included in our anti-aging formula. In addition to usual reasons for using statin; rapamycin can cause elevation of lipids. This elevation is a result of beneficial effect in that rapamycin prevents lipids from entering tissues and rapamycin has a robust anti-atherogenic effect regardless of elevated lipids. However, lowering serum lipids with statins through decreased production in liver is beneficial and synergistic with the rapamycin effect of removing lipids from atheroma.
In the 2013 Cochrane report, which reviewed 19 trials involving 60,000 patients with mean age 57, statins reduced all cause mortality (OR 0.86). In a VA study, all cause mortality was also decreased (OR 0.54) and the conclusion was "statins showed a highly significant negative association with death."