Evidence for mTOR to be Involved in Vascular Aging and thus Vascular Dementia
Research into mTOR and aging is becoming quite diverse. Researchers here present evidence for mTOR to be involved in the aging of the vasculature, and thus also in the development of vascular dementia. One of the noteworthy aspects of aging is the declining ability of the vascular system to deliver sufficient nutrients and oxygen to cells, and this is considered important in the decline of both brain and muscles, two of the more energy-hungry tissue types.
The research here is a good example of the way in which most researchers restrict their scope to relationships between areas of protein machinery that are very close to the disease state, without looking back down the chain of cause and consequence towards any sort of root cause. Detailed changes in proteins and their interactions are cataloged, but there is next to no consideration of why these changes in levels and interactions of proteins take place in aging. Instead of working further backwards - or better, starting with the known root causes of aging and working forwards - the impetus is to intervene in order to adjust the protein interactions of the disease state in some way.
At the SENS Research Foundation, the home of interventions that target root causes in aging, this tendency in the scientific community is known as "messing with metabolism." It fails as a strategy precisely because it doesn't look to the root causes, but instead becomes distracted into mapping and tinkering with the details of the immensely complicated dysfunctional state of cellular biochemistry exhibited in age-related conditions. If root causes are left alone to fester and continue to produce any number of downstream issues, then there is very little that can be usefully done to cure such a condition - no amount of tinkering will help greatly.
Brain vascular dysfunction is involved in the etiology of dementias. Cerebrovascular dysfunction is one of the earliest events in these dementias, best exemplified by diminished cerebral blood flow (CBF). A recent study suggested that vascular dysfunction indicated by decreased CBF may be the first abnormal biomarker in Alzheimer's disease (AD) progression, as well as the one that shows the largest magnitude of change. A significant barrier to effective treatments for AD, which are currently unavailable, is that we still do not sufficiently understand the mechanisms that drive its onset and progression. While the neuronal contributions to AD pathogenesis have been extensively studied, cerebrovascular mechanisms of AD, which show substantial overlap with those of vascular cognitive impairment and dementia (VCID), are only partially understood.
The mechanistic/mammalian target of rapamycin (mTOR) may be a critical effector of cerebrovascular dysfunction in AD and potentially other dementias. mTOR is a major signaling hub that integrates nutrient/growth factor availability with cellular metabolism. mTOR also regulates the rate of aging across phyla, including invertebrates and mammals. Rapamycin, an mTOR inhibitor, is the first drug that has been experimentally proven to slow down the rate of aging in mice. Work from our lab and others has identified mTOR as a major regulator of cerebrovascular damage and dysfunction in AD. While mTOR has a critical role in the regulation of cellular metabolism through actions at multiple signaling pathways, some mTOR-dependent mechanisms are uniquely specific to the regulation of cerebrovascular function.
Underlying the CBF reductions observed in AD are decreases in regional and global vascular density. mTOR drives cerebromicrovascular density loss, leading to profound CBF deficits, by decreasing microvascular nitric oxide (NO) bioavailability in brains of mice modeling AD through inhibition of NO synthase (NOS) activity. Therefore, mTOR attenuation with rapamycin induces endothelium-dependent cortical vasodilation via NO release. In agreement with this notion, prior in vitro studies showed that mTOR inhibits endothelial NOS (eNOS) phosphorylation and activation and NO-dependent arterial vasodilation.
Aβ, causally implicated in AD, is generated in the brain by cleavage of the amyloid precursor protein (APP) in association with neuronal activation. Aβ is released at synaptic sites into the interstitial fluid. Several physiological mechanisms act to prevent Aβ accumulation, but the largest contributor is transvascular Aβ clearance, as over 85% of Aβ is continuously cleared out of the brain through the blood-brain barrier (BBB). Consistent with a critical role of microvascular integrity and function in Aβ removal from the brain, systemic mTOR inhibition reduces Aβ levels in the brain and improves cognitive function in mouse models of AD. In these AD models, mTOR promotes the accumulation of Aβ in the brain by inhibiting autophagy and by decreasing Aβ clearance as a result of decreased vascular density and reduced CBF.
The BBB is formed by a monolayer of vascular endothelial cells that line the brain microvasculature and dynamically regulate the exchange of molecules. Studies indicate that BBB breakdown is one of the earliest events in the pathogenesis of AD. It was found that mTOR attenuation reduces or prevents BBB breakdown in several models of age-associated neurological disorders, suggesting a broad role of mTOR in BBB dysfunction in age-related brain disease states. The exact mechanisms by which mTOR promotes BBB breakdown, however, have not yet been sufficiently studied.
Rapid increases in blood flow to areas of the brain with high neuronal activity are required to maintain cellular homeostasis and function. This is accomplished through neurovascular coupling, a homeostatic response mediated by complex intercellular signaling events. Significant neurovascular coupling deficits are observed in patients with AD. NO production via activation of the neuronal form of NOS (nNOS) contributes significantly to the neurovascular coupling response by inducing local vasodilation in response to neuronal activation. Dysfunctional neurovascular coupling in mouse models has been reported to occur both from reduced neuronal NO production as well as from a diminished CBF response to otherwise unimpaired NO signaling. Since mTOR is a key driver of cerebrovascular damage and disintegration in several mouse models of AD, it is reasonable to hypothesize that mTOR contributes, at least indirectly, to neurovascular coupling deficits in these models. Very little is known at present, however, about the role of mTOR in the regulation of neurovascular coupling.
i take rapalogs. i dont expect it will do a lot, and i agree with aubrey that it will only likely add up to 2 years to lifespan, but those 2 years may be the difference between making the cut or missing out. ide rather avoid the latter
I take 250mg of resveratrol from biome every day.
When I do this I follow the advice of Dr. David Sinclair who says the smallest dose of 250mg has the best effect. He himself take it and so do his children.
@norse i give resveratrol to my cat too
@scott: makes sense to me...
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At what point in the causal chain does an intervention become a prevention strategy rather than a repair strategy? It always seemed to me that mitoSENS (moving mtDNA into the nuclear genome) is more a prevention than a repair approach - which is all fine and good, an ounce of prevention and all that - except that it seems really, really hard with present technology (not just the moving genes part but getting the regulatory mechanisms to function as well).
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I recently watched William Shatner's, 'The Truth is in the Stars'. He interviews Stephen Hawking and asks him about 'immortality'. As they discuss the topic it becomes clear they are not talking about immortality per se but radical life extension technology. Hawking is thoroughly dismissive, saying something along the lines that the entire human genome would need to be re-written. I believe I've seen Michio Kaku make similar statements.
@CD not sure i agree that the human genome will need to be re written. mitosens seems to be doing better at the moment.
And there is the problem. I would not ask a biologist about black holes and supernovas so why is so much stead put in the opinion of scientists outside of the field who don't have the same level of understanding those working in biology do?
@CD/scott emptage: Remember that Hawking and Kaku are astrophysicist/physicist. they have no detailed knowledge about gerontology. if you asks ordinary persons what we have to to to lengthen lifespan radically the very great majority answers we have to tamper with the genes. in this age of genomics it has been so popular to answer that all problems/info/everything are in our genes. I disagree!
@steve hill i agree i was rather confused by that comment too.
@norse yeah i always remember that anyone who dosent work in the field and says its impossible should not be taken seriously as they have no knowledge of what aging actually is. sounds like kaku buys into the "programmed aging" theory
I would conversely argue that it is those who are not afraid to bridge the gap between biology and various other disciplines who are going to truly guide the field to success in the 21st century
Much of the current "re-merging" of biology with various themes found in turn of the 20th century physics, such as the work going on at the Levin lab at Tufts University, on bio-electric fields and regeneration (https://ase.tufts.edu/biology/labs/levin/), or that of bio-magnetic resonance at the DNA level, at the Cosic lab at RMIT, to explain how a 50 trillion cell body so "close to peferctly" maintains itself over decades (http://www1.rmit.edu.au/staff/irena-cosic), are going to be providing answers that "biology in a silo" has been unable to acheive
@Ira S. Pastor: I think that some of the innovations coming out of what you are writing about is applications in transplantation medicine. I think it might be possible with bio-magnetic resonance to solve the problem of immune rejection of organs without the need for immunosuppressants.
To clarify, I personally do not take Hawking's or Kaku's comments seriously. However, they both have a wide fan following and are considered knowledgeable scientists by a large number of people. Some people here might want to review that program since Hawking certainly holds more sway over public opinion than, say, bioethicists who are not known outside their own academic circle.
My comments on mitoSENS were unrelated (hence the ~), except perhaps as a memory-chain ... 'hmm- re-writing a portion of the genome - oh wait, Hawking made that comment about re-writing the *whole* genome...'
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As far as silo-ing and innovation goes - here's an interesting discussion of 't-shaped people':
https://youtu.be/KaRz9KFwF2s?t=19m21s
You know, atherosclerosis as a disease is somewhat related to AD in that it affects the vasculature so profoundly and is closely connected with delivering oxygen and nutrients to the brain on an adequate basis. If we could solve atherosclerosis, it seems we would go a long way in addressing related problems with AD as discussed in the article.
I think the link is MTOR drives mitobiogenesis and vasoconstriction in the blood vessel walls. It's quite a tangential link but it shows how a fundamental cause of aging, I.e. failing maintenance of mitochondria, can effect multiple diseases of aging, which then feed into each other. For example mitos affect atherosclerosis that then effects things like AD, and mitos also effect AD directly.
@Mark: If mitochondria are so central to these widespread diseases of aging, maybe we should rejuvenate and/or replace them with copies by taking the so called new vitamin PQQ, which stimulates division of mitos to form new copies. I recently added a supplement with PQQ, and just read an advertisement for PQQ earlier this morning in my email. They claim Goldie Hawn (72) and Sergie Brin of Google take it and have no wrinkles in the ad. Take it for what it is worth.
I've found PQQ works really well for athletic performance, ellagic acid (urolithin A via gut microbiome) are a close second and much cheaper. Exercise and time-restricted eating (15+ hours) also do it (mitochondrial biogenensis) and they are not just cheap, they're free. But those interventions are just stop gaps. Perhaps between now and mitoSENS there could be nanobots or synthetic microbes designed to 'kill' malfunctioning mitochondria - I think similar approaches have been suggested.
@CD: You mentioned in an earlier post that it may possible to move the mitochondrial genome to the nuclear genome. Perhaps we wouldn't have to move the entire genome into the nuclear genome, if we could extract the parts of the mitochondrial genome that are important in aging and make a lot of copies of those parts and inject them back into the organism to control diseases such as diabetes or atherosclerosis. I was thinking of the MtRNR2 gene rs2854128 A allele that increases humanin levels and can be a target for reducing atherosclerosis (Cohen, 2014, Mitochondria in aging, diabetes and atherosclerosis).
I think the basic idea behind mitoSENS is that mtDNA is particularly vulnerable to DNA damage due to being close to the site of ROS generation and not subject to the repair mechanisms that nuclear genome has at its disposal {someone please correct me if I am wrong on this; they say the best way to learn something is to try to explain it to others}. That's why they want to move the whole thing over. I have questions regarding things like cellular allometry and how gene expression will be managed.
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Upregulating humanin expression does seem to be something to be explored.
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I should probably mention that I have misgivings about PQQ. I like it because it makes me feel good, but things that make us feel good aren't always good for us over the long term. It could be the placebo effect, but I've tried (probably recklessly) an awful lot of supplements and very few have any discernable effects and a number have had intolerable side effects. I wonder if PQQ may lessen the benefits of exercise, for example. Like anything else, the dose and timing make the poison and I don't think it has been studied enough to really know what's optimum. I feel better exercising when I take it, but exercise is supposed to make you feel somewhat awful while you're doing it, right? Exercise is safe and is actually known to extend life, so that's probably what I should stick with for mitochondrial biogenesis (and the time-restricted eating is safe, also).
@CD: I was so impressed with the 2014 Cohen presentation that I cite above on reducing atherosclerosis that I bought some shares in the company CWBR that he is affiliated with for the solving diabetes, AD, and atherosclerosis diseases of aging. I am fortunate to have the A allele, which raises levels of humanin in the blood stream endothelium. I have also begun to question the need for PQQ supplementation, and plan to discontinue it after my current supply runs out.
PS: Forgot to mention. About 2 years ago I had my arteries scanned for calcium plaque. None was found in my carotid, coronary or other arteries, so perhaps the absence of calcium in my arteries would seem consistent with higher humanin levels in the blood stream found with the A allele, though I am 77 years old.
The title of paper is "A Perfect sTORm: the Role of mTOR in Cerebrovascular Dysfunction of Alzheimer's Disease: A Mini-Review" Veronica Galvan.
Veronica Galvan is one one world's leading experts in AD since 2010. This is very excellent paper. Anybody who wants to understand the 2018 conception of AD should download paper.
To editors of Fight Aging. Many thanks for finding such an excellent paper.
@ Alan Green: Very interesting review article on the Role of mTOR in cerebrovascular dysfunction and AD. I found another very interesting reference describing the relationship of the protective protein humanin to atherosclerosis, endothelial dysfunction, and AD. The reference article is found at Anti-Aging Firewalls posted June 6, 2010 by Vince Giuliano Humanin, health and Aging.
I particularly noticed in the Galvan review article you cited, the close connection between atherosclerosis and AD. The article I referenced shows the role of Humanin in these diseases of aging.
After further reviewing how high Humanin levels are very protective of atherosclerosis, and probably diabetes, AD, and many other diseases, and that Humanin is coded for in the 16S section of mitochondria, I have come to the conclusion that we should do all we can to promote active mitochondria. To that end, extensive aerobic exercise and supplementation with mitochondria enhancers like PQQ and NAD+ seems reasonable for lifespan expansion via protection against many main forms of chronic diseases.
I hope you are right, Biotechy. I've been tapering off the PQQ and I had a relapse of what I assume to be symptoms related to medium-chain acyl-CoA dehydrogenase [MCAD] deficiency (hypoglycemia and extreme fatigue). I found out last year from 23and me I'm heterozygous for it; it is supposed to be a recessive trait but I've had the symptoms on and off since my teen years. Coconut oil makes it worse; I'm glad I never tried MCT oil. Strangely, I'm fine when I fast - the hypoglycemia is the reactive type. In fact, over the holidays I did a four day water only fast and never felt better. I'm not sure what PQQ has to do with it; I have not seen PQQ named as an MCAD co-factor. I might try cycling a few times to see what happens (Reason just posted about self-experimentation being confounded by caloric intake, though mine has been fairly steady for three weeks now).
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Thanks for investing in the humanin research - hope it pays off :)
@biotechy i take nr and pqq, plus i add mitoq too enhance mito function