Physical Activity, mTOR Signaling, and Alzheimer's Disease

Alzheimer's disease is a condition that sits atop a mound of many contributing causes, layered in chains of cause and effect. Given that chronic inflammation and age-related impairment of the cellular housekeeping mechanisms of autophagy both appear to be significant, somewhere in the mix, it is perhaps to be expected that many of the usual healthy lifestyle choices have some modest impact on the progression of the condition. Exercise and calorie restriction both act to upregulate autophagy and it is thought that this accounts for a sizable fraction of the resulting benefits to health and life span. Unfortunately, the sort of stress response upregulation appears to scale down in impact on life span as species life span increases, though the effects on short term health and metabolism appear quite similar. Mice can live up to 40% longer when on a calorie restricted diet, but that is certainly not true for humans; we gain a few years at most.

Autophagy recycles damaged structures and broken proteins inside the cell. Neurodegenerative conditions such as Alzheimer's disease involve the presence of toxic molecules, such as those associated with amyloid-β and tau, but even if not directly involved in clearing away disease-associated damage, increased autophagy is generally protective of cell function. Given that this includes everything from neurons to the microglia responsible for clearing away intracellular debris and protein aggregates, we should expect increased autophagy to modestly improve just about every issue in the aging brain. Sadly, doing better than modest improvement is probably not within the scope of what might be achieved via increased rates of autophagy, even when researchers directly influence regulatory genes such as mTOR.

Physical Activity Alleviates Cognitive Dysfunction of Alzheimer's Disease through Regulating the mTOR Signaling Pathway

Autophagy as an evolutionary-conserved process can maintain normal physiological events or regulate the progression of a series of diseases through sequestering mis-folded/toxic proteins in autophagosomes, thus executing its cytoprotective role. Growing evidence demonstrates that autophagic capacity to degrade harmful proteins in cells declines with increasing age. Moreover, dysfunctional autophagy has also been linked to several aging-related neurodegenerative diseases including Alzheimer's disease (AD). Previous studies have documented the critical role of autophagy in the pathogenesis of AD, including amyloid-β (Aβ) production or deposition, Aβ precursor protein (APP) metabolism, and neuronal death. Furthermore, insufficient or reduced autophagic activity can lead to the formation of harmful protein aggregates, which results in increased reactive oxygen species (ROS), cell death, and neurodegeneration. As a result, autophagy has a crucial role in the regulation of longevity.

Mammalian target of rapamycin (mTOR) regulates a series of physiological processes. On the one hand, mTOR plays an important role in different cellular processes including cell survival, protein synthesis, mitochondrial biogenesis, proliferation, and cell death. On the other hand, the mTOR signaling pathway can execute an important role in memory reconsolidation and maintaining synaptic plasticity for memory formation, due to its regulatory function for protein synthesis in neurons. Moreover, mTOR also can interact with upstream signal components, such as growth factors, insulin, PI3K/Akt, AMPK, and GSK-3. Currently, although the molecular mechanisms responsible for AD remain unclear, more and more studies have confirmed the involvement of dysregulated mTOR signaling in AD. Activated mTOR signaling is a contributor to the progression of AD and is coordinated with both the pathological and clinical manifestations of AD. Furthermore, there is a close relationship between mTOR signaling and the presence of Aβ plaques, neurofibrillary tangles, and cognitive impairment in clinical presentation. Therefore, the development of mTOR inhibitors may be useful for the prevention and treatment of AD.

It has been reported that regular physical activity can improve brain health and provide cognitive and psychological benefits. Mechanically, regular exercise training is related to the inhibition of oxidative stress and apoptotic signaling, thus effectively executing neuroprotection. Previous studies have demonstrated that treadmill or voluntary wheel running is beneficial for the improvement of behavioral capacity, and can promote the dynamic recycling of mitochondria, thereby improving the health status of mitochondria in brain tissues. Moreover, other studies have demonstrated that regular exercise has a beneficial effect on the structure, metabolism, and function of human and rodent brains. Interestingly, our recent study has also documented that the brain aging of d-gal-induced aging rats can be noticeably attenuated by eight-week swimming training, due to the rescuing of impaired autophagy and abnormal mitochondrial dynamics in the presence of miR-34a mediation. Therefore, physical activity is regarded as an effective approach against AD.

Comments

That is a re-post from an earlier thread in the hope it fits better here to get answered.

As a layman, active gym goer and outdoor man, I struggle to understand the mTOR pathway in the context of exercise and aging. On one hand exercise, especially resistance exercise is said to activate the mTOR signaling pathway to enhance protein synthesis to build more muscles. On the other hand, inhibiting the mTOR pathway is mentioned, besides other importing effects, to slow down aging.
Does that mean that I, a very active person in his 60ties, might stay healthy for longer but age faster and will die prematurely?

Posted by: Stephan at April 24th, 2019 7:47 PM

Hi Stephan ! Great question.. Just a 2 cents.

mTOR is very complex/interplay...and I feel that you should not worry...the benefits offered by dosed exercise (in moderation/or short 'hard bursts') far outweigh the negatives that come with them. Thus, to answer your question, yes, you will stay healthy longer, but your speed of aging won't be That affected; in the sense that, mTOR is omnipresent and already part of the whole thing; with aging, frailty is major concern, sarcopenia, BMD (bone mineral density) loss and other diseases (like osteoarthritis falling in that frailty umbrella term) too. Because you keep fit, you increase body fitness...fitness in an evolutive advantage (for sexual reproduction/specie continuation), but of course, you need nutrient input; exercise taxes your body. In low-to-moderate dose it's benefitial, in high-dose up to exhaustion, it isn't anymore, and now you Truly see advancing of aging (seen as accumulation of damage and lipid peroxidation in cells). Thus, to make 'slowing' of aging, exercise must be dosed. Exercise activates telomerase/PCG-a/makes fat burning/ketotic...switches from glucose to fat energy burning, and in doing muscle contraction you damage muscle fibers (Type I/II); but mTOR comes to the rescues and makes new fibers, it's like a contraction signal and a 'fitness' signal (activating IGF/mTOR), thus improving insulin sensitivty signaling by skeletal muscle formation (as said, muscles contribute to insulin homeostasis; muscle mass replacing visceral fat mass is good and improves fitness).

Now, to answer more your question, it's a Double-edged sword, it ages you - anyway (because of replicative senescence/hayflick/cells stop dividing one time after so many bouts, mTOR accelerates the cell size growth to 'point of senescence' (something like 17microns and then the cell stops/senesces or apoptose); and it's why CR (Calorie Restriction) and Rapamycin block mTOR's geronconversion to senescence and keep a youth state to the cell).. a bit lik eyou said...mTOR increases cell senescence entry/is a geronconverter to senescence when is very high activity. Too much mTOR/insulin signaling and then you end up with the inverse effect of CR (calorie restruction) where is 'over nutrient' intake..thus too much insulin/insulin receptor IR activation (insulin resistance/diabete), too much mTOR, fat creation, etc...it must be dosed.

If you do it dosed, you have nearly nothing to worry, and it will improve/maintain your health, giving more chances of raeching your maximum (120 years human; it is not an assurance because living above 100 years is Very Genetic Dependent (inherited family genetics for example), it just 'helps' your chances).

So to end, have no fear, if doing it reasonably (listen to your body, its signs), about dying prematurely, if you feel healthy and are active.

Just a 2 cents.

Posted by: CANanonymity at April 25th, 2019 2:25 PM

@Stephan - I agree with CANanonymity that the crucial thing is cycling mTOR. Both having it activated all the time and having it inactivated all the time is going to be bad for you in the long run, which is why among self-experimenters, Rapamycin is only taken weekly, not daily. So I wouldn't worry about exercise ageing you prematurely - unless you were overdoing it by running an ultra-marathon every week!

Below is the abstract from an article I've been trying to get my hands on the past few days, but Sci-Hub doesn't appear to be able to get past the paywall (I don't suppose anyone on here has it?). In it, calorie restriction would be a proxy for mTOR inhibition.

The Panacea of Human Aging - Calorie Restriction Versus Exercise

"Primary aging is the progressive decline in health and fitness and depends on metabolic rate and oxidative stress. Untoward changes in body composition and metabolic function characterizes secondary aging. We hypothesize that both exercise and calorie restriction improve secondary aging, but only calorie restriction improves primary. However, calorie restriction followed with exercise is a superior strategy for overall healthy aging." -"healthy aging" - such an oxymoron!

Posted by: Chris Linnell at April 25th, 2019 4:06 PM

Hi CANanonymity and Chris,

thanks so much for your response.

Yes, I practice CR by intermittent fasting 16:8 daily, no food intake on Saturdays and twice a year I do a 5 days fast only drinking a cup of self-made bone broth with some Moringa powder to ensure basic nutrient supply.

I could not get a prescription from my doc for Rapamycin or Metformin but supplementing with Fisetin, Quercetin and Pterostilbene.

Also, I make my own brew out of Ginger, Turmeric and Ashwagandha roots with Boswellia.

In addition, I supplement with basic vitamins and minerals.

I guess that the best I can do?

Posted by: Stephan at April 25th, 2019 5:23 PM

Michael Ristow has suggested glucosamine as an alternative to metformin:
http://geroscience.com/glucosamine-the-new-metformin-interview-with-dr-michael-ristow-part-ii/

Side effects include possible increases in LDL and intraocular pressure (glaucoma) & don't OD:
https://www.sciencedaily.com/releases/2010/10/101027111349.htm

Acarbose, another Rx antidiabetic drug, has been found to increase lifespan of male mice by 22%. Xylitol seems to have similar activities (and side effects) but I can't find any studies on lifespan in peer-reviewed journals, only this:
https://genomediscovery.org/2018/03/a-candy-way-to-extend-lifespan-sugar-based-lifespan-extension-therapy-xylitol-a-sugar-alcohol-and-artificial-sweetener-in-drugs-confections-toothpaste-and-chewing-gum-may-increase-life-spa/

Also, no studies on lifespan in mammals on the antidiabetic herb amla (Emblica officinalis)- only studies on worms and flies, used in combination with other substances.

Posted by: CD at April 26th, 2019 10:17 AM

Hi Stephan - if you're willing to go down the non-prescription route, you can get both Rapamycin & Metformin from https://antiaging.clinic/ referral code "research", which I found out about from the folks at https://age-reversal.net/ . I'm kinda trusting age-reversal.net that they are the real deal, as I've not had them tested. Both products shipped to Canada no problem without a prescription. caveat emptor

Posted by: Chris Linnell at April 26th, 2019 12:25 PM

Stephen, if you want to go a bit deeper in the woods clear out some bad cells with fisetin or LEF senolytic activator occasionally. Also, there are a lot of other things that age us that may be worth trying to tame. Take something like Niagen to increase NAD, Glutithione to increase your master antioxident. Hormone replacement therapy if low. Optimize thyroid levels. Perhaps shoot up a human growth hormone stimulating peptide. Consider PPQ to repair DNA,
lower stress, take things to regain proteostasis. Make sure to take enough k2 to prevent calcium accumulation in vessels and skin. Consider Carnosine or carcinine if you can get your hands on it to lessen glycation. Do something about your telomeres but not enough to cause cancer, Optimize methylation. Avoid sugar and air pollution. Figure out how to stop TGF-b from breaking down your subcutaneous fat layer, pioglitazone maybe? Reduce progerin, take care of good gut bacteria,floss, Slather on tri lipid cream all over to keep inflammation from entering through the skin - maybe spike it with some methylene blue. Do something about your stem cells, Increase Sirt....the list goes on and on.....
,

Posted by: August at April 26th, 2019 10:46 PM

PPS: I would also suggets rho-kinase (ROCKi) inhibitors...most of them you can't but because they refuse to sell them for personal use/patients...and they cost ridiculous price 500$ for 10mg or so...
Thus, an alternative are polyphenols/flavonols, the likes of quercetin glycosides/resveratrol (ptero)stillbeness....but, more specifically, rho-kinase (ROCK1/ROCK2) targeters...such as phloretin or less so baicalein (apple leaf/scutelaria baicalein/skullcap). These may notbe strong antioxidant like quercetin or resveratrol but they are something much better, they are rho inibihors/PIP (phosphatidyl inositol phosphate/PIP3, especially)..PIP/Rho is causal to many of the cytoskeleton problems and also mitochondrial problems with age; such as accumulation of mitochondrial ROS/emission elevation...which ages you, shortens telomeres and makes redox loss, while creating epidrifting, splicing errors, deleterious nuclear mutations, mtdeletions, chromosome laxing, histone loss/H3K, SIRT/FOXO/DAF loss and transcriptomic wack...in other words, extremely 'far' reaching. One study showed that rho kinase inhibition is truly the 'gateway' to hTERT/telomerase activation and that there is a concerted action between Rho and Tert...they were able to increase replicative lifespan upwards of 150-200 PDs by rho signal stopping..something unheard of by no antioxidants existing...because most cells will succomb of replicative senescence, p53/p16INK is highly expressed and so Beta-Galactosifase staining, showing senescence entry and very low telomere lenghts size...
Rho abrogation keep teloemres Much taller, reduced telomere shrinking rate, or let's say made 'Telomeres 'freeze' in their shrinking..because telomerase keept 'on adding' to counter loss...and more importantly, Rho blocking, made cancer destruction...for telomerase was not hijacked anymore by cancer when Rho is cut. Also rho-blocking made activation of hTERT, activation of 'stem cell' genes, such as Oct/Sox...those ones..except Nanog...so basically a full on 'epigenetic reprogramm talk' by Rho stopping. Antioxidants cannot do that, they only quench/consume ROS that'S about it, it's limited.
Kinase inhibition has very deep effect..

One study showed that arachidonic acid activates up to 6-8 folds 'Rho' kinase..arachidonic Omega-6 is highly responsible for Many diseases/inflammation and Rho is activated in cancer...too much long-chain OMega-6 = diseases, that's because of Rho/PIP3 activated, Rho kills telomerase activity, likewise for PIPs. Another study in C.elegans showed that the LONGEST lived C.elegans (10-fold longer lifespan, something unheard...) htat lived for 250 DAYS..nearly a full year..when most wild type 'normal' c.elegans worms live not even 20 days....is because these C.elegans mutants showed abrogation of PIP signaling...thus,RHo signaling. Rho/Pip = Entire Inflammasome/Immune inflammation/ROS production activity...and also control of longevity genes (DAF/SIR/FOXO..these C.elegans had about 100x times more activity of DAF-16/SIRT3/SOD-3 enzyme in nucleus and had dramatic ROS quenching/consumption in mitos/they accumulated 'no elevation of ROS' with age, plus they maintainted taller telomeres, little to no lipofuscin intheir intestine cells/their redox was clearly improved/maintained (they have higher much NAD+ levels (kept)/GSH content and more GSSG recycling)...and they lived *10-times* longer than regular c.elegans; the Longest extension of longevity in all animals yet). Goes to show that Rho/PIP pathway is major decider of lifespan and if we target it the MAny many 'downstream effects' are so numerous, and Far more effective than simply attacking ROS alone or antioxidant...and such, it is Multi-Causal/Multi-Genetic/Systemic...in effect. Hence, why such drastic effect in lifespan or in cell lifespan. Rhos inhibition made conditional replicative senescence abrogation the instant the signaling is blocked, p53/p21 are nearly abolished -even at 'senesnce' point, thus senescence is 'unfeasable', and that is how most cells imm*rtalize and become cancerous/evanding replicatinve senescence (The danger is how much loss of tumor supressors will this have on cells..there could be spontaneous tumors just like OSKM after 11 days/teratomas (but one study showed no tumor/cancerous formation in at Least 200-300 PDs, thus stable and even IF LESS tumor suppressor activity; this means LESS INFLAMMATION = LESS CANCER = LONGEVITY = NO NEED FOR TUMOR SUPPRESSOR because tumor suppressors like p53 are a double-edged sword 'only meant' to safeguard health but each time they are activate they aged you on replicative bouts 'towards Hayflic senscence')...but, clearly, it means that tumor suppressors are far more consequential to aging than we thoug ht...they protect us from tumor/cancer formation - yet kills us at the same time (by senescence entry via mTOR), double-edged sword - antagonistic pleiotropy meant to 'protect us/fitness/a protection against cancerous transformation/cancer cells' but in the inverse..and Pro-Aging element - it means it is 'limit' imposed on us to 'not live forever'. And why, p53/p16/p21/p38/p27 abrogation makes imm*rtal cells that accumulate no lipofuscin, no epidrifting, no redox loss, no mtROS accumulation with time, no protein carbonylation/accumulation of AGEs/ALEs/no loss of homeostasis/integrity, keep inflammation 'minimal' and damages too (like SSBs/DSBs in nuclear DNA/telomeric DNA/mtDNA) etc... and keep 'telomeres size frozen' (never shrinking below 1kb size)..hence, can divide eternally and would never encounter senescence (which is, pure LEV).

Just a 2 cents.

Posted by: CANanonymity at April 27th, 2019 4:32 PM

Thanks for all your valuable information.

For a layman there is lot more to learn to understand the basics.

For the next 3 months I will continue with Fisetin and afterwards trying rapamycin - thanks Chris for the link. NAD and Glutathione are definitely on my radar.

mTOR pathway yields another question: What takes precedence when on CR and at the same time doing rigorous exercise? Or does one eliminate the other?

Posted by: Stephan at April 28th, 2019 12:50 AM

RE Thanks for asking. Just a 2 cents.

I would say if doing both CR and rigorous exercise, it is both synergical and redundant...redundant because many pathways similar between CR and exercise...such ketosis/fat burning (instead of glucose), CR will reduce mTOR, while exercice won't because exercise makes you fit - unlike CR...CR is a famine survival mechanism in front of nutrient deficiency/starvation...while exercise is a fitness body improver...mTOR/IGF is needed for that; CR will reduce oxidative stress, so will exercise, only in low-to-moderate bursts dosed...not exhaustion (when exhausted after strenous exercice there is clear destruction of muscle fibers and lipid peroxidation in cells (seen as MDA/TBARS)...thus you must rebuild the body by consuming carbs/protein/nutrients..that is when mTOR/IGF (by insulin on insunlin receptor/activation signal) comes back and makes muscle fiber formation. CR is a longevity enhancer...while exercise is health/fitness enhancer, far less so in terms of longevity..simply because you will activate mTOR...with that said, exercise was shown to increase telomerase, so it does increase longevity yet it also increase mTOR for fitness/muscle creation...thus it is slight self-defeating and paradoxal..but we have to understand that unhealthy/unfit, your chances of living a very long life are slim because you can succomb of frailty/unfitness. While CR will stabilize things and make a longevity effect for your will reduce calorie input, thus less calorie converted to energy/creating residue byproducts of metabolism...damaging you/aging you. Less calorie means less damage, thus less aging going on...but you will 'stable enough'...or should I say 'fit enough'..but it could be not enough and you could succomb of frailty - WHILTE DOING CR...I know...I tried to do it and was half-dead...CR hastens things like frailty death; your health can Worsen on CR, yes, frailty is very dangerous when you are sick...and CR, like exercise are BOTH STRESSFUL on body..because you stress it..by lack of nutrients (CR) or by 'taxing it' with hard physical momevements (exercise)...some animals are sleeping so long, they almost get No exercise..and they still live quite long..demonstrating we are made to do exercise but very much dose it; we can't stay up on our feet 24 hours a day...gotta sit some times..and rest.
With that said, studies showed that excessive 'sitting/staying sit' is very bad in the long run..you must get up walk...do some light/moderate exercise (just like your long ago ancestors did everyday while 'going for the hunt' to catch meat 'game fowl'; we don't do that anymoer, we 'work in offices/computers/desk job..and sit Too Long...' that creates 'blood clots' in legs and can travel to your brain (creating a stroke...I know I had blood clot (atherosclerosis, I have it))...you can die just because 'you sit too long/hours on end..' and one study showed that people that are sedentary and very 'TV couch potatoe' sitting on and on...well had shorter telomeres and in like 5-10 years there level of mortality was 25-50% higher than exercising people or people who at least stand up every day and get at least a few 'hundreds steps' (you are suppose to do a few 'thousands' steps each day..of walking...to keep your health and burn fat/not become obese; practising CR negates many effets of sedentarity and no exercise activity; but does not stop diseases because you need both CR and exercise as part of a 'healthy lifestyle' regimen (and, of course, whatever you eat during that CR must not be toxic junk).

Just a 2 cents.

Posted by: CANanonymity at April 28th, 2019 12:20 PM

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