Cancer Disease

this talk is a departure from othertalks are given in the past so people who have seen me speak may not befamiliar with any of the terminology here about will explain it as we go andit'll be adjustable and easy and i hope interesting i started looking into thisbecause of my dad and many of you know his story in the mid to late nineties hestarted developing heart failure by $96 crime apathy to the point where withoutheart transplant it about a six-month prognosis and i diagnosed with lyme withnegative blood tests and he was treated successfully and never need a hearttransplant so it's my hope that somebody seizes video eventually in distressaccord and people become motivated

looking to this topic so this talk isabout a topology and autophagy is a cellular clearance mechanism that we allhave and it's something that helps our souls to survive it's basically amechanism of the grading and recycling solar components when the body is instress and it throws out the trash so abnormal proteins accumulate as part ofeither normal aging or abnormal aging proteins are involved inneurodegenerative illnesses such as alzheimer's and parkinson's andfrontotemporal frontotemporal dementia those connection be digested byautophagy and organelles of mitochondria their malfunctioning can also bedigested by autophagy so the body can

get rid of the stuff that doesn't needto renew itself it also has a dual purpose though because it serves toeradicate the souls from having interests other infections and in thisway what up and really either save the soul or duma sell most times it saves aso that's what it really is when is a million variables involved but when you distill it all down the majority effectsof autophagy or for survival of a cell rather than causing disease processes soit seems that it's a rocky player along a number of axes of disease states andthey've shown that impaired autophagy and my top g again which is thedigestion of abnormal mitochondria has

been demonstrated in a range ofneurodegenerative illnesses so these proteins i guess said and ismalfunctioning mitochondria accumulate in this disease states and autophagyalso is important in clearing up the cells and helping prevent thedevelopment of cancers so it's a very good thing obviously but once cancersare already present it can help those cancer cells survive just like can helpother cells survive so it's kind of got a double edged sword a little bit it canstop users from starting but once they're there it can help them help themlive and autophagy is also central to the delayed aging that you see withcaloric restriction anyone's heard that

reducing your caloric consumption hasbeen associated with prolongation of life and health spent among all thespecies that are tested and the key to that is actually autophagy which kind ofmakes sense to me because if you clear out the souls of the bad stuff and itcan live longer happier lives so in terms of autophagy and its role withinfection is a critical part of the innate immune response to intracellularbacterial infections and for many if not most of these intracellular bacterialinfections that helps control the infection but some of them the reallyold weird ones that doctors don't understand take advantage of autophagythey're so old they've co-evolved with us

over the eons and they've used what wewould like to use to get rid of them to their advantage and examples of bacteriathat take advantage of autophagy unfortunately our brucella bartonellaand coxiella lyme is unknown so the take-home point is that for manyinfections autophagy induction can be beneficial if you induce autophagy youcan help clear the body of infections but some of them it could be riskyparticularly again coxiella bartonella and brucella. it's not known if you induceautophagy in conjunction with antibiotics if you can help clear theinfections that's a big question mark so now like to introduce you to rapamycinthe other name of rapamycin is called sirolimus

lemus so it's got two names and is achemical that was discovered on easter island and they named it after thepeople there the rapa nui and its was secreted by atype of boat chirapol streptomyces and it's a soil bacteria and the purpose ofits secretion was to stop competing fun joy from growing so because it hasantifungal you know affects whose research initially as an antifungal found out it was a powerful immunesuppressant and as soon as they found that out they totally switch gears andthey proved it in the fda approved in 89 has been sold as immunosuppressive fororgan transplants so it's related to a

couple of other drugs on the market coldtemps early muslim everolimus and it's not related to tacrolimus which isconfusing it's completely different class of medicine and tackle the mrsmore related to collect cyclosporine so you know these drugs are kind ofinteresting draws most drugs you can avoid side effects if you use them atlower doses than the doses of which they cause side effects both these types ofdrugs you have differential effects that high doses they cause once of sideeffects and a lower dose doses they don't just not cause side effects thatcaused the opposite of what they cause at high doses

and i'll elaborate on them so now liketo introduce you to emptor which is called mammalian target of rapamycin sothis is an enzyme system that they've named after rapamycin it was justdiscovered not too long ago and they didn't know what was going on with itfor us know the kind of figured out that these are really critical to most ofcellular functions and they are now known to be the master regulators ofcell growth and longevity and integrate information regarding nutrients andgrowth factors in order to determine if the cell should be an anabolic so growthshares versus a catabolic like a starvation phys and they kind ofreconcile those two so the cells can

survive the most efficient way and thisis present in all plants animals and used on planet so when you see somethingand i'm talking bout target of rapamycin that is so extremely concerned onevolutionary basis you have to take notice there this stuff is present onalmost all life on planet earth it's got to be very very important and if we canintervene in this process able to make real differences on thestate of aging and age-related conditions so they have found that touragain mammalian target of rapamycin is involved in aging and neurodegenerationand i'm quoting now from this article from 2015 the says that mtor signalingpathway is involved in cellular

senescence which means aging of thesouls organism or aging so aging of the entire animal and age-dependent diseasesas saying that disturbance and mtor signaling in the brain affects multiple pathways key players inage-related cognitive decline such as the development of alzheimer's diseaseso others have been researching the relationship of mtor to alzheimer's andthey've shown that there is a relationship between type 2 diabetes andalzheimer's and that relationship hinges on tour so again according from thisnext article and it says here that high shirt consumption diabetes increases therisk of developing alzheimer's and in an

animal model of alzheimer's the show thesucrose intake induced obesity amyloid beta production and tell phosphorylationamyloid beta and tell or two of these abnormal proteins accumulate inalzheimer's and they've shown that this sucrose media to increase in alzheimer'slike pathology is precisely due to high priced the tour so employers you knowvery good for us and very bad for us at the same time as usual they would havesomething like that your body is they've also shown that rapamycin mtor inhibitorprevents the detrimental effects of sucrose in the brain without alteringchanges in peripheral insulin resistance and that they shone through animalmodels so just seconds ago that it's

very good for us in very bad for us youknow why do we have mtor if we didn't have em tour we couldn't grow up wecouldn't grow from being theaters to a baby and and analysis and just wouldnever grow but once you're full grown in once you have reached reproductive ageevolution kind of turns its back on us and tour doesn't stop so it kind ofkeeps driving growth in this kind of useless manner and literally drives usto grow old and the term growing old is more accurate i think than peoplerealize because i'm tour converts reversible so arrest to senescence andthat means reversible so arose is when the souls you know they they can divideanymore because of their called

genetic or epigenetic problems you knowever hear of telomerase telomeres in the telling their stories shorten and thegenetically become unstable and tour still driving replication is so drivinggrowth and so where does it drives them to become the senescent phenotype andthat means that the cells turn into an aged type of cell those souls don'tfunction properly they all of a sudden become inflammatory and kind of bloatedand that is what you see an old folks type of souls and biopsies so in thisother study then referencing 03 stories on this page tour is a central pathway teachingobesity cancer and autoimmune disorders

and all those are linked together youdon't know which came first the chicken or the egg they have done other studieswith isolated the variables and found that mtor in isolation if you stimulatedit's sufficient to promote cancer so it should come as no surprise the mtorinhibitors or useful as non cytotoxic anti-cancer medications sewn oncytotoxic means that they're not like chemotherapy don't kill so directly theydon't kill cancer cells but rapamycin / certainly missus same drug and itsderivatives are useful against the range of human cancers and derivatives therapamycin which our terms early mass and everolimus or actually fda approved forthe treatment of breast owner and real

cancer respectively and perot comes backto rapamycin the struggles generic it's cheap and it's been around for a longtime and it is the kind of you know archetypal mtor inhibitor so rapidly andpowerfully inhibits mtor one and it does not affect tour to short-term exposure and 2001into its two different enzyme systems that are linked and if you inhibits mtorto you can get some side effects and side effects primarily alike i diabetes-like condition it doesn'tseem to have the all the bad stuff the regular diabetes association worth butit's a diabetes or more of a benign

version of adobe's like condition butwith intermittent or short-term exposure to rapamycin that doesn't occur it'sonly with chronic long-term exposure and by inhibiting mtor one you powerfullyinduce autophagy their number of studies so i wanted to examine a theory thatautophagy and mtor inhibition could be useful to intervene for age-relatedneurodegenerative disorders and in doing that i didn't want to just concentratearound my son even though that's the classic mtor inhibitor i had a safe thisthere would hold water would have to hold water across multiple domains andso that other mtor inhibitors and look for data and all seems to line up so i'mlisting on this slide their top

producers some of them emptor dependentand summer independent and we just gotta lists some you sure you've heard ofothers maybe not so much vitamin d is actually an autopsy inducer that isemptor dependent metformin which is a type 2 diabetes drug most of thetetracycline class antibiotics or there are some limited data that minocyclinecan sometimes prevent autophagy from occurring but by and large they are topproducers human which is a spice that's in curryegcg which is the green tea extract and that has mixed emptor dependent and mtorindependent autophagy induction and calorie restriction again

stuff that publishes so many studies ofextends life and health span is dependent upon autophagy and mtor so andexercise actually in the brain will induce autophagy inhibiting mtor but the opposite is trueand skeletal muscle intellectually stimulating tour and turn off the top asshe saw it has kind of opposing effects and then the mtor independent ones of ushere on this slide or tree halos which type of sugar and carbamazepine andvalproic acid with a boat which are both anti seizure medications and lithiumwhich is a mood stabilizer for bipolar disease and lithium is tricky thoughbecause it also stimulates emptor

induces autophagy and independent wayand then stimulates emptor which would then have a feedback will be introducedat alpha chi so that's useful if you give it worth and mtor inhibitor so mostof the folks are are spoken seriously about this i give us talk once beforeand i leds and sorry for doctors and everybody's familiar with everythingthat i mentioned but you guys maybe not so much but the next slide explainstreet halos as most artists are from a tree a loss is a shoulder that ispresent in many forms of life but not mammals and it's composed of two glucoseunits and we just don't use it but it's found in lots of foods especiallymushrooms its cool mushroom shoulder and

it's approved food additives availableuss really cheap but when you eat it it's largely metabolized by enzymes inthe intestine to glucose but some of it gets absorbed orally and it's the next13 referencing here is a summary of eight different safety studies on treehalos in this area it's safe for human consumption and then in this area thebottom of slide they've shown that high-dose intravenous tree halos is safein humans as well and that is actually being studied as one of early drugs by about a company toreverse a couple of genetic neurodegenerative disorder so thatpeople are thinking along these lines

and and it is comforting to know that alarge dose of dose of intravenous tree halos is safe they haven't come out withthe efficacy reports from that study for just the safety reports made public soyou know what if you have chronic sensory nerves and chronic centralnervous system infections inflammation insulin bad diet what is therelationship between all these things unfortunately in some folks with orwithout susceptible genetics they will accumulate abnormal proteins and willpresent in the following three groups of neurodegenerative illness in thosegroups or alzheimer's where the culprit protein as beta amyloid and then theyhave this new clean up with these which

the protein alpha-synuclein and thoseconsist of parkinson's dementia with lewy body dementia and multiple systematrophy and then you have spectrum disease of a lesson frontal temporallobe dementia which are actually related and that's only recently been discoveredand that protein is tdp 43 so-called the tdp 43 protein opportunities and in thenext slide we talk about the als in front of temporal lobe dementia spectrumwith involving tdp 43 shows that every two proteins and coating history or keyfeature of the pathology of all the major neurodegenerative diseases a lesswas brought into this fall quite recently with the discovery of tdp 43inclusions in nearly all ellis cases and

at this discovery was fueled by therecognition of the clinical overlap between a low and frontotemporal lobardegeneration where tdp 43 inclusions were first identified so the next study referenced here they did not upsetsixty-four patients with frontal temporal lobe dementia with or withoutmotor neurone disease and als patients with or without cognitive impairment andfound this tdp 43 and everybody so this seems to be the predominant playerthat's involved in a las and frontotemporal dementia so withalzheimer's there have been links to infection and inflammation for very longtime presenting for studies on this

slide the first just says that noinformation plays a critical role in alzheimer's second is alan macdonaldstudies dating from back to 1987 where he was able to culture brillianceparakeets from the autopsy your brain tissue from patients with alzheimer's inthe next 30 talk about amyloid metabolism being altered with somenervous system lyme disease is the fourth study here and i quote sospirochetes contain amyloid orogenic proteins so their proteins on thesurface asperities that induce the production of amyloid our bodies andwith parkinson's they also show that sensory nerves information is animportant contributor to the

pathogenesis of the disease again thisfor studies on this slide and they've demonstrated parkinsonism in brucellosisthe only difference in parkinsonism in parkinson's is when they find out thecause of parkinsonism know what the cause of parkinson's and callparkinsonism so it's a parkinsonism due to line partners and due to brucellosisto bartonella and represent three different studies where they foundparkinsonism due to brucellosis part no landline so we know that multipleinfections can cause parkinsonism and if those infections do not diagnose thosepeople be defaulted to a parkinson's diagnosis and it's the same the nextslide looks at a less and motor neurone

disease and general information is acritical part of a less and there was a study dating back from 1990 with it tookpeople with head typical ellis none of them had typical i'm and demonstratedthat the antibody test for lyme disease were five times more common in a listgroup and the control group and they showed that a subset respondedantibiotic therapy and then next study is line was initially diagnosed as aless and to respond to antibiotics the person go up earlier in the day diagnosis was changed and there havealso demonstrated more than urine disease brucellosis is the next slide ona team so because of the suspicion of

infection in these illnesses they havedone a few very limited but a few randomized placebo-controlled trials inthe general disorders they did one where doxycycline rifampin versus placebo forthree months and they showed less decline in the treatment arm in a lesspatience as you may also restrictions and that was published in 2004 but thenwhen they repeated the study in 2013 for 12 months there was no significantbenefits the treatment arm so you getting kind of small benefits ofcontradictory results and they've done studies of minnesota won for multiplesystem atrophy parkinson's type with a randomized placebo-controlled trial andthey did show less inflammation in the

brain but there was no significantdifference in the rate of functional decline in their study also on thisslide here middle cyclone vs created responsiblefor early parkinson's and didn't show any change in the need for storingsymptomatic treatment so again not much of a benefit and leaders study of a less with arandomized ceftriaxone for 20 weeks and there is a large study is 30 to 40patients and there was no significant difference in the rate of functionaldecline so this is my slide where i reference the big bang theory gotamyloid beta amyloid alpha-synuclein

4343 now what is you may be feelingfrustrated and hopeless and let it says what would you be if you're attached tothat object by an inclined plane wrapped around and access and sheldon says screwand i would say that that's an appropriate feeling you know you mayfeel screwed but screws to be made to be unscrewed and i think the weather's likethis hope and for me it all came back to autophagy which is like rosetta stoneand now here on this line of reasoning multiple studies that autophagy and ijust misfolded proteins across a range of neurodegenerative illnesses and mightobject and just damaged mitochondria so the next slides do a lot of animalstudies rapamycin to see if they can

show benefits also with models andhere's to slide showing that reverses alzheimer's in the animal models ofalzheimer's are uppermost and rescues the deficits the animals behave normallyand here's a couple more slide same thing and all models for alzheimer'sshow the rapamycin reverses the changes in the first study to establish changeshad no effects and only work to prevent the changes in the second study has toreverse the changes such that the alzheimer's mice behaved normally afteroptimizing treatment they couldn't tell the difference between the ones thatwere also amazon student but when you look at large-scale studies ofalzheimer's you find that it's very low

in rural india among the lowest in theworld and they've linked it to the consumption of curry spice ankaracurcumin turmeric curcumin is a key component and when they give harrycurcumin basically to the alzheimer's mouse model it reduces the plaque burdenby 43 to 50% which is huge but only works for a low dose low-dose discriminate high-dose sothere's so many variables here is like a twisted web that someone had kind ofmade it's impossible to follow variables but you find us a lot throughout a lotof my slides here we'll talk about you know those relationships with advocacyand why would a high dose not work with

a low dose of work i mean to cubansadaptogen its kind of has a mix of in the us and process of equalities andoxidation is not great it's bad for us and sometimes but and outsourced don'twork well that appear in the us since you need a mix and this is very hard tofind this kind of balance between them so because of that the limited studiesare you human in you know randomized controlled trialseven case reports they're hard to rely on presenting two cases two studies hereone is only 34 patients randomized to one gram for gram 0 grams of turmericfor six months they found no changes in the mini-mental status exam scores andthen the next study is a case series of

three patients to charm for one year ata lower dose and they'll get benefits so one of the three of them had afive-point increase in many mental status exam scores you say is thatsignificant five points as shit as three points is considered significant andthat's what the aricept drugs usually do three points and two out of three peoplescore solo this goes up to thirty in the head 120 and 121 is a very very severe dementia patientswho didn't recognize their family and couldn't participate in any aspect ofnormal life and they began to recognize the family in the case of course theywere laughing at the television shows

with their family and they weren'trunning out of the house and you know it's just normal but something that'svery very safe like turmeric was hoping so when you say ok let's look at largernumbers how many times have i done big studies is very very few you will findvery few studies that are of significant power on medications that are cheap andreadily available and i'm sorry say that's the case most the time because isnot big money to be made by pharmaceutical companies but in thisstudy they did look at 2010 none demented participants and compared thefolks who never or rarely consumed curry with the people who did consumed koreaon you know he was there occasionally

are frequently found very statisticallysignificant changes in many mental status exam scores even in non dementednormal people what's normal in you know is there such a thing as normal so thefaux suede curry did better and then we look at green tea extract an exercise andthey've shown that both green tea extract and exercise separately and incombination this is an animal study of the mouse model of alzheimer's help their cognitive performance ontheir maize testing and everything else and it showed that they had lower levelsof beta-amyloid in a trance and again

cheap readily available substanceswithout a ton of data behind them and therefore look at carbamazepine that'sthe seizure medicine that i reference list after three months achieved withcarbamazepine in alzheimer's mouse model i'm quoting now we demonstrated that thespatial learning and memory deficits of these mice or significantly alleviatedwe also documented that the cerebral amyloid plaque burden in these mice orsignificantly reduced so i struck by the fact i started looking into this thatall these are top agenda sirs show benefits across many demands right nowi'm just looking at also members if we went through all the diseases and allthe different axis of how you know topic

changes to help people would be veryvery long talk but just when i tell you i have gone through them and for hoursand hours and hours in the day is like holy crapola crippled crab so here i amtalking about alzheimer's entry halos and there's a couple of studies on thisslide so sure that the effects of tree halos in the alzheimer's mouse modelthat impaired cognitive and learning ability was improved and then again thatbeta amyloid deposits in the hippocampus which is part of the brain was reduced and the next study from 2013 they saidthat neurons tree halos induced autophagy reduced tell aggregation and alimited cytotoxicity means that

eliminated the crisis it's a nerve cellsit also inhibited the towel from congregating in video normally directfashion and the authors conclusions and quoting treeless may be a good candidatefor developing therapeutic strategies for alzheimer's and other toweropportunities they know evaluated also members here with vitamin d vitamin d inthis 34 studies on this page and vitamin d stimulates the clearance of amyloidplaques by macrophages and reduces amyloid toxicity and cortical neuronsand they've shown again and nerve culture studies their vitamin d iseffective on its own and additively with curcumin oils which are like turmericcurcumin tape things to enhance the

clearance of beta-amyloid and vitamin denhances the clearance of beta-amyloid across the blood brain barrier in mousemodel and reduces amyloid plaques to study their research and it is easy andcheap one we do study with alzheimer's limited data so vitamin d plus momentumin witch's room and its type of medicine used for memory impairment that is adifferent mechanism of action from harris up and that was associated withan improvement in many mental status exam scores of six months but here theyshowed that single asian women teen or vitamin d was not associated withimprovement and then they did a randomized controlled trial of high-dosevitamin d for eight weeks

and there was no benefit but this studyin my opinion is flawed and number one of only three weeks number to these thehigh-dose again there's a dose-response curve with many of these agents and thenext few sides go over the dose-response curves with vitamin d is completely nonlinear u-shape response across everything and the first study i'llquote here that participants with both low and high vitamin d concentrationslow meeting before below 25 and high meaning above seventy-five aged 45 yearsold performed significantly worse onimmediate word recall so take home message that low vitamin d will impaircognition and high vitamin d mission and

the next 30 the show the toddlers withthe lowest quintile of cord blood vitamin d exhibited deficits andtoddlers with the highest quintile of cord blood vitamin d also hadsignificant developmental deficits and larger prospective observational studiesthey also find a u-shaped association with vitamin d and cardiovascular health it shows up and so many demands ofhealth it's kind of ridiculous the next there are three studies on the slide thenext one shows that kids 6 to 12 was quoting from the article here a u-shaped association with vitamin dlevels and respiratory health

and they've even looked at it withcancer as well and showed that both low and high vitamin d is associated withincreased risk of prostate cancer and they did a summary from 10 prospectivestudies where they included 2227 lung cancer events and found i'm quoting andevidence of a nonlinear relationship between vitamin d in the risk of lungcancer with the greatest reduction in risk nearly 53 53 is a very nice levelof vitamin d to be a general population on so many levels so so switch away fromalzheimer's for a moment and so we look at the new clean up it is okay socynically nobody's that those three major classes again parkinson's lewybody dementia multiple system atrophy

and so they're saying here in this studybecause rapamycin simulates autophagy and increases the clearance ofalpha-synuclein that it merits consideration as a potential therapeuticeffect is therapeutic for parkinson's this is the theory's going back since2003 and then in 2015 that showed that rapamycin restores mitochondrialdysfunction and gets rid of the near the general features in a rodent model ofparkinson's and other mouse models of parkinson's they show the rapamycinquoting now is able to prevent the loss of the th positive and and i put inprison serious play a few goes that he is positive means tyrosine hydroxylasepositive and that's the end zone that

produce dopamine and dopamine you knowgoes down in parkinson's so it prevents the loss of the th positive neurons andameliorates the loss of gopac which is a dopamine metabolites and then furthercynically apathy mouse models rapamycin improve motor function reduces theaccumulation of those abnormal secondary system proteins and fixes the injury tothe brain and tree halos in parkinson's mouse models just oral tree halos mostof it is getting most of which is getting converted to glucose attenuatesproblems were motor function of the generation of parts of the brain thatmake dopamine and accumulation of alpha-synuclein which is again theadmiral protein for parkinson's and they

showed that in the test tube that eventreat hair loss at very low concentrations dis aggregatesalpha-synuclein proto fibriles and fireballs into smaller groups or evenrandom quote structures which is how it should be and that a high concentrationsit slows down the transition into beta sheets and completely prevents formationof mature fibriles so to translate all of that this widely available safe sugareven when consumed orally when most of its metabolized into glucose and mousemodi's mouse models is is very compelling and they've shown thesame thing for a lawyer but it is so says your coding and lewy body diseasewhich includes parkinson's disease and

dementia with lewy bodies inside herbalalpha-synuclein is widely deposited in the presynaptic terminals as well as inthe neuronal cytoplasm indistinct brain regions and laurel tree halos increasethe level of phagosome or protein c three which means that increasedautophagy which again is a sale clearance mechanism and decrease thelevels of insoluble alpha-synuclein so that his bed proteins in the most andthen in this model of cynical and apathetic the four different autopsyinduces and they all prevented parkinson's so they used a neurotoxinthose known to induce parkinson's called rotenone and they show the rapamycinlithium valproic acid and carbamazepine

which all induce autophagy protected theneurons and stop the development of parkinson's so here the authors aresaying that our results suggest that while protests and carbamazepine themost commonly used in the epilepsy mood stabilizing medications with low riskand easy administration may be potential therapeutics for parkinson's the onlyreason that include rapamycin and lithium and they're in their conclusionsof the study is already concluded that and it was part of the discussioninitially so for the new clean up a fee and parkinson's and vitamin d they'vedone good so i studies on this actually and they've shown they looked at threethousand one hundred and seventy three

men and women aged 50 to 79 without parkinson's andfollowed them and show that low vitamin d was a risk for developing parkinson'sand vitamin d in another study vitamin d deficiency was a source of parkinson'sand vitamin d supplements as well as working outside which makes you know youmake your own vitamin d in sunshine was associated with a reduced risk ofparkinson's but then they did a study that was well designed where they took arandomized controlled trial of vitamin d at lodos for 12 months and the russianbeneficial effects two subgroups of parkinson's patient's that supposed tothe high-dose short-term study with

alzheimer's or may not have been signedso so well so the next slide talks about the tdp 43 als and frontal temporal lobedementia models and we look at a few different animal models look at firstzebrafish which i know sounds crazy lookin zebrafish but you know we shareeighty percent of the genes was a profession to do these things all thetime and they show the rapamycin is beneficial data clears out the tdp 43and helps the zebrafish with alzheimer's do better and then they did atp 43 modelfor fruit flies same thing rapamycin was hopeful that helped the fruit flies witha less the look that a nerve culture model for a less show thatautophagy in general

enhances the tdp 43 turnover andsurvival of the nerve cells and in frontotemporal dementia model which usestcp 43 as the human protein they showed four different autophagy inducers werebeneficial to both cognitive function and motor dysfunction and they showrapamycin tamoxifen was beneficial knows emptor dependent autophagy inducers andspur madine and carbamazepine were effective in those are emptorindependent they said quoting the authors sharing their conclusionsadministration of these for chemical drugs to six-month-old transgenic micefor one month effectively ameliorates the motor dysfunction and they did astudy of a less patience with lithium

and had 44 patient's where they gavethem either lithium plus reviews all versus really is all by itself is alsothe only drug that they use for a less and it works like this muchunfortunately and they found that the patients lithium they all were aliveafter 15 months follow-up and that disease progression was markedly reducedcompared with the control patients were treated just was really is all by itselfso and also at that time they did a parallel study we looked at mice withthe superoxide dismutase mutation realest which is the first mouse modelfor a less so pttep 43 has taken the place of superoxide dismutase for thesea less mouse models and i'll tell you

why but they look to this older model tostudy was in 2008 and they showed a market neuroprotection associated withmarket increase in autophagy so again really revving up what our 4g isallowing the clearance of admiral proteins andprotection of the nerves the problem with refusal is that ashley impairedautophagy on this slider bars in three studies showing that rules all does dothat so we have to wonder what is the full effect of lithium when it's used inconjunction with really is all so others have followed up on an initial verypromising results show that lithium study and they do follow-up studies toit and they didn't show any benefits

there were no safety concerns thelithium but they didn't show that our help and in all those cases it was usedas an add-on to treatment with real and not just looking buy it so to compare toresolve so there are people who are just called a robust are writing articleslike when is enough is enough when we get all those lithium clerk for airlessand then the very next year after those studies were written they came out thisstudy showing that they had taken the spinal fluid from als patients to showthat it was toxic to the motor cortex nerve cells and if you includedmemantine minocycline or lithium any of those three agents becameneuroprotective and it didn't damage the

motor cortex neurons created really isall to the mix it stop those chemicals from protecting the motor cortex neuronsand the royals all was antagonistic of any protective effect in the test two sothe authors conclusions here or the inclusion of a group of patients free aroyal treatment may be mandatory in future clinical trials performed a lesspatient's with novel neuroprotective compounds but those for i haven't seenany any studies on its own they did do a study however with lithiumand valproic acid i'll program and they show that when you do that coach treatment it significantlyincreased survival and the p value there

was was a point zero one six and they showthat the biochemical markers of inflammation normal clothes withtreatment and i'm quoting it says this treatment also exerted neuroprotectionin our patients because all three markers the reparative remarked isreached levels that were not statistically were not significantlydifferent from the match samples of healthy donors and there was a studylike i said of lithium and valproate together unfortunately those a high dose study inthis study after a year and a half or so

the participants got a lot of sideeffects from the lithium you know it's not completely benign drugso in this slide talks about the superoxide dismutase mutation with ellismouse model and it turns out there 1.5 to 2 percent of als patients have thismutation superoxide dismutase and the mouse model that have the heads ofsuperoxide dismutase rapamycin ischemic disease worse so toward dependentautophagy may be dangerous to people who have the superoxide dismutase mutationthey also showed and to back my theory up they also showed a separate studythat caloric restriction in a mouse model

superoxide dismutase petition also makespls worsen the most and whereas tree halos again with the saudi mutation inthe mouse model of a lowes improves as the disease so it's not that a child topedges the culprit it's here the mechanism whether it's emptor drivenwithout 4g ram tour independent autophagy say why i mean these arecomplicated questions but i think the answer lies in the fact that with mtorthere's an oxidative signal as part of it and people with a super i said thismutation or so people animals with the superoxide dismutase mutation can handlethe extra oxidative stress member eric said autophagy of the souls too far gone

yes sir mostly as a survival enhancementtechnique but it was too far gone it'll push the cell to cell death and i thinkthat's how it's making the is worse in this light it's not really germane to to the other diseases were talking aboutby include a slide on muscular dystrophy mail small rapamycin because here isjust purely genetic thing and they show the rapamycin had a bit of effects youknow it decreased mtor activity the diaphragm it had no effect on some ofthe other muscles but i wanted that included next studied in a few yearslater that they showed rapamycin loaded nanoparticles improved skeletal musclestrength in cardiac contractility

whereas regular rapamycin failed so ialways have an interest improved delivery methods like lip assumes thingslike this and i know that tree halos it comes to mind is not absorbed from thejudge charge very well but that could very easily be made love paso muy buenacompounding pharmacy so this is a study of normal age-related cognitive declinein mice showed that the mice treated with rapamycin since the age of twomonths on had improved learning and memory as compared to the mice or notthey said in this study that the mice that rapamycin wants to develop normalage depending co declined did not reverse their cognitive deficits but thenext study it's almost very reminiscent

of the alzheimer studies with withrapamycin where one shows that it's good to prevent that once they're allreverses the next one shoulder versus a but that's what makes a ballgameeverybody's different results but this next area says that rapamycin improvecognition and young adult mice and block the normal cognitive decline even astory 18 months and that's all for amounts and i did make a note therapamycin treated my said less anxiety and depression at all agesstudied and rapamycin is a very important drug for a lot of reasons butit is the lifespan and health span extensionin mice that is made this study in 2009

what are the ten most interestingstudies voted on some worst of that year turns out and genetically heterogeneousmy streptomycin extended lifespan 9% in males and 14% in females even whentreatment was started later in life so they gave these mice who were theequivalent of about 65 years old in human years rapamycin at a low dose so roughly 12%the doses used for immunosuppression and it made them live much healthier longerlives and when i looked at the dynamics of what it did do it just improvedmultiple age-related conditions and all my such as cardiac dysfunction tendonstiffening cognitive decline and

decreased mobility and they found thatthis life extending property was age dependent that it three times initialdose that was studied the genetically heterogeneous mice lived even longer soi got up to 23% longer in the males and 26% longer in the females you say whatare the women people are living longer than the term as long ago as just thethey think the blood levels of the females are higher and there was areason just how its metabolize but and in the study they showed that thereactually are some similarities but some very key differences between howrapamycin works and how clerk restriction works well spent and eventhough rapamycin is approved here as

immunosuppressive memory so before itdoes the opposite of what does a low dose versus high-dose at these low dosesdoes not immune suppression is not that it fails to be immune suppressing theirsee restores immune function back to normal healthy levels so rapamycin whenit's given in his lower doses it doesn't just make the light the mice live longer better responses toinfluenza vaccination international human study on this with everolimuswhich is a cousin to rapamycin and they showed that lw ministry of low-doseeverolimus had restored immune function as measured by better responses to fluvaccines and then in this kind of

summary oracle 2013 as rapamycin rapalogs which again in those drugs derived from robert mason i'll just quoted saysit has recently become clear that rapamycin and other apple dogs for whicha long time have been viewed and used in the clinic is pure immunosuppressantscan mediate robust immunostimulatory functions but we have to remember thatat high doses they are immune suppressants and that they are even though they're approved for youknow cancer even have really missin terms are lemus if the dough society ofit will suppress the immune system so here i list want to 3167 studies showingthat rapamycin prevents introduces

cancers and multiple studies ofgenetically cancer prone nice and very effectively prevents the occurrence ofcancers so led a group of authors to say well as i'm really an age in it theaging effect was just an anticancer effect so this is a study those writtenby forty authors and they said they evaluate aging traits and young and oldmice and it said that rapamycin improved pretty much all aging trades but it isso in young mice as well as old mayest therefore because it improved the agingtraits in young mice we're not going to believe that is an anti aging kind ofintervention and the authors concluded that the lifespan extension was fromcancer prevention because it remarkably

reduce the amount of cancers in the mostthe problem with this is several fold number one their version of young mice transmittedtranslated to 46 years old in human years and i don't feel the same way ifelt when i was 21 and i think that that's one and the other is that to saythat it's just from a reduction of cancers its true cancer is a commoncause of death in mice the rapamycin extends the life of houston fruit floesneither of which died from cancer so this study was written by forty peopleit was a very power powerful study very data rich and i just think they justmissed the more but you know what even

if they're right if they're correctwhich i don't believe they are but if they are there's a pill that effectivelyprevents cancer hello sign me up i mean they will do something for baldness so in terms of tetracyclines theyevaluated with it within aging domains as well the show the middle stanza lifeor fruit floes and that doxycycline extends the life of earthworms whichdoesn't sound like they'd be related in any way to us but that very samemetabolic change that made the earthworms live longer they say isevolutionarily conserved in humans we have the same basic enzyme system so gofigure i had read a study and baby

rabbits along time ago the tetracyclinethroughout the life of the rabbit had was associate with an unknown reason itcouldn't figure out why the rabbit loves so much longer with tetracycline icannot find a study of vitamin d naging they show that with earthworms thatexposure to vitamin d increase the lifespan by 39% p value was 2001 theyshowed in mice the same u-shaped curve too much or too little vitamin d experience premature aging prematureaging and tape today bezel in the same axis you know mutant mice with too much vitamin d thatexperience premature aging when they

knock out the vitamin d also knocks outthe premature aging features to go stick to that 53 is a magic number halos an aging they showed thattreatment with tree halos in earthworms extended the mean lifespan by over 30%with no side effects and even when they started tree halos when the orearthworms are really old extended their remaining lifespan by 60% so lithium andaging i was like studies that have a large groups of people that get elegiesthirties and in this 1 i'm just gonna quote here japanese study they said in humans wefind here an inverse correlation between

drinking water lithium concentrationsand all-cause mortality in eighteen neighboring japanese municipalities witha total of 1.2 1.2 plus million people and a very low key value point 003 andbasically lithium in the water low levels were so serious increaselifespan and decreases in all-cause mortality andthey did a parallel study where they expose earthworms again it really isauthorized to don't live very long and believe it or not they have so manyshared mechanisms to humans and they said here according to insist that wefind that exposure to comparably low concentrations of lithium chlorideextends lifespan of these reforms and so

my summary of conclusions is that mtorthis million target of rapamycin these enzyme systems are central to aging andtherefore age-related conditions the neurodegenerative diseases in particularor a set of illnesses when you go to the neurologist they basically give you noteno nothing no hope i mean nothing to give false hope and there were accusedof being an optimist but my mom says where there's life there's hope and keeptrying and it's true the neurologist will give aricept and namenda things and hit a sacado whatnot butthere's nothing they can give to interfere with the process noting thatmakes a change in the natural course of

the illness i don't know that anythingwe talked about will reward it is my hope though i give us talk for bothaltruistic and selfish reasons and i i hope that that the stock ones up asviewed by somebody that has the interest of capacitative other parts of the showresearch in the field but it seems clear from a number of studies that inhibitionof mtor may slow or halt these processes and that induction of autophagy bothemptor dependent and independent may be beneficial but there may be specificrisks if infections like bartonella coxiella brucella and we don't know whathappens with one because i haven't done any studies we don't know if we'll berisky to induce autophagy in the subset

of patients certainly in the absence ofany business owners rescue them with antibiotics for all we know and do someat alpha chi accommodation in basra hope clearly information we just don't knowcause nose during the research so were you in research is needed and includestalk thank you