Lifespan.io Now Crowdfunding a Short Human Study of the Effects of Rapamycin on Biomarkers of Aging
Today's question: are we at the point at which it make sense to run a great many short human trials of potential interventions to slow or reverse aging? The answer tends to be quite conditional on the details. If the trials cost little, meaning that they can run for a year or less, and involve low-cost assays conducted before and after, then exploration sounds more viable. If the potential interventions have sizable, reliable effects in mice, then that makes it more attractive to devote funding to the project. Testing senolytics such as the dasatinib and quercetin combination in old human volunteers, with assessments of epigenetic age and blood markers of inflammation and disease, for example. There is no reason to leave that entirely to the Mayo Clinic, as they certainly won't be covering all of the bases any time soon. The wheels of the formal clinical trial system turn very slowly.
Use of the immunosuppressant drug rapamycin is a reliable way to slow aging in mice, with data that is far better than that for metformin. It triggers some of the mTOR related pathways that are involved in the calorie restriction response. The outcomes in mice are not as impressive as those for senolytics, but at some cost, testing rapamycin against potential biomarkers of aging makes sense. Biomarkers based on blood samples are becoming quite cheap. Volunteer organizations can run viable, useful studies of a few hundred volunteers at a tiny fraction of the millions of dollars it would cost a major institution to conduct the same work. And so Lifespan.io is doing just that. They have crushed down the cost of a rapamycin trial of 200 people or so, and are looking to raise $75,000 to perform the minimum version of that trial. I encourage you to take a look at this project: we'll be seeing a lot more of this sort of thing, as the community grows and more people ask why there is a lack of human data for existing approaches and biomarkers.
Pearl: Participatory Evaluation of Aging with Rapamycin for Longevity
The medicine rapamycin has been shown to extend the healthspan of all organisms it has been tested on - mice, warms, yeast - for decades, and yet to date there has been no trial to sufficiently demonstrate safety and proper dosing for this purpose in humans. It is now time for this to change. With your help, we will be conducting a large clinical trial named Participatory Evaluation (of) Aging (with) Rapamycin (for) Longevity Study, or PEARL, to find out. This will be the first study to see if Rapamycin works as well in humans as it does in mice (for longevity).
Rapamycin works through the mTOR signaling pathway, one of the master regulators of cell metabolism and a key controller of autophagy (recycling in cells). Basically, it tells our cells to switch from growth to repair, and to clean out all the garbage. Not only that, but the quality of the proteins our cells produce increases, which means that there is less garbage in the first place. What all this amounts to is improved health and lengthened life for worms, flies and mice - now it's our turn!
The PEARL trial will follow up to 200 participants over 12 months testing four different rapamycin dosing regimens. It will be double-blind, randomized, placebo-controlled and registered with clinicaltrials.gov. The principal investigator is Dr. James P Watson at UCLA, who was also a PI for the famous TRIIM trial. To ensure safety the participants' blood will be regularly monitored and side effects noted.
A battery of tests and measurements will be taken, both after 6 and 12 months. These will include autonomic health tests, blood tests, body composition tests, fecal microbiome testing, immune and inflammation health tests, methylation age clock testing and skeletal muscle tests. With your help we will find out if and how well rapamycin works to combat human aging. And, armed with a positive result, we will finally be able to help slow down onset of age related damage for you and those who you love and care about.
I cannot find the original information so i will quote this blog: https://www.nextbigfuture.com/2021/05/lifespan-io-starting-rapamycin-antiaging-human-trials.html
Hey there! Just a 2 cents.
Rapamycin does not increase lifespan like does Calorie Restriction (CR), that is because acts on many targets of which are related to epigenome.
I now have a nearly full Order picture of aging:
Global Heterochromatin/Histones Loss -> Nuclear Envelope changes -> Transcription De-Repression (Activation) -> Epigenetic De-Methylation -> Gene Activation/Expression -> Accelerated DNA damage/SAFH/y-H2AX/DSBs/SSBs/Telomere Foci/Subtelomere demethylation/Deleterious mito and nuclear epiMutations -> Mitochondrial ROS increase/Mitochondrial DNA and ETC lesions/deletions -> Further Damage -> Epigenetic Drifting/Landscape change -> Accelerated Telomere shortening/Instability/Uncapping -> Senescence
There is a cross-talk between the Epigenetick clock (epigenome/methylome), the Transcriptome, the Spliceosome, the chromosomal Telomere, the Heterochromatin/chromosome
The Nuclear Chromosome Arrangement is the highest order, and decider, it is dictated by the Histone H3 and H4 (several histones are expressive or repressive), but these ones are important for cell life to proceed, the epiclock is affected by the chromatin levels and arragnement, Histone need to be Trimethylated to maintain a state of repression/gene silencing (same as methylation), thus 'compaction of chromosome/coiling', because when they 'loosen' (with age), that is when they demethylate, uncoil, unpack, and become loose/untight -> Gene Activation/Expression.
Gene Silencing -> Tight/Coupled/Compact Chromosome -> No proceeding of the cascade.
HGPS (Hutchinson Gilford Progeria Syndrome) IS after all a TRUE Aging - THE SAME - as ours (in terms of 'end result' -> death 'from aging'), but, only much much more accelerated.
It's normal human aging - 'in Fast-Forward'.
Global Heterochromatin Loss is Highly Accelerated in HGPS fibroblast, same thing in Werner Syndrome fibroblast - but lessened in speed; Likewise - for people - with immunosenescence; for example, people struck with HIVAIDS/viral disease, had severe reduction in T-Cells/NK-cells and immunity, basically they are experiencing immunosenescence 'in accelerated'; so much so, that someone 25 years old with the disease showed leukocytes whiteblood cell telomere as low as someone 80-90 years old. This is true aging, in accelerated. Werner Syndrome lack Werner Helicase as such suffer accelerated aging, they live 50-60 years, they are a 'mild form' of progeria (in between) vs HGPS (15 years lifespan).
HGPS people live 15 years and at the end show 'old age person' visual apperance - in a teenager size child body (very 'premature aging'); they have Severe DNA damage everywhere, shortened telomeres, lesions everyhwere, stain for Beta-galactosidase (B-Gal), Senescent everywhere, accumulate 'progerin' and wild-type LAMINa (but have actual reduction of *normal* lamin a/c levels that is needed to maintain correct chromosome structure), their chromosomes are loosened and disassembled; they have loss of histone and heterochromatin - Much - faster:
''Depleted nuclear Lamin A/C Frequency %:
- Healthy 9 years old donor = 5%
- Healthy 96 years old donor = 80%
- HGPS 15 years old donor = 80%
''
People that were 96 years old, had EXACT same cell arrangement, as those from HGPS.
''However, a striking change in lamin A/C localization was detected in cells from *old donors* (Fig. 3, C to E). Whereas in cells from young individuals a substantial fraction of lamin A/C was present throughout the nucleoplasm, this fraction was almost completely absent in cells from old donors, and the vast majority of lamin A accumulated at the nuclear rim (Fig. 3, C and D). This distribution was similar to that in HGPS cells, where the presence of the mutant lamin A protein leads to the accumulation of wild-type lamin A at the nuclear periphery (Fig. 3C) (6). Importantly, lack of nucleoplasmic lamin A/C strongly correlated with reduced amounts of Tri-Me-K9H3 and HP1 at the single-cell level (Fig.3D).Thus, *****as in HGPS patients, cells from [healthy] old individuals express the Δ150 LMNA mRNA, and lamin A is **aberrantly localized** in the cell nucleus****.''
Global Chromatin Loss/Histone Loss -> Epigenome Global Demethylation -> Epigenetic Drifting/Unstability -> Progerin Formation/lamin depletion -> Chromosome Loosening/Gene Unsilencing -> DSB/SSB/nDNA damage -> Telomere Shortening Acceleration -> Replicative Senescence
The visual appearance (phenotype) shown in HGPS is the same as people who are aged 100 years old; it's basically, someone 'biologically' 100 years old -> but in a chronologically 15 years old (only) body.
HGPS people lose 500 bp (basepair) telomere DNA nucleotide/year vs 50 for regular healthy humans; they live 15 years while a healthy human can live 122 years. Thus, they age by a rate/speed factor of 10X. 10Times faster aging (prematurely). They also deplete
10-15X times Faster the lamin and accumulate progerin just as fast; thus, it means, they Deplete Heterochromatin and Histones 10-15x times faster than normal long-lived humans.
It's important to undertstand that Normal Healthy People Accumulate Progerin/wild-type lamin and deplete lamin a/c - Very Slowly - over their 100 years of life...while HGPS people accumulate it in 15 years and 'reach the threshold maximum' for it at that age.
Thus, same process, same End-Result; just faster. 10x times faster.
It's like a Mouse vs a Naked Mole Rat (NMR); 3 years vs 30 years; a mouse depletes its chromatin/histone and lamin 10x faster than a NMR; it thus lives 10-times less.
Mouse lose 2000bp/year in telomere rate, while NMR, lose roughly 150-200bp/year, thus, they live 10 times longer than mouse.
IT's also explainable, because Heterochromatin is IN telomeres themselves, and telomeres are IN the Chromosomes, all Inside the cell Nucleus. Likewise for epigenome; it's all in the nuclear domain, because that is what houses the nuclear DNA/Chromosomes. This makes the nuclear surrounding Causal to Aging. Normal Healthy Aging or Progeria/Premature Aging (HGPS/Werner Syndrome/Trisomy21/Down Syndrome)...
In other words, if Chromosome become loose, decondensed, unpacked, DNA uncoiled, and just 'hang' out..like a 'hanging appendage'...that is when Aging Proceeds (during cell mitosis/replication) because of chromosomal dysfunction/misarrangement -> Cell Senescence/Apoptosis.
Tight chromosome -> Waterproof/errorproof/Silence -> Block epiAging/drifting/damage accrual
Loose chromosome -> Waterfilled/errorfilled/Unsilencing/'Noise'-> epiAging/drifting/damage accr.
Just a 2 cents.
PS: What I fear is if we do reach LEV, we may very much suffer Gigantism (after several centuries of growing/developing/aging...kind of like a giant multi-centenarian pine tree measuring 40 feet tall), because bones grows over time.
Bowhead whales and giant sea turtles live 150-211 years and Greenland sharks 400 years...they become big at the end. Real big. Because they had all this time to grow. Plus, the whales are mammals, like us. Quahog bivalves can live 500 years and all very small after centuries growing slowly; but they are the exception and are not mammals like whales. I.e. we grow much more than a clam...
Bone Mineral Density Loss = Death.
Bone Mineral Density Increase/or Retention = Youth.
It is very possible that if a human lives 400 years they will be roughly half the height of a slow growing tri-centenarian Pine Tree, so maybe 7-11 feet tall (just like people struck with gigantism, acroMEGAly (acromegaly from pituitary tumor causing excess HGH); like basketball players or wrestlers measuring 8+ feet tall). If humans Already Reach 8 feet tall (with gigantism/hyperpitiutary hormone (growth hormones) during adolescence) like these people...then yes, we would reach just as high (10+ feet tall) if living centuries and 'growing non-stop' for such a long time (instead of dying at 120 years old). Greenland sharks and bowhead whales reach 15-45 feet long after centuries aging. Galapagos Tortoise are Huge/Massive at 175 years. Check the photos of people over the decades, from 0 all the way 120, there clearly is a 'widening/enlarging' skeleton over the decades (we don't stop 'growing' at 20 years old, body deposits bone mineral over whole life). In the late decades there can be 'height shrinking -> (BMD) Bone Mineral Density loss (in eldery) -> skeletal height loss'. If we live centuries...there is no more BMD loss, thus 'we grow and grow and grow'...like gigantism-struck people. It's not 'terminal'..it's liveable...but of course humans will need to rebuild everything 'bigger' for the such tall humans..if we ever 'non-stop' grow this big over centuries (by LEV). Artificially making BMD loss (to reduce skeletal height) = accelerated aging. Thus, if we ever artificially made aging to 'make us smaller size' by bone loss...we would need to immediately get back on LEV...because we can't stop growing or else die. That has been seen in lobsters...they never stop growing their whole life (become largest size at the end)...and reach 140 years...and then die of some exoskeleton/shell body problem...
@CANanonymity
Regarding the gigantism dangers. We will have centuries to deal with that. Probably by a series of micro-surgeries to trim the overgrowth tissues. Let's cross that bridge when we reach it.
@CANanonymity - if demethylation is such a driver of aging how come demethylation via TETs is indispensable for cellular reprogramming, and also why does Horvath's multi-species clock show that is is actually methylation of various important promoters (not demethylation) that is most important in aging? I do not dispute that spooled out DNA and unwound histones are often a bad thing, but I'm not so sure the order you espouse is the right one. Also, don't forget the telomeres are in contact with the nuclear envelope, so their shortening will have an impact. For me it is a chicken or egg argument whether methylation is impeding stem cell telomerase or stem cell telomere shortening is driving a mal-adaption of stem cells leading to an altered methylation landscape.
PPS:
Hi Cuberat! Thank you for that. Just a 2 cents. Let's hope! When I see gigantism and acromegaly end cause of death, I am left wondering;
Giant people struck with this die - young - of their height, but especially of heart failure...they have a 'gigantic heart' (''Large Heart Syndrome''), for humans, it is incompatible with life...you Can't Be - Too Big....it just does not work. Organs fail when that happens, we are made a 'certain size window' and we can't grow much beyond that - to preserve organ 'function'/life...
when I compare them to Greenland shark or Bowhead whales...which Are Gigantic...and live centuries...then it means it Just Does Not Work - for humans...it works for aquatic whales...not humans...our skeleton body just can't take it...we might be able to 'replace' our heart with an Artificial Heart/Mechanical Heart or Nano-robot controlled-heart or bioprinted pig heart...or something, like just removign our 'enlarging heart' with age...to avoid heart failure later
Enlarged Heart is seen is athletes and gigatism, and also in fibrosis diseases...the Left Ventricular Hypertrophy Syndrome (of the heart), ventricular hypertrophy shows oxidative stress inside the heart to cardiomyocytes, it's basically aging/fibrosis causing this enlarging heart and then it stops being compatible with body/organ(ismal) function/compatibility (because too big).
Perhaps, a large heart may be compatible with centuries lifespan - because it IS compatible in these whales....and they are mammals like us...so it is possible that Unlike gigantism from excess hormones, 'normal gigantism over the centuries' could be possible...but I am not sure because Centenarians are Bigger and die..so it could not be compatible..too big. Of course, if your body is 20 years old and you are alive 300 years so far...you would be a Giant..and your body is Young...Maybe it could work (like...a Giant Bowheadwhale verterbrate mammal/greenland shark) and the heart could 'accept' such growth (like it does in these whales) and 'adapt' over time...not with Fulgurant Growth over little time (such as Acromegaly or Gigantism in basketball players/wrestlers...people with Hyperpituitary HGH)
The Bowhead whales Heart is Gigantic at its adult size...it is the size a Car/or huge engine of a plane. and pumps blood in the entire 50feet vasculature of the whale. Humans can 'fit' inside its heart...that big it is. The world's biggest Heart is the BlueWhale's heart, it is so big and powerful; it's probably the single most powerful pump. Blue whales don't live as long at all as bowhead whales...so it (large heart) works in some..and doesn't work in others....
Maybe in humans, it just too big/can't work/incompatible with function in our body...we would then need an artificial 'small' mechanical/genetic/organoid heart...that pumps automatically.
Maybe if we shed/microcut the tissues as you said, it might be enought to counter excess growth of tissue/bone with age. That is solid possiblity/solution.
Hi Mark! Thank you for that. Just a 2 cents.
That is a good question....from what I gathered epigenetic reprogramming requires 'loosening' of the chromodomain, to 'access' it sort of..and then Do the reprogramming...it cannot work if the epigenome is 'refractory'...this has bee shown in Naked Mole Rats..their genome is Tight-Tight...and refractory and is why they are 'negligeably senescent'; they just preserve very tight/coupled chromosome/epidomain - so much so- that it is very hard to do reprogramming in their cells. This shows that epigenome loosening and demethylation is important to 'access it' and 'make the reversal happen' (epireprogrammin). Our cells, like those of Naked Mole Rats, are more refractory and this is a reason why we live this long - because of Strong/Tight epigenome that does not 'loosen'....in essence, we need to 'untie (like shoe laces)/unknot' the epigenome and then we can 'erase it' and return it to its configuration when young (its land peak and valleys are 'inversed' and thus back to age 0 configuration). Then, you have to ReTighten it and thus 'close the shoe lace/make buckle/tighten shoe', it's interesting that Demethylation of it is important to reprogram it; I liken it to untying your shoes to get in them..and then retying them, once in them. It's ingenious, it's meant to Prevent 'epidysfunction'...a protective mechanism to insure chromosomal/epigenomic stability; the minute you 'open it'...like a treasure chest..that's it..now it's 'Vulnerable' and anyone can 'mess with it'..it'S a safeguard mechanism this 'refractory' capability of an epigenome to be reprogrammed. 'Basically, 'god' (superior being or whatever made us at the very start) did not want us to reprogramm our cells..that much seems clear, it was not part of the evolution plan. It is Compromising to 'open up' the genome...it's like a bank chest..it's meant to stay closed (never open willy-nilly by any/one stranger) and you can't access its content/its private for security/privacy reasons.
Naked Mole Rat Cells Have a Stable Epigenome that Resists iPSC Reprogramming
1. https://pubmed.ncbi.nlm.nih.gov/29107597/
PPS: Horvath's clock showing methylation being important to aging is actually showing you that certain CpG are important to aging, but that with age, there is Hypermethylation in specific CpG...while there is Global Demethylation/loss of methylation in histone methylation (off CpG), thus it means that there is a 're-arrangment' of what is methylated and what is not..so that specific areas become hypermethylated (mainly ones relating to Cancer/inflammation) with age, while others, such as Histone/heterochromatin preservation become loose/lost/demethylated or hyperacetylated. In other words, it is as if, the epigenomic land becomes more and more into activating cancer/onco genes with age and inflammatory genes; while anti-inflammatory ones and other histone ones (like SIR/SIRTuins, which H3 activates, sirts are histone related), become lost/deactivated...this methylation will mean that the DNA genes are 'read/expressed' and that is when problems happen; Gene Unsilencing -> Program following its course. Gene Silencing -> Methylation of Histone/Chromatin retention (HP1/Heterochromatin Protein 1) -> DNA reading silence. This was shown in children that ahve much more 'Gene Silencing' than old people... old people are a continuous 'mutation acquiry/program unfolding'...there is so much stuff/and genetic 'Activation' that in the end this causes 'error acquiry'...by this loss of 'silence' in the genome. The Genome itself becomes unstable until it is incompatible with continued cell life -> senescence/apoptosis/cell death. Thus, to end, it's as if we are getting 'wrong methylation' with age...that we don't want...but it happens, there is a shift in 'where' there is methylation and this becomes deleterious with age.
Yes, telomeres are connected to nuclear envelop...and it is why they are consequential to aging...cells that were epireprogrammed of mouse showed reversal of Horvath's epiclock...but they did not see much or no changes to the telomere length....that had me very worried.
If I remember iPSCs reprogramming Had telomere length increase After reprogramming..but that was Complete Reprogramming..not Partial programming to preserve 'cell identity' and avoid differentiation (back to Stem Cell state from aged cell, losing its cell signature)..that's what dangerous waht reproamming you may Erase the 'cell adult identity' to become a youthlike stem cell...and that even erases the 'memory/identity' of the cell -> become pluripotent stem cell again. In other words, De-differentiate -back - to an Undifferentiated Stem Cell. That is Erasure of cell identity...it is problem, because we don't want to Erase Completely an Adult...we just want to reverse to a 'young enough' age....not go back to age 0 neither..
Partial Reprogramming was the solution, they use YAmanaka Factors for 13 days....and have to Stop the exposure/remove the factors at that time...this make just enough reprogramming but does not make Full Reprogramming, only Partial Reproamming; the cell retains its identity and the Clock is Also reversed (they said about 30 years reduction in Horvath DNA Methyl epiclock age),
Full Reprogramming = Telomere Elongation/Loss of Cell Identity/Undifferentiated again/Pluripotency again;
Partial Reprogramming = Not Enough Time/No Telomere Elongation/Cell Identity kept/differentiated...
I am guessing that telomerase just does not have 'enough' time to make telomere elongation with partial reprogramming, or ALT (Alternate Lenghtening of Telomeres) just doesn't happen, because too dangerous (telomere fusion/recombination), the epigenome unallows it,
What's interesting is that longer than 2 weeks and the reprogramming is Weaker...so the 'sweet spot' is 2 weeks ....to obtain partial reprogramming..that's great...but telomere 'unchanged size' problem is still there after partial reprogramming. If the telomeres are Already Tall..they don'T need to be lenghtened...but if they Are Small..tehy Would Need to be lengthened...except it does not happen in partial reprogramming.
Yes, I understand that chicken&egg dilemma....Methylation itself Impedes Telomerase, when DNMT's (DNA Methyl Transferase/methyl donating) increase there is a reduction in telomerase;
an 'open' unmethylated telomere structure allows Telomerase Access to Legnthen it.
Mouse that have DNMT KO have hyper long-er telomeres, this is demonstration that methylation is Negative Telomerase protection mechanism, it's meant to safeguard telomere structure...and when it stops - telomerase has now 'access' to it and can increase size (it's why mouse have much longer telomeres when methylation is inhibited using a methylation inhibitor such as
5-azacytidine (5-Aza) or 5-hydroxymethylcytosine (5-hmC). These Block methylation and Demethylate the epigenome - and - telomeres too (subtelomeres become demethylated due to them).
But, which comes first?...stem cell telomere shortening Definitely impacts the rest, because this means that tissue renewal will be hampered as the stem cell age (acquire short telomeres),
Methylation Impedes Stem Cell Telomerase...yes. As something First..before the stem cell's problem of telomere shrinking (due to no telomerase access to their telomeres).
Methylation -> Block Telomerase -> Stem Cell Problem/Shortening Telomeres -> No Tissue REnewal -> Aging.
2. https://en.wikipedia.org/wiki/CpG_site
Probably the most interesting thing is that they are running a 200 person stage 1 clinical trial for only a bit more than 75k.
However this is with an already FDA approved drug, I cannot imagine that getting a new intervention into a stage one trial could be done so cheaply unfortunately.
Although they could still carry out a trial of Dasatinib + Quercetin, although Steve from lifespan.io didn't seem to think the data on that treatment was that good (although I cannot remember why?).
James P. Watson is the PI? The plastic surgeon who administered a rather weird coctail of HGH, DHEA, Metformin, Vit-D, Zinc, .. to humans and claimed it increased thymic mass and set some epigenetic clock to a 'younger' state, but failed to show the thymic regrowth is actually active, functional tissue that develops thymocytes? That JP Watson is PI here?