Existing Drug Found to Slow Progression of Transthyretin Amyloidosis
Researchers have discovered that an existing drug can slow the progression of rare forms of transthyretin amyloidosis caused by mutation by interfering in the formation of this type of amyloid. It is unclear as to how useful this would be in practice for the age-related accumulation of transthyretin amyloid known as senile systemic amyloidosis that occurs in every individual, however, as that happens at a much slower pace over a greater span of time. The growing presence of this amyloid is implicated in a range of age-related conditions, particular cardiovascular disease. The ideal approach to amyloidosis, whether age-related or not, is clearance of amyloid rather than slowing its formation, however. Clearance can be applied at any point in the progression of the amyloidosis to obtain benefits, and applied repeated as needed, at a much lower cost. Slowing progression requires constant treatment at a much higher cost, and produces smaller and diminishing benefits. Fortunately a therapy capable of transthyretin amyloid has already been successful in a small trial, though the pace of clinical development in this field is, as ever, glacial.
Researchers have published the results of a drug repositioning study in which they describe a powerful drug, SOM0226 (tolcapone) that could significantly improve the pharmacological treatment of familial transthyretin amyloidosis (ATTR). ATTR is a rare degenerative disease that mainly affects the nervous system and heart muscle tissue (myocardium), and which is usually passed on from parents to children. It originates when the liver and other areas of the organism produce mutations of the protein transthyretin (TTR), which lose their functional structure. This causes toxic aggregates of amyloid fibres to build up, which, depending on the mutation involved, are deposited in different organs, such as the brain, the kidneys, the nerves, the eyes, or the myocardium, causing them to malfunction and bringing on the various forms of the disease. To prevent the disease from progressing, a liver transplant or liver and heart transplant is needed.The researchers conducted trials in vitro in cell cultures and ex vivo in human plasma and in mouse models of the disease to show that tolcapone is a powerful inhibitor of the aggregation of amyloid fibres by TTR. Tolcapone acts by imitating the process by which the thyroid hormone - T4 or thyroxine - binds to TTR in the bloodstream. Just like the hormone, the drug binds closely to the protein, tying together the four protein sub-units that form the protein's structure. This binding has been proven to stabilise the protein, preventing the sub-units from separating and then forming aggregates. This is a hitherto unknown property of the drug, which is used to treat Parkinson's disease. The compound turns out to be four times more effective than the only medicine currently available for treating the polyneuropathic variant of ATTR. The results were positive for all variants of the disease that were studied: familial amyloid polyneuropathy and cardiomyopathy (which affects the peripheral nerves and the myocardium, respectively) and senile systemic amyloidosis, a sporadic form that appears in a very high percentage of men over 60 years of age (and also affects the myocardium). In addition, the treatment was shown to cross the blood-brain barrier, making it the first to tackle the variants that affect the central nervous system.
According to the researchers, this molecule has the potential to become an effective drug for preventing the protein depositions that cause the disease and slowing down its progress, one that could be on the market within five years, as it has already been tested in a clinical trial with persons affected by the neuropathic variant.
Great find Reason, a $2.50 pill which is available right now 4 times as effective as the current treatment.
As senile systemic amyloidosis is what kills the majority of supercentenarians this should extend maximum lifespan in humans. If in the future supercentenarians stop dieing of senile systemic amyloidosis I wonder how long they will be able to live and what they will end up dieing of.
@CANanonymity what do you think of this?
@Santi
Hi Santi ! Thanks for asking !
It's a good question. In my opinion, I believe it won't make all that much difference
for these supercentenarians. Heart Amyloid deposition of Systemic transthyretin amyloidosis in supercentenarians, like lipofuscin (another aggregate),
is part of the whole thing of aging. It is not the sole contributor.
There are many fine lines between pathological aging and 'regular' intrinsic aging.
Regular intrinsic aging is like a 'low-background' oxidative stress state (by regular mitochondria ROS destruction of mtDNA and telomeres) that continues one.
Pathological aging is often a combination of excessive oxidative stress inflammation (called spontaneous/induced/stress-induced senescence), the phenotype is nearly the same as
replicative senescence (both have senescent cells appearance) - but it happens very quickly through a different pathway (p53 and others)), and is not a full telomere-based pathway like intrinsic aging is.
Telomeres may be lost in pathology but there are cases where telomeres have not moved one bit during pathology - demonstrating that replicative senescence is different than pathological senescence.
Only long-lived post-mitotic cells are subject to that problem of replicative aging. Highly proliferating and immediately dying/replaced cells such as red blood cells don't have as much say in this. Still, even these
cells are bound by telomeres (many studies verified telomeres in mitotic cells too, and found out that replicative senescence is basically in the entire body).
If we remove transthyretin, Beta-amyloid, ceroid, drusen, A2E or lipofuscin, we greatly allow the possibility
of supercentenarians of going above maximum lifespan (and more if the other damages are removed, in unison, too). How much ? I guessed roughly 100% if lipofuscin is entirely removed, which would mean double MLSP (125 x 2 = 250 years).
Still, as said, other damages still accumulate and I don't think we will be capable of removing/reversing/or slowing lipofuscin - enough - to really make that much difference. Same thing for transthyretin.
How do I base myself to come up with that ? Well, for example, the quahog, albeit is far less complex than us (which immediately makes it less revelant, but for the fact it lives a maximum lifespan of 508 years is relevant because it shares organs we have).
it accumulates very finite small quantities of lipofuscin in its gills, mantle and pedal foot. This shows, that this age pigment is important, is correlative and causative - partly, in the aging process (lipofuscin increases ROS production (through lipofuscin-iron Fenton reaction creating hydroxyls) in lysosomes/clogs them making autophagic failure)
Supercentenarians will still die of 'age', damage accrual, will catch them, the figures I gave are for people who start these therapies very young below 40 or at birth altogether. Not at a 115 years old...late like that...the damage train is immense. And, I have certain
doubts we can entirely remove all of the damages they, already, accumulated.
This ATTR therapy is impressive because it reduces existing transthyretin so it will definitely abate pathology at 120s.
But we have to remember something,
replicative senescence continues its course, these supercentenarians have very very short telomeres.
For example, one study found out that a 115 year old woman had 3kb telomeres in her leukocytes, the study said that
the supercentenarian was ''at the limite of human specie lifespan''. Below 3 kb, replicative senescence is immediately activated, creating death.
So basically, we still have that problem too, wether we reach 120s. I maintain my stance, that like that 500 year old clam, modulating damage via redox is the only way to live to 500 years old. No Sens therapy will make us reach that (because damage accrual wins in the end), even repeated continuously as we accumulate every-second damage in mitochondrias during 'normal' mitochondrial oxidative respiration (OXPHOS/complex ROS production/membrane peroxidation/propagation degradation of mtDNA).
That's just my pov. : )I think we are approaching incredible things. But also, we approaching the 'uncanny valley' where we always seem to fall in it 'too real/too human/too good be true/must be fake'), or let's say the 'diminishing return' with advancement (kind of like videogames becoming - like reality. How much more can we make them 'more real', we can't, we reached that maximum, They are as real as real is possible, can't go further. Same thing we selling cars...I mean you continuously see car ads...cars improves through the centuries (wheel...charriot..steam car...oil car...'futuristic car'...and now what ? flying car...how is the 2013 version of car So different from 2014 version, nothing...but it's a business and it keeps on maxing out - the maximum that it reached long ago. That is what I fear with biogerontology real future and the fact, we problably won't even be there to see it because things happen in centuries, decades are more common now, even miraculous 'next year' discovery of miracle, it just is not something common, it is rare and time is rare resource too).
@CANanonymity
I found another article which stated the results of the study on Tolcapone which showed it stabilized 100% of TTR in plasma. As TTR amyloid deposits will continue to build up in my system if I don't, I will likely add low dose tolcapone to my daily stack.
Oleuropein is what I currently take for lipofuscin as it slows lipofuscin accumulation through proteasome stimulation. I have never seen it quantified though so I can't say by how much. It also extends life span of human embryonic fibroblasts in vitro.
Your 115 year old woman example reminds me of the importance of maintaining telomere length or having telomerase gene therapy. Are you planning on getting telomerase gene therapy done when Bioviva offers it to the public?
@Santi
I hope this agent is capable of reducing TTR in organs, that is really where it creates a large problem. Perhaps, by stabilizing it in the plasma, there will be less TTR to begin with and available to accumulate in organs from plasma transfer depot to organs. Especially to the heart, since that is what many latest supercentenarians die of, heart transthyretin accumulation and systemic transthretin. It surely cannot be bad and, most likely, by reducing blood TTR availability, you reduce its deposit rate in crucial organ like the heart. I read that men over, just, 60 years old are at higher TTR deposition risk in different organs, that in men it accumulates much earlier/faster too than in women. This makes sense with the oxidative stress (accelerating protein denaturing/unfolding creating aggregates like amyloid TTR) where men have shorter lives because of faster compromised/oxidized biology (since men carry a large 'female' 'X' chromosome and a small 'male' 'y' chromosome (Xy), women carry two large female Xs (XX) chromosomes; as such, are less vulnerable chromosomally to mutations/chromosomal damage than men (since female chromosome X is a more genomically stable version/less susceptible to oxidative damage than a small male y chromosome). This is also, in part, the reason why supercentenarian woman outnumber/outlive men massively (something like 7-8 female supercentenarians vs barely 2 male supercentenarian making it, out of 10).
Oleuropein, found in olive oil and olive leaf (20%), is a great antioxidant, like another one of olives, hydroxy-tyrosol. I will be honest though, just my opinion, it may improve proteasome and slow lipofuscin (reducing aging and pathology), but it will not extend maximum lifespan of humans; if it does, it will be marginal. Even if it may increase human embryonic fibroblasts replicative lifespan. The reason is because people have been intaking on oleuropein since olives existed in Greece, which means basically thousand years (and no one got past the current maximum lifespan intaking olive leafs/olives/oil). And for example, Jeanne Calment the oldest human of humanity, who puts the MLSP, she lived to 122 years old and 164 days; she lathered her food in olives, olive oil and what not (she sayed something like ''I put olive oil on everything I eat''), she definitely got a boost by her olive oil Oleuropein, and the fact she at 2lbs of dark chocolate each week (she was rich), tons of polyphenols from olive and cocoa (of her chocolate) and from drinking red wine (Quercetin, resveratrol...)...still, it does not explain that she lived 122 years...because other people ate the same thing as her and ate tons of olives/olive oil/red wine/dark chocolate/etc...and they never made it to a 122 either..
what really - is - the reason she reached 122 is that she inherited a genetic that protected her (she smoked for 100 years (!, from 20 to a 110)...other people die from that very quickly..she didn't, her lucky genetics protected her) Jackpot lottery genetics..and we can infer that, because she had family members (siblings I believe) who lived long lives - too, like her. Thus, it was indeed inherited genetics that made her live this long...not eating olives or getting oleuropein from her olive oil binges. Still, antioxidants polyphenols, such as Oleuropein are definitely good to protect and slow regular aging. But, as with her, we won't go above 122 on it, she didn't, still she made it to 122, so we can hope for that, it's just if you don't have a lucky genetic background (in your family/genetic predisposition for diseases), oleuropein won't change things that much.
I can give you an example, such as m uncle who died of Alzheimer's at 73 years old, he was fit, thin, bicycle for miles (marathon like), he ate olive (got oleuropein), he never smoked (like her), and he still died anyway. See...makes very little difference, if you have genetic predisposition, you can only slow/postpone them and do your best; but what is inscribed/inherited in your DNA at birth (such as diseases) will come one day.
Eaxctly, telomeres length maintenance is crucial if we wish to go above maximum human lifespan.
I might, out of slight fear and just wanting to see what happens in many people, I will wait before jumping in it and 'see' how it goes; like if there are super nasty side effects that 'pop up' later on as the therapies goes mainstream. I won't wait eternally though, and it will depend on the prices. Lots of ifs, I know : ).
Still, many others pointed out, that there many other hurdles, that despite increasing telomeres by telomerase, ECM crosslinks are not solved and 'removed' by themselves (you need those MMP enzymes to degrade the damage/crosslinked collagen); so we have so many problems yet.