• Dec. 17, 2019, 6:31 p.m.

    So as it turns out, traditional theories of the causes of aging were wrong. In retrospect, they obviously had to be wrong.

    To review, the most popular theory of what causes aging is the "free radical theory of aging", which posits that gradual damage to our DNA due to free radicals is what causes our cells to break down and become senescent over time. (note: I'll cover some of the other failings of SENS's theories in a bit)

    There are three problems with this theory:
    1. Our DNA does not actually change as we age. DNA tests can easily confirm this. Some cells do suffer permanent and irreversible DNA damage as telomeres burn out, but for cells that are still functioning at all DNA damage just is not apparent.

    1. Cells from old animals can be used to clone whole new animal babies, which are exact copies of the original and which (at least now that cloning tech has improved) live normal, healthy lifespans. If the DNA was damaged this would not be possible.

    2. Perhaps even more obviously, if accumulated DNA damage caused aging, then it would follow that such accumulated damage would be passed on to our children, causing them to have high rates of mutation and to be completely non-viable within a few generations (given how quickly age affects individuals). Obviously this is not what we observe, or life as we know it wouldn't exist.

    (edit: numbered lists are broke)

    Aging does obviously involve some form of information loss, our cells gradually fail to do what they're supposed to, but that loss cannot be in DNA. As it turns out it's in the way DNA is interpreted, ie "epigenetics". Epigenetics is the stuff that controls gene expression. It tells our cells how to be whatever type of cell they're supposed to be, ie neurons or skin cells or muscle cells or whatever. All those different cell types in our body have the same DNA, but by expressing different parts of that DNA to different degrees they can adopt dramatically different forms and behaviors. This is all controlled by a bunch of proteins which live in the nucleus along with DNA and which are collectively called "chromatin".

    Chromatin is responsible for bundling, or unwrapping, DNA in chromosomes as is required for turning genes into proteins. Chromatin also repairs DNA when it gets damaged and handles copying the whole thing when a cell divides. It probably does a bunch of other things too, but that's the basic gist. The most important (and oldest) of these proteins are the sirtuins. Sirtuins handle DNA repair and control (at least) the expression of genes which respond to bad conditions, ie by preventing the cell from dividing and activating stress responses to protect the cell (and DNA) from damage.

    This is where the free radical theory of aging ultimately comes from. It's actually pretty close to the truth, but misses the real mechanism. When sirtuins are called off to fix DNA or deal with disaster management, they leave their posts managing DNA expression. Normally they come back to the same place when they're done and do their jobs as normal, but occasionally they end up going back to the wrong place, which causes the DNA to be expressed incorrectly and the cell to suffer dysfunction. These errors accumulate over time until the cell gradually ceases to function as the type of cell it's supposed to be, and eventually shuts down into senescence mode to prevent it from turning into cancer.

    This discovery was made by David A. Sinclair et al, and he covers all the nuances of it in his book "Lifespan: Why we age and why we don't have to". It's a pretty good book (at least the first half of it, anyway) and I definitely suggest giving it a read.

    The important takeaway is that we now know what it is we need to do to cure aging. That is, to reset our cells' epigenetic states to their "factory settings", and then they'll become just like young cells again. The idea that our cells can't deal with "junk" like lipofuscin and beta amyloid is also nonsense. It's just that old cells produce more junk and are less able to get rid of it. Otherwise we'd all have alzheimer's and be covered in liver spots by the time we hit the ripe old age of 30 (which incidentally is our 'natural' lifespan without the benefit of civilization).

    That said, we don't yet have that capability. There are promising leads and tons of studies going on right now, and others that are done but won't be published for some time, but the long and short of it is that we haven't figured out how to achieve practical immortality yet, and it'll be some time until we do. However knowing the root cause of aging has also provided us with the knowledge to understand how to better stamp out its nastier symptoms. A decade or so ago the best we had was resveratrol, but today we can do a lot better than that. A lot better.

    What we've got can be broadly divided into two basic categories: senolytics (and senomorphics) and restoratives.

    Isaac mentioned senolytics in at least one of his videos, but at the time we didn't really have anything specific. Basically they kill senescent cells. Senomorphics are similar, but merely temporarily suppress the spam of carcinogenic, senogenic, and inflammatory chemicals which senescent cells constantly emit. Since senescent cells are responsible for most of the symptomatic diseases of aging, and for the worst of them at that, and since they also accelerate the aging process (and carcinogenesis) of surrounding cells, killing them off or silencing them is one of the most important things you can do to combat aging in general. In vivo studies of senolytics in animal models confirm this.

    Luckily there are two rather potent senolytics and one senomorphic compound available over the counter as supplements. These are:
    Fisetin (senolytic, antioxidant found in many foods, particularly strawberries)
    Curcumin (senolytic, you may know it as the antioxidants found in turmeric)
    Quercetin (senomorphic, antioxidant found in many foods but particularly in shallots and vidalia onions)

    Generally fisetin and curcumin are best taken together, and are only effective when taken in high doses. You can grab both of them over at pure bulk for about $35, and that's probably several years' worth. Stuff them into the biggest capsules you can get, take 3 a day for 5 days straight, repeat every 6 months. As for their effectiveness, well they're worth way more than what you'll pay.

    Note that they don't kill every type of senescent cell (of which there are as many types as there are types of cells in your body), but they do kill off a lot of them and they do get a good kill rate at that. Together they can prevent or reverse a large number of horrible conditions including back problems, atherosclerosis, immunodeficiency disorders, and plenty of others.[1][2] It's an ongoing subject of research but even the preliminary results are downright impressive.

    Quercetin is somewhat less impressive, and unlike the others it's something you have to take continuously, but we'll come back to that in a bit.

    Our second category is restoratives. Pretty much like they sound, they restore the functionality of aging cells, which in turn restores health and prevents conditions related to reduced cell functionality that comes with aging. This includes issues like type II diabetes, general frailty and loss of athletic ability, and so on. This is the really exciting bit, because with knowledge of the root cause of aging we now know how to reverse the symptoms in a very broad way by treating them much closer to the source. With only 3 supplements you can restore around 65-75% of youthful cellular function and in some cases even exceed it. These are:

    nicotinamide mononucleotide (NMN) (also synergized by apigenin, the main antioxidant in chamomile)
    Dimethylaminoethanol (DMAE)

    NMN was a direct result of the research into epigenetics as a cause of aging. Sirtuins use NAD+ as their primary substrate, and NAD+ levels also decline sharply with age. NMN is an NAD+ precursor with a very high conversion efficiency, and in experimental studies it has been demonstrated to be nothing short of miraculous in its effects. Mice given NMN that were equivalent in relative age to 80 year old humans ran over 3km, where normal young healthy mice can only run 2km on average. It can reverse diabetes, heart diseases, osteoperosis, age-related weight gain, general frailty, and in both mice and humans has even been shown to reverse menopause in some cases. It's pretty expensive (about $20 for a month's worth) and you have to take it for a few months before the effects become obvious, but obvious they are.

    NMN is also synergetic with apigenin. Apigenin inhibits the expression of a gene called CD38, which tends to get overexpressed as you age and which suppresses NAD+, increases inflammation and autoimmune responses, and other evil things. When combined with NMN it increases the effectiveness by 50%.

    Which is why I recommend N-STAC as an NMN supplement. Not only is it cheaper than most other NMN supplements (by a good margin, and all the ones I checked contain the same amount of NMN), but it also contains apigenin and quercetin. The research checks out, too, so it seems like they're serious about the product. It's still pretty expensive, but NMN is still very new and will probably get a lot cheaper within the decade (like resveratrol and curcumins did in response to demand).

    DMAE is nothing new, but recent research has shown it to be rather underrated. It's also pretty cheap. Traditionally it was used as a nootropic (the effects of which are felt very rapidly), then later as an anti-aging ingredient in skin creams, but more recently it has demonstrated itself as a potent restorative and lifespan extender in mice. Basically as you age your cell membranes break down and your cells get stuffed full of potassium and lose the ability to take in water. This results in higher cytoplasm viscosity which hampers the cells' ability to produce proteins, and also to exchange vitamins and minerals, and hormones and neurotransmitters, which contributes to things like dementia and diabetes. DMAE is modified by cells and then incorporated into cell membranes replacing normal phospholipids. It acts to restore cell membrane function and also as a potent antioxidant which protects cell membranes from further oxidant damage.[3] It is highly complementary to NMN.

    Co-Q10 is nothing new either. Nor are its benefits. It's essential to mitochondrial performance and especially concentrated in your heart, liver, and brain. It's very potent in mitigating heart diseases and improving athletic performance, and it also gives you a ton of energy like drinking a cup of coffee but without the caffeine addiction or tolerance (or jitters..). Obviously it's something you should take in the morning and not at night. There's also no harm in taking it even for young people. It is complementary to the above mentioned restoratives and its role in restoring mitochondrial function is as straightforward as you can get.

    Because they treat the low-level symptoms of aging, the three restoratives have very broad effects and when combined those effects become nearly all-encompassing. Compared to the massive list of things people were taking as anti-aging supplements a decade ago they also simplify things a whole lot. Take all of 3 restoratives daily, and a week long course of senolytics twice a year, and your chances of living to see a full and proper cure to aging skyrocket while your medical bills plummet. Seriously, gotta love 2019.

  • Dec. 23, 2019, 4:30 p.m.

    Aeonios, the chemicals you found probably do most of what you (and your sources) think that they do, however, you are not going to gain any significant lifespan extension just by consuming those kind of chemicals.
    Because the chemicals only patch over underlying problems. "It doesn't matter how fancy the bandage if the wound doesn't heal."

    If you want real and significant life extension, then you have to solve all of the underlying and root causes.
    -> Consider these articles:
    "Mice with hyper-long telomeres show less metabolic aging and longer lifespans" www.nature.com/articles/s41467-019-12664-x
    "Harvard scientists reverse the ageing process in mice – now for humans" www.theguardian.com/science/2010/nov/28/scientists-reverse-ageing-mice-humans

    If you do a deeper search of the web, you will be able to find a rapidly growing database of Scientific articles and Genetic manipulation experiments which will further demonstrate the point:
    Fully active Telomerase and constantly-long Telomers are the 1st steps to fully halting the process of aging. That is, the 1st step towards "Eternal Youth" involves Telomerase.
    It is possible to restore youth to an old individual by fully reactivating Telomerase in All of their cells; therefore, aging is tied to a measure of the length of the telomers, not just lost or damaged DNA resulting from a lack of telomers.

    I look forward to the Eternally Youthful future which should only be ~15 years away.

    The chemicals you describe patch over problems related to shortened or lost telomers. Those chemicals don't actually fix anything.

  • Jan. 30, 2020, 9:54 a.m.

    Telomeres are not magic. They don't fix epigenetic drift, they don't fix zombie mitochondria, they don't fix cancer, they don't fix the fact that certain cells in the body do not have corresponding stem cells to replace their losses, they don't fix AGE crosslinks..

    The experiments you linked started by artificially inhibiting telomerase, which caused accelerated symptoms of aging, but because of that the models were not the same as they would be in animals that had undergone real aging. Reduced telomerase activity and reduced DNA repair activity are symptoms of aging in general, which contribute to the process but which are not primary causes.

    If increasing telomerase activity increased maximum life spans, which it doesn't, then we'd be hearing about nothing else in the entire anti-aging research community.

  • Jan. 30, 2020, 6:03 p.m.

    Aeonios, I have a question on this topic as you seem well read on it.
    As you mention in regards to Co-Q10 that it is save to take for young people as well. I am myself 33 years old, not young persé but certainly not at the age that many age related problems are cropping up. This does not however stop me from wanting to mitigate as much age related damage as I can but only when there is minimal risk of serious side effects. Therefore the question becomes, which of these are save and helpful to take even at a relatively young age?

    Going through the list my idea would be that the 3 senolytics are save to take at any age. The riskier category seems to be NMN and DMAE. If these increase NAD+ levels as you age, at young age they might instead cause overexpression of NAD+ and as such result in negative side effects. Similarly I wonder if DMAE might be harmfull if it replaces normal phospolipids at a young age. This is naturally all speculation on my part.

    I also wondered how many of these compounds have been studied in humans at the dosages you describe? Or are most of these based on mice studies.

    And finally you mentioned enjoying the first half of Sinclair's book but not the second half. I haven't read his book yet but I am curious what you disliked about the second half of his book?

  • Feb. 1, 2020, 11:37 a.m.

    As far as I know all of the supplements I've listed are GRAS. NAD+ overproduction is not harmful and seems to occur naturally when you exercise. NMN's effects are very similar to a combination of exercise and calorie restriction. DMAE is also a nootropic, and has been used as a nootropic since long before it was discovered to have beneficial anti-aging effects. If you're 25 years old or older, there's really no reason not to take all of the things I mentioned, except maybe cost. If you can afford it though...

    Some of the things I listed have been tested in humans with positive results, like DMAE and NMN. The senolytics have been mostly limited to mouse studies, although iirc there was at least one study done showing improvements vs human arthritis and back problems. CoQ10 has been known for a long time to prevent and ameliorate heart disease, and to reduce damage in people who have suffered heart attacks.

    The reason I didn't like the second half of Sinclair's book is because he goes way off topic. He goes on this nonsensical political rant about social justice and "futuristic" medical technology where the government monitors your "health" 24 hours a day. Some of it was actually interesting, but mostly it was a bunch of unsolicited opinions that, if implemented, would result in the most god-awful dystopian nightmare imaginable. Ultimately it had nothing to do with his research and doesn't even really solve the problems, if they were valid problems to begin with, that he was basing his arguments on.