Chapter 1: The Hunt for the Fountain of Youth
Hi I'm Wendy, and you're listening to Science Vs. Today on the show we're pitting facts against … the fountain of youth… as we find out: Is there anything we can do, or take to live a longer and healthier life?
For millennia… people have searched far and wide for the elixir of life.. the thing to keep our brains sharp as a tack and our bodies sprightly as fuck.… It's said that Gilgamesh searched at the bottom of the sea[1] … Rulers have sent armies to their death - kind of ironically - on the desperate hunt for a magic potion… something to help us live forever.[2] It's like for all of human history we've been Indiana Jones reaching for the Holy Grail… so close… But now - it feels like the search is over.
<<Now scientists say they've made a breakthrough in the search for a fountain of youth.
<<If you're looking to increase your longevity and slow your aging, the brain, the body, everything, you've got to check this out.
Millions of dollars[3] are being poured into start ups and research labs in the hopes of finding the secret to a long and healthy life. One place they're looking? In the blood from young people … This made headlines around the globe when millionaire Bryan Johnson[4] gave it a go – getting blood plasma transfusions from his teenage son… he even made a short doco about it[5]
<<This is amazing! A long healthy life united by the beauties of biology
<<He recognizes how insane this all sounds.
Could he actually be onto something?? And away from blood boys, these days it feels like if you ask any expert sounding person online what they're taking to keep them young and healthy… one group of supplements is coming up over and over again.
<< Of the people that I know that look freakishly and unusually young for their age, I cannot get over how many of them have told me that I'm on NAD.
<< I've been supplementing for about seven years now
<< I felt like I had more energy - I did notice like my hair and nails are growing at a ridiculous rate.
And - finally - some scientists are so excited about a blockbuster drug for diabetes that could fight aging that they're literally singing about it.
It makes me feel so young. It makes me feel so young
Today on the show we'll explore the potential powers of young blood, dig into the science on the latest supplements — and we will tell you what actually works.
When it comes to longevity there's a lot of…
this is amazing!
But then there's science
AHHHH
Science Vs Longevity… is coming up… Just after the break…
BREAK
Chapter 2: Can Young Blood Keep Us Sprightly?
Welcome back. Today on the show we're talking about longevity.... and the anti-aging tricks that are seemingly at our fingertips.
Let's start with the most bonkers. Getting blood from your teenage son. When that millionaire Bryan Johnson did it … people made fun of him…cos this just feels like the latest in a long line of kooky shit that rich dudes do… y'know while they're not getting into sketchy submarines, they’re getting blood from their teenage sons. But the idea that there is some elixir of life in young blood is something that scientists have been looking into for decades.[6] And one of those scientists is Jim White[7]… from Duke University. And he loves researching the potential magic inside young blood…
JW It's the perfect mix of like sci-fi world meets academic science. And it's just been an obsession and a fun obsession.
So recently, Jim did this study[8] to find out what happens if you get some crotchety old thing and give it a tonne of blood from a hot young thing… now, Timothee Chalamet was busy.. so Jim had to use the next best thing: mice. And his big question was:
JW If the mouse, the old mouse, gets this young blood for a long time, could we then start slowing all the hallmarks of aging?
The idea is that some old mouse would get blood from a younger one for about 12 weeks, which is roughly the equivalent of eight years of human lifespan. So how on earth do you get all that blood from a young mouse into an old one?
JW Basically we join the mice together, surgically join them.
WZ OK — I'm gonna need some details. How does that work?
JW Yes haha. So small incision on the flank of the mouse
WZ On the belly? Is that the flank?
JW Basically the armpit to the to the hip is kind of the incision. Right? Right.
WZ Okay.
JW You open that up, and then you bring that together with the other mouse, and it's basically like, you know, sewing two pieces of cloth together.
Stay with me here. This procedure of stitching animals together is called parabiosis… and it sounds pretty gruesome … but scientists have actually been doing it for over a hundred years,[9] to study all kinds of things.[10] So Jim does some cutting, then connects the skin[11] and other tissues of the mouse, which is possible - because these mice are basically identical twins
JW: So genetically identical to one another. It just thinks it's, ‘Oh, that's another part of skin. That's my skin.’ And it fuses with it. Just like you would get a cut on your skin, and it would close.
WZ So the blood vessels line up, like if one of the blood vessels would be like, “Ah oh, no, I'm severed. Wait, you'll do - boof!’ And then it finds it’s
JW Yes! It's beautiful! It's basically they find each other and connect without —
WZ Whaaaat
JW That's just biology doing cool stuff.
And once biology has done its cool stuff…and all the blood vessels are fused… Jim runs these tests to see that yes the blood of the young mouse is now flowing into the old mouse… and vice versa … Jim's team also checks to see how rough this whole procedure has been for the mice … look for markers for stress… and weirdly…after this pretty hectic procedure, the mice don’t seem that bothered by it all.
JW So they take a pretty harsh surgery pretty well. And then within just a few weeks, they're cruising around together and like nothing happened.
Yeah, so the mousies… are walking together, squeaking together, sharing all that blood for 12 weeks…. and then… Jim’s team gives them an anesthetic…
JW And then we detached them. And then. Then we let them live the rest of their days.
And it's here where Jim and his team will really start to take a close look at these mice ... to find out ... did all of this work? Are the old mice healthier? And he said that he noticed this difference right away ... in the older mice … because compared to other old mice, who went through this hectic surgery, but didn't get the young blood ...
JW They got up from anesthesia quicker.
WZ That like from the anesthesia of the surgery? Yes.
JW Yes, So once we detached them, a couple times, these mice just had a little bit more of a pep in their step. That was the first “huh” moment.
Huh. So he lets the mice recover… and then Jim's team starts running some tests on them .. to find out stuff like ... how fit are they? How strong are they?
JW So that's like, exercise test and grip strength
WZ How do you measure a mouse’s grip strength?
JW Yes. So it's a little bar and then the mouse grabs it and you just gently pull the mouse tail until they release it. So they tug and you can measure.
WZ Oh my God, you pull the mouse tail???
JW Just very slightly and you can measure how much they pull. And then finally you know, measure what they're resisting against you.
Jim also puts the mice in a little body comp machine… it’s like those machines that you get at a fancy gym where it will show how much muscle and fat you have. And what Jim found is that the old mice that were getting all of that young blood, they had more muscle, and they were leaner, than old mice that didn't get the young blood.[12] And Jim could even see a benefit here – when he watched them around the cage, and tracked their movements.
JW They were running like laps, literally around their older cohorts there.
WZ Wow.
JW They ran better. They were stronger. And they maintain this, whereas the old mice just kind of took a dive.
WZ And then did they live longer? With with all these benefits?
JW They did. Yeah. They lived. I think we got about 9 or 10% extension in longevity.
WZ Interesting!
The mice lived about 10 percent longer than other old mice! Which Jim says feels like this true feat of science … we can extend life…
JW We can do it. For years you just assumed Father Time was you know, a one way street. But we can manipulate that a little bit- I think we were a little shocked to see how much we can. We're able to slow the clock down.
And other studies doing this kind of surgery in mice, have found that young blood can help rejuvenate livers, and even brain stem cells.[13] So - we really wanted to know …
WZ How the hell does this work? Like, what is it in young blood that's doing this?
JW So that's the magic question.
There's a few ideas running around the cage. Like this could be about the immune cells that are swimming around in young blood…
JW The beauty of the youthful immune system is, it really it doesn't get the credit it deserves. For the most part, our young immune cells cruise around. It picks off what they call senescent cells[14]
Senescent cells are basically cells that have gone a little janky … which can happen more and more as we age[15] … and when you’ve got more janky cells, it can lead to stuff like inflammation and even cancer … so typically, when these kinds of cells show up …
JW The young immune system kills them. Gone. Get out
It could also be other stuff in young blood that could be making a difference here too,[16] like it can have higher levels of certain hormones[17] - which have been found to help muscles[18] and neurons grow.[19]
So that's idea number 1. There's something magical in young blood. But it could also be that there is something crappy in the blood…of old mice[20]…that was kind of getting diluted out… And Jim saw some evidence of - because the young mice that were getting all of that old blood… .[21] [22]
JW They accelerate aging.
WZ The power of the young blood.
JW Yes. The power of youth.
WZ: So what does all this mean for humans? Like if you had some. Some young blood. Maybe some. Some very keen students perhaps. Would you be interested in taking some of their blood?
JW That's, of course, the follow-up question. I don't think, you know, even a monthly transfusion - because that's, everybody says, ‘oh, if we transfuse blood, like every month or so.’
I don't know if that's enough.
Jim says – remember these mice were conjoined for the equivalent of Eight Human Years… eight!! Sharing all that blood… So he's not sure that a couple of pints from a monthly transfusion would work the same magic.
But who knows? Studies in people are just starting to trickle in. Like, we found one that got almost 20 folks with Alzheimer's and gave them the plasma of young men once a week for a month.[23] They were just tested to see if it was safe, and it was… but they found something surprising. Some patients seemed to be doing a little better at things like[24]… like feeding themselves or remembering to take their medicine. Which is curious eh?
Researchers are going to keep studying this … but for now … Jim isn't gonna be putting his arm out for a transfusion of that sweet sweet Gen Z blood…
JW No … maybe they'll all be laughing when they're 150 years old at everyone that didn’t try it. Good for them, but I don't know. If it works, I hope it does. But.
OK – so what else have we got?? After the break could the key to longevity be as simple as popping a pill? Some say the secret to a long and healthy life is sitting in your pharmacy right now. Should you take it?
Coming up!
BREAK
Welcome back today on the show the quest for immortality!!! Or just to live a long and healthy life…
Chapter 3: Do NAD Boosters Work?
If you look at basically any health-fluencers list of the stuff they're taking to live long and healthy - there's a particular group of supplements that comes up over and over and over. The internet is going nuts for them…it's all over socials, with some calling it the "Miracle Cure for Aging."[25] And they're called Nad Boosters
WZ I should say. I shouldn't say “nad.” N.A.D. Is how —
MM Yeah. That’s what I call it anyway. Some people say “nad” yeah, but yeah I say N.A.D..
WZ Because nads is something else, right?
MM I think so, yeah.
Ok so I just orchestrated a joke so that we could make fun of balls …that’s what we did there, that’s all it was, and Melanie McReynolds …at Penn State University[26]…. Was polite enough to laugh at my joke. Thank you. And after we talked about balls … she went on to say that there are feisty debates about NAD supplements - with some scientists saying they're dangerous and others saying they’re a game changer…
MM One person is ringing the alarm and the other person is saying, I take this daily. Hahaha And yeah, you see influencers, you see scientists, even various people on reality TV are talking about taking these supplements. So it's everywhere.
So what are NAD boosters?? And do they work?? To know what a NAD booster is - first we got to know what the devil NAD is. It stands for Nicotinamide adenine dinucleotide … It's this coenzyme that's found in our bodies - and is super super important.
MM So you have NAD in every single cell. So it lives everywhere in every single tissue.
Basically it is the food that fuels hundreds of reactions throughout your body… including reactions involved in repairing your DNA[27] [28]
MM So say if you're out in the sun for a long time, you may get UV damage.
Your DNA is squealing!! OH NO I've been hit! I'm damaged… So enzymes come to the rescue to fix you up ... and those enzymes?[29]
MM They are going to consume NAD.
WZ Oh, so NAD is like the food for the enzymes that we need to repair DNA?
MM Exactly.
WZ — and that's just one thing.
MM Yeah. And it's so many others.
NAD fuels our energy production, helps control our responses to stress and inflammation… I mean you name it NAD is right there…
MM So when I think about NAD, NAD is playing a vital role in every aspect of biology and chemistry within our bodies. Mm hmm
WZ Is it like having like Usher at the Super Bowl? Is that.
MM Where it’s essential?
WZ For my enjoyment of the Super Bowl, right?
MM Hehe
But unlike Usher … NAD is affected by aging. That's how it got wrapped up into this anti-aging world in the first place ... Because as we get older, there's more stuff for NAD to do … we have more inflammation, more DNA damage … and since NAD is the fuel that feeds all these reactions…we start running out of it![30] So as we age… we have less NAD hanging around[31]
MM It's not as drastic as infomercials or salespeople make it seem, like, ahhhhh when you're 65, you lost 50% of your NAD. It's not that bad. You know, it's not that drastic. But is there a steady, slow decline that probably averages around 30%? Absolutely.
And we think this is a problem. In mice studies, lower levels of NAD have been linked to a lot of yuck stuff that happens as we age - things like cancer, diabetes, cognitive decline, muscle loss, and hearing loss.[32][33][34]
Which is why some people are saying… if dropping NAD levels are linked to all this nasty stuff… then surely we can fix some of them by bumping those NAD levels back up, right?? And that's what the supplements - NAD boosters are supposed to do.
Now you can't just eat NAD straight – it doesn't work like that. So instead the stuff that you can buy, the supplements, are what are called "precursors" … so your body takes them … and then turns them into NAD. And I know this is going to sound like an alphabet soup here, but two of the most supplements like this on the market are known as NR and NMN[35]…
And a lot of the studies where they give them to people… and see what happens… are funded by the supplement industry in one way or another. And even then overall, a lot the results from these studies have been pretty meh … Like just zooming in on NMN for a second, research has looked into whether it affects muscle mass, or blood pressure, or cholesterol, or glucose or insulin - have found that it doesn’t help.[36] With NR, which stands for Nicotinamide Riboside, the research has been a little more promising. Several studies have found they might lower inflammation[37] … and blood pressure[38]… [39]
MM I can say there are seven published human studies[40] showing anti inflammatory effects of Nicotinamide Riboside…
WZ So the idea of taking these supplements doesn't it doesn't sound stupid to me. Right?
MM Yeah. I mean, that's the reason why that's the reason why so many people are doing it.
WZ Now I feel a BUT coming on …
MM But. Yeah.
WZ Should I go out and buy some?
MM ahhhhh [sigh]
The reason that Melanie is giving us the ol’ ahhhh … is because she's not sure if these supplements are safe.[41] They haven't been tested on that many people, or for that long… and some early research in mice are showing that perhaps when we take these NAD boosting supplements, maybe we’re not just gonna boost our NAD … but we might also be bumping up some other stuff, that's perhaps not so good for us. So for example, Melanie’s been worrying about this particular enzyme that can get cranked out when mice take these boosters. And this enzyme can drive changes to our genetics... and it maybe could increase our risk of cancer.[42] And y’know there is this one study that took mice at increased risk for pancreatic cancer, it gave them a NAD booster - and found that yes - it upped their risk for getting cancer.[43]
It's early days here… and there's just a lot we don't know. About the benefits or the risks…so I asked Melanie …
WZ Given all these unknowns, what do you tell, like older people in your life who are like, “I want to be healthy for the longest period of time? Like, should I take these precursors now or not?”
MM Yeah. I've always been hesitant …
WZ: You think it’s too soon?
MM It's too soon for me. Exactly. That is, that is it. It's too soon for me. But a lot of the NAD researchers, I would say, are just running away and selling it. This is an unregulated market and people are running away with it. Hahah … I hope they don't cancel me for this!
WZ Hahaha
Chapter 4: Is Metformin a Game-Changer?
So if you're slamming down the NAD boosters… as your Holy Grail… maybe you chose poorly…? But on the shelf of cups to choose from… and sorry if you haven't watched Indiana Jones in a while cos this analogy, you’re gonna get lost a little … but on that shelf of cups to choose from there's a drug that's been getting a lot of attention in this space, and it looks tantalizing … attracting headlines like "Anti-ageing pills are real, and some of us are taking them without knowing it."[44] And if you want to know more about this, there is one guy that everyone is talking to: Nir Barzilai, a professor at Albert Einstein College of Medicine in New York.[45] And he’s been thinking about this stuff for a long time …
NB Even before I became a medical student. You know, when I looked at my grandfather, I said, you know what's going on? How come he when he was young, he had all those stories of bravery and achievement, and he barely can walk now?
And so Nir wanted to know - how can we stop this from happening? Which took him to this drug that so many people are excited about. It's called Metformin. It comes from this gorgeous purple flower called the French lilac[46] ... and people have actually been using it for ages, saying it can work for all kinds of things ...
NB Metformin was used by mothers, grandmothers, healers to treat osteoarthritis, to prevent flu… [47] Lots of stuff.[48]
But today metformin is prescribed for type 2 diabetes, because it helps control blood glucose levels.[49][50] And it is a blockbuster drug, over 150 million people around the world take it[51]… But more recently … scientists like Nir have started thinking that maybe this drug could do a whole lot more … perhaps it could boost our longevity… And one paper in particular kind of jump started this …
NB There was a study that really excited me. It was kind of a shocking study because it took people that are treated in pharmacies in the UK …
They got around 180,000 people. And the researchers said —
NB Let's look at the people who had diabetes. Some of them were treated with metformin and others were treated with another drug.
They followed people for several years and found that those who were taking metformin … were less likely to die by the end of the trial – compared to those who were taking a different diabetes drug. And it was by around a third, which is quite a lot.[52] Since then other research has shown similar things – that metformin helps people with diabetes live longer[53]. And Nir says it's not only that…
NB People on metformin who have diabetes have less cardiovascular disease, they have less cancers[54][55], they have less cognitive decline,[56] Alzheimer's …
Early research in mice has also found that metformin can help with a bunch of other stuff that’s linked to aging, including reducing inflammation[57] and boosting antioxidants[58] – which could improve the health of our blood vessels. And Nir's like — well, if this drug is so great, at least for people with diabetes — what about the rest of us???
NB All of a sudden we said, you know what? Non-diabetics could do better on metformin?
And there is a little bit of evidence for this. So, like in that big UK study – y’know the one that shocked Nir? Well they found something pretty odd. And it's this: People who have diabetes who were on metformin actually lived slightly longer than those who did not have diabetes … what we’d tend to think of as the "healthy controls"! Now, it wasn't by a lot, but it was enough for Nir to take notice.
NB And that was kind of really cool. I mean diabetes decreases life span, OK? So we are expecting them to do worse, but they are on metformin and yet they do better
And it's studies like this that are really driving these exciting headlines – saying that metformin is the new anti-aging pill of our lifetime … but the thing is, there's been some newer research that’s gotten a lot less buzz. And if we were writing the headlines for these newer studies, it would be… Metformin doesn't make you live longer[59] [60]… like, these scientists out of Denmark[61] – they tried to replicate that big UK study – and they actually found the opposite thing – that people taking metformin for diabetes didn’t live longer than healthy controls.[62] Another huge study out of the UK compared people taking metformin for diabetes to a group without diabetes – and found that while in the first three years… the metformin group seemed to be living longer… after 5 years the trend reversed.[63] For Nir? He told us that he doesn’t think these papers are the nail in the coffin for metformin – and he's not losing hope ...
NB It's not about hope it's about evidence…
Nir says that what we really need now is a randomized control trial in older people – who don't have diabetes. And that study is exactly what he’s planning to do.[64] This would help tell us … if the drug actually does anything for aging, if you don't have diabetes. In the meantime, though, what metformin has going for it – unlike, say, NAD boosters[65] – is that Metformin is an FDA-approved drug.[66] And it's pretty safe.[67] Yeah there's some side effects to look out for, like nausea[68], plus a recent study in men, found that maaaybe it was linked to birth defects in their kids, we're not really sure …[69] But if you're not trying to father a child any time soon ... it seems pretty low risk. And Nir — he actually takes it.
NB I do. I do. I started this for pre-diabetes, which I'm not anymore for ten years, but it has measurable effects on my health. … [sings] Makes me feel so young. It makes me feel so young.
Chapter 5: How the Nerds Stay Young
Ok - the end of this episode is nigh! And here is where we're at… we're still waiting for the final word on metformin. This drug - it still could be exciting! But we're gonna have to wait and see. As for NAD boosters, we’re gonna give them a miss … So is there anything else that we've got?? That's what I asked Jim — you know, the researcher that sews the mice together …
JW When people ask that they have, like, their pen out, like, you must you must know something from your studies
WZ Exactly!
JW What do you take, what supplements? You must take all of them. No I don't –
WZ So what do you do? What do you tell people?
JW Yeah. This is the part where everyone. Yeah, everybody kind of. This is like the womp womp, response. Right? I tell people it's like … exercise, diet, and you're like, oh, we've been hearing that all the time. Who wants to do that? Boo!
Boo! Yes you’ve heard these before but we’ll say it again. Stuff like a healthy diet with fresh fruit and veggies, whole grains … olive oil … fish and nuts — that has been linked to living longer…[70][71][72] Research has found that exercise – while there’s some debate[73][74] about whether it can make you live longer, we have good research to show it can make you healthier for the years that you've got.[75]
And there’s a few other things that can help you win the longevity lottery …
So studies have found that being less stressed may save you from dying from heart disease.[76][77][78][79][80] I hate this one too; I get stressed all the time … stress management, I guess we should give it a go?
Something that’s more fun to give a go is — being more social, seeing mates, trying to avoid loneliness, that’s been linked to longevity[81][82]…. And one of the most surprising longevity boosters we came across: Hearing aids. Yeah, a study published this year found that people with hearing loss who regularly used hearing aids were 24% less likely to die compared to similar people who didn’t use them … we're not exactly sure why that is.[83] And finally: Don’t smoke. One huge study estimated that if you can quit before you’re 35, it can add around seven years to your life… [84] which is more years than you'd get from having a young mouse sewn to your belly!
So there you have it… diet… exercise ... stresssss management …
WZ But wait, what if we said it in a more excited way?
JW Exercise! Diet! Stress management!!!
WZ Yay!
JW Yay!
That's Science Vs.
CITATIONS
This episode was produced by Michelle Dang and Wendy Zukerman, with help from Meryl Horn, Rose Rimler, and Joel Werner. We’re edited by Blythe Terrell. Research help from Timmy Broderick. Fact checking by Eva Dasher. Mix and sound design by Bobby Lord. Music written by Bumi Hidaka, Emma Munger, Peter Leonard, So Wylie and Bobby Lord. A special thanks to all of the researchers we spoke to for this episode, including Dr. Janet Choi, Dr. Gideon Meyerowitz-Katz, and Dr. Xue Li. A special thanks to the Zukerman Family and Joseph Lavelle Wilson. I’m Wendy Zukerman. I’ll fact you next time.
[1] In the nearly 4,000-year-old Epic of Gilgamesh, the titular hero is king of the Mesopotamian city of Uruk. He befriends the wild warrior Enkidu. When Enkidu dies, Gilgamesh sets out to conquer death and consults the wise Utnapishtim who offers him two routes to immortality. First, he is told he will escape death if he stays awake for a week straight; he fails and falls asleep. His second chance is to consume an herb found underwater.
[2] In the 16th century, the famous Spanish explorer and conquistador Juan Ponce de León led the expedition around the Caribbean islands and eventually into Florida to find the Fountain of Youth, a magical water source supposedly capable of reversing the aging process and curing sickness [1]. Although the explorer made no mention of the Fountain of Youth in his letters, led by the rumors, the expedition continued the search and many perished.
an executive order issued by Qin Shihuang, demanding that his subjects search for an immortality elixir that would keep him alive forever
[3] Fig 3 https://longevity.technology/investment/report/q3-2023-longevity-investment-report/
[2023 was more on magnitude of millions, previous years 2021-22 were billions]
[4]https://www.forbes.com/sites/alexzhavoronkov/2024/02/27/the-kardashian-of-longevity-is-bryan-johnson-good-for-the-nascent-longevity-biotechnology-industry/?sh=9b73d8460b7c )
[6] Parabiosis was invented in 1864 by the physiologist Paul Bert in order to see whether a shared circulatory system was created. Clive McCay, a biochemist and gerontologist at Cornell University in Ithaca, New York, was the first to apply parabiosis to the study of ageing, but this technique fell out of favour after the 1970s … [Renaissance] Since 2005,a number of papers have reported the anti-ageing effect of heterochronic parabiosis, which is joining an aged mouse to a young partner.
[9] Parabiosis was invented in 1864 by the physiologist Paul Bert in order to see whether a shared circulatory system was created. Clive McCay, a biochemist and gerontologist at Cornell University in Ithaca, New York, was the first to apply parabiosis to the study of ageing, but this technique fell out of favour after the 1970s
[10] Researchers from a variety of different fields (e.g., endocrinology, metabolism, transplantation, nephrology, radiology, allergy and immunology) started to take advantage of the parabiosis model for their own scientific investigations. A main question at that time was whether transmissible, humoral factors present in one animal have a physiological effect on its adjacent partner.
[11] Under isoflurane anesthesia, incisions were made through the skin and fascia on opposing lateral
sides of the abdomen of each mouse followed by suturing of the fascia and suturing of the skin.
[12] Figure d Lean mass (g) Old HET vs Old ISO https://www.nature.com/articles/s43587-023-00451-9
[13] Review 2017: The hallmark of aging is the decline of regenerative properties in most tissues, partially attributed to impaired function of stem and progenitor cells. In the parabiosis experiments, it was elegantly shown that factors derived from the young systemic environment are able to activate molecular signaling pathways in hepatic, muscle or neural stem cells of the old parabiont leading to increased tissue regeneration.
[14] Senescent cells have a lifetime on the order of days to weeks [25] and are therefore continually produced and removed over the lifespan. Their removal is carried out by immune cells including NK cells and macrophages [26]. … Parabiosis between a young and old mouse, called heterochronic parabiosis, reduces senescent cell levels in the old mouse, while raising senescent cell levels in the young mouse. … The mechanisms by which heterochronic parabiosis exerts its benefits remain unclear. Effects are attributed to blood-borne factors such as pro-inflammatory factors [30], or to the recruitment of young immune cells
[15] Senescence is cellular program that induces a stable growth arrest accompanied by distinct phenotypic alterations, including chromatin remodeling, metabolic reprogramming, increased autophagy, and the implementation of a complex proinflammatory secretome
[16] In the parabiosis experiments, it was elegantly shown that factors derived from the young systemic environment are able to activate molecular signaling pathways in hepatic, muscle or neural stem cells of the old parabiont leading to increased tissue regeneration. Eventually, further studies have brought to identify some soluble factors in part responsible for these rejuvenating effects, including the chemokine CCL11, the growth differentiation factor 11, a member of the TGF-β superfamily, and oxytocin.
[17] one of the anti-aging factors circulating in the blood: oxytocin, a nonapeptide produced by hypothalamus, which is involved in parturition and bonding. They observed that oxytocin levels declined in old mice (18-24 months), and when injected subcutaneously into aged mice, oxytocin recovered the regenerating capacity of muscle cells upon cardiotoxin injury.
[18] Here we report that oxytocin—a hormone best known for its role in lactation, parturition and social behaviours—is required for proper muscle tissue regeneration and homeostasis, and that plasma levels of oxytocin decline with age.
[19] These results demonstrated for the first time that oxytocin treatment can promote neural differentiation of the ADSCs in a dose-dependent and time-dependent manner. Oxytocin has a significant role in neurogenesis
[20] As blood samples taken immediately after detachment contained a mixture of old and young blood (Extended Data Fig. 2a–c), we initially chose to quantify methylation changes in blood after a 2-month detachment period. At this time point, we could investigate whether epigenomic remodeling on exposure to young circulation persists without young blood contamination, as we did not observe blood crossover 2 months after detachment … Fig. 2d, Percentage of blood (left) and bone marrow (BM, right) crossover after 2-month detachment
[21] Experimental groups for the longevity study were isochronic old (old ISO) and heterochronic old (old HET). … Experimental groups included isochronic young (young ISO), isochronic old (old ISO) and heterochronic old (old HET). https://www.nature.com/articles/s43587-023-00451-9
[22] They found that heterochronic parabiosis reduced senescent cell load in the old parabiont and mildly increased senescent cell load in the young parabiont. This suggests that the rejuvenating effects of parabiosis may be due, at least in part, to reduction of senescence cell accumulation in the old mouse.
[23] The results from this study using yFFP in patients with AD demonstrate that treatment with yFFP is safe and warrant further exploration in larger double-blinded clinical trials that use measures that are designed to detect change within the treatment time frame and are powered to determine efficacy.
The Plasma for Alzheimer Symptom Amelioration (PLASMA) study randomized 9 patients under a double-blind crossover protocol to receive 4 once-weekly infusions of either 1 unit (approximately 250 mL) of yFFP from male donors or 250 mL of saline, followed by a 6-week washout and crossover to 4 once-weekly infusions of an alternate treatment. … After an open-label amendment, 9 patients received 4 weekly yFFP infusions only and their subjective measurements were unmasked.
[24] On functional measures, there was improvement on the Functional Activities Questionnaire (−4.56 points; 95% CI, −6.11 to −3.01; P = .001) and the Alzheimer’s Disease Cooperative Study Activities of Daily Living
[25] https://healthnews.com/longevity/longevity-supplements/nicotinamide-mononucleotide-nmn-may-be-the-miracle-cure-for-aging/
[27] Serving as crucial co-enzymes for redox reactions and co-substrates for NAD+-dependent enzymes, NAD+ and its metabolites function as a regulatory hub controlling a broad range of physiological processes, including redox homeostasis, genomic stability, gene expression, RNA processing, energy metabolism, immunity and inflammation, and circadian clock.
[28] Given that DNA damage-activated PARPs account for up to 90% of cellular NAD+ consumption, the DNA repair activity is highly dependent on the cellular NAD+ concentration.
[29] The constant challenges from endogenous ROS/RNS or exogenous insults, such as radiation, chemical mutagens and carcinogens, render the DNA damage a relatively common cellular event. … As key regulators of multiple DNA repair pathways, PARPs and sirtuins modulate the post-modification of repair components using NAD+ as co-substrate (Fig. 4). Consistently, NAD+ deficiency leads to an impaired DDR and an increased genomic instability, suggesting an interplay between genomic stability and NAD+ metabolism
[30] Fig 3. … Ageing is associated with aberrant proinflammatory immune cell activation or ‘inflammageing’, leading to sustained low-grade inflammation. This is caused in part by the accumulation of senescent cells, which via a senescence-associated secretory phenotype (SASP) promote the phenotypic polarization of macrophages towards a proinflammatory M1 state, thereby driving inflammation. There is evidence that in response to the SASP in these macrophages expression of the NAD+ -consuming enzymes CD38 and poly(ADP-ribose) polymerases (PARPs) increases, leading to NAD+ level decline, and that these mechanisms importantly contribute to the decrease of NAD+ levels in ageing. … . There is evidence that the ageing-associated loss of NAD+ is related to increased expression of PARPs, which can be caused by increased levels of DNA damage and the need for DNA repair during ageing
[31] NAD+ concentrations in humans may be ~10%–80% lower with advancing age (2–8). Additionally, numerous diseases are as- sociated with reduced NAD+ levels, including metabolic disorders, cancer, and neurodegenerative diseases (1,9). Although such declines in NAD+ levels have not been observed univer- sally across all tissues
[32] Metabolic/Diabetes: Additionally, a decline in NAD levels is closely related to the development of various metabolic disorders, including diabetes and fatty liver disease. In addition, many studies have revealed that administration of NAD precursors, such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), efficiently increase NAD levels in various tissues and prevent such metabolic diseases.
[33] NAD+ levels decline during ageing, and alterations in NAD+ homeostasis can be found in virtually all age-related diseases, including neurodegeneration, diabetes and cancer. … neuro-muscular, cardiometabolic, liver and kidney diseases
Muscle: Aged muscles also have diminished regenerative capacity203,256,257 and NAD+ content203,258, thus indicating that similar mechanisms might be implicated in ageing-related declines in muscle mass and function.
Neurodegenerative: Neurodegenerative disorders characterized by accumulation of misfolded and aggregated proteins and associated with severe pro- teotoxic stress—such as AD, PD, ALS and prion disease—have also been linked to NAD+ depletion197,198 and altered NAD+ homeosta- sis199,200.
[34] Indeed, we previously showed that NAD+ supplementation improves synaptic connectivity in the cochlea and prevents the progression of hearing loss in a premature aging disease model associated with dramatic hearing loss (Okur, Mao, et al., 2020). … Taken together, our results demonstrate the therapeutic potential of NR treatment for ARHL and provide novel insights into its mechanism of action.
[35] NAD+ precursors, that is, endogenous molecules involved in the synthesis or regeneration of NAD … we specifically focus this review on supplementation with nicotinamide riboside (NR); NR in combination with the polyphenol, pterostilbene; and nicotin- amide mononucleotide (NMN), as these compounds make up the majority of published clinical trials to date
[36] https://academic.oup.com/biomedgerontology/article-abstract/78/12/2435/7126788?redirectedFrom=fulltext&login=false
https://www.sciencedirect.com/science/article/pii/S2161831323013595
[37] The single somewhat reproducible beneficial effect of NR in these trials has been a reduction of inflammatory markers in whole blood or immune cells (26, 29–31, 33).
[38] Our results also provide initial insight into the effects of chronic NR supplementation on physiological function in humans, and suggest that, in particular, future clinical trials should further assess the potential benefits of NR for reducing blood pressure and arterial stiffness in this group.[This work was supported by NIH grants AG000279 and TR001082 and was completed while C.R.M. was a Glenn/AFAR Postdoctoral Fellow. Study pills, NR standards for metabolite analyses and partial funding support were provided by ChromaDex, Inc.]
[39] The whole blood NAD+ response to NR correlated with increased respiration and decreased proinflammatory cytokine expression in PBMCs, providing evidence that boosting NAD+ acts on peripheral immune cells to reduce systemic inflammation. [Nicotinamide riboside and matching placebo were supplied by ChromaDex, Inc. The company played no role in trial funding, design, conduct, data analysis or interpretation, nor in manuscript drafting or revision.]
[For fact-checking context – mitochondrial respiration in PBMC blood cells, which is linked to heart failure: Studies indicate that PBMCs may function as a feasible non-invasive novel biomarker of heart failure and surrogate for myocardial mitochondrial respiratory function [16,17].]
[40] Inflammation papers: Zhou et al 2020; Wang et al 2022; Brakedal et al 2022; Wu et al 2022; Elhassan et al 2019; Han et al 2023
[41] https://www.science.org/doi/10.1126/sciadv.adi4862 NR Table 1 - Duration
https://www.sciencedirect.com/science/article/pii/S2161831323013595#tbl2 NMN Table 2 - Dose & Duration
[42] Further, the enhanced NNMT activity and increased NNMT reaction products due to the conversion to nicotinamide from NAM, NR, or NMN supplementation might potentially be related to cancer development [166]. …
NR and NMN may increase nicotinamide levels, thus enhancing the NNMT activity due to the higher substrate availability [166]. NNMT catalyzes the N-methylation of nicotinamide, using S-adenosyl-L-methionine (SAM) as a methyl donor, thus yielding N1-methylnicotinamide (MNA) as a product and releasing S-adenosyl-L-homocysteine (SAH) [167]. NNMT activity can thus affect NAD+ biosynthesis and ATP production, as well as drive epigenetic modifications and impact gene expression by modulating the intracellular SAM/SAH ratio [167].
[43] Here we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest. … there was a significant increase in the amount of desmoplastic tissue in NMN-treated pancreata compared to controls, as indicated by Masson trichrome staining
[46] Metformin and other biguanides have taken inception from the French Lilac Galega officinalis. https://www.sciencedirect.com/topics/medicine-and-dentistry/galega-officinalis#:~:text=Metformin%2C%20class%20biguanide%2C%20is%20a,humans%20for%20diabetes%20%5B24%5D.
[47] In the 1940s, metformin was rediscovered in the search for antimalarial agents and repurposed to treat influenza, before its introduction, in 1957, for the treatment of adult-onset diabetes
[48] Its common names include goat's rue, French lilac, Spanish sanfoin and false indigo (Figure 1). Aerial parts of the plant were used medicinally in medieval Europe to treat plague, worms, snake bites, miasma, dysuria and St Vitus dance, and the plant was fed to livestock to increase milk yield
[49] Metformin is primarily used for the treatment of type 2 diabetes mellitus, particularly in obese patients. … Metformin was first synthesized and found to decrease the blood glucose level in the 1920s; however, it was not used for a long time. The use of metformin was rekindled in 1957, when the results of a clinical trial were published confirming its effect on diabetes.
[50] Metformin lowers blood glucose levels by inhibiting gluconeogenesis and increasing insulin sensitivity. Metformin also acts on the intestine, and reduces blood glucose levels and body weight by various mechanisms. … Metformin mainly acts on the liver and inhibits mitochondrial respiratory chain complex I, leading to an increased intracellular adenosine monophosphate (AMP)/adenosine triphosphate ratio. As a result, AMP‐activated protein kinase (AMPK), an energy sensor, is activated to inhibit gluconeogenesis 4 .
[51] Hence, it is not surprising that metformin is still the most commonly prescribed oral antidiabetic medication worldwide with the prescription rate of 45–50% of all prescriptions and taken by over 150 million people each year
[52] There were 7498 deaths in total, representing unadjusted mortality rates of 14.4 and 15.2, and 50.9 and 28.7 deaths per 1000 person-years for metformin monotherapy and their matched controls, and sulphonylurea monotherapy and their matched controls, respectively. With reference to observed survival in diabetic patients initiated with metformin monotherapy [survival time ratio (STR) = 1.0], adjusted median survival time was 15% lower (STR = 0.85, 95% CI 0.81-0.90) in matched individuals without diabetes
[53] Diabetics taking metformin had significantly lower all-cause mortality than non-diabetics (hazard ratio (HR)=0.93, 95%CI 0.88-0.99), as did diabetics taking metformin compared to diabetics receiving non-metformin therapies (HR=0.72, 95%CI 0.65-0.80), insulin (HR=0.68, 95%CI 0.63-0.75) or sulphonylurea (HR=0.80, 95%CI 0.66-0.97)
[54] Metformin users also had reduced cancer compared to non-diabetics (rate ratio=0.94, 95%CI 0.92-0.97) and cardiovascular disease (CVD) compared to diabetics receiving non-metformin therapies (HR=0.76, 95%CI 0.66-0.87) or insulin (HR=0.78, 95%CI 0.73-0.83).
[55] There was no association classified as convincing or highly suggestive from meta-analyses of observational studies, but some suggestive/weak associations of metformin use with a lower mortality risk of CVD and cancer.
[56] Meta-analysis of three studies showed that cognitive impairment was significantly less prevalent in diabetic metformin (Odds ratio = 0.55, 95% CI 0.38 to 0.78), while six studies showed that dementia incidence was also significantly reduced (Hazard ratio = 0.76, 95% CI 0.39 to 0.88).
[57] More and more evidence shows that metformin can regulate the function of macrophages in atherosclerosis, including reducing the differentiation of monocytes and inhibiting the inflammation, oxidative stress, polarization, foam cell formation and apoptosis of macrophages. The mechanisms by which metformin regulates the function of macrophages include AMPK, AMPK independent targets, NF-κB, ABCG5/8, Sirt1, FOXO1/FABP4 and HMGB1.
[58] In the case of ROS accumulation, metformin can induce the production of antioxidant proteins (SIRT3, GPx7) to maintain ROS homeostasis and reduce the level of oxidative stress.
[59] a study of almost 130,000 people with diabetes taking metformin were compared to a group without diabetes – and found that in the first three years… the metformin group seemed to be doing better… but after 5 years the trend reversed.
https://bmcpublichealth.biomedcentral.com/articles/10.1186/s12889-023-15764-y
[60] In summary, while reductions in weight, cardiovascular risk factors, and incident diabetes were achieved with metformin and lifestyle interventions in DPP, these interventions did not lower the risk of all-cause or cause-specific mortality over 20 years’ follow-up. https://diabetesjournals.org/care/article/44/12/2775/138471/Effect-of-Metformin-and-Lifestyle-Interventions-on
[61] In case–control pairs matched on birth year and sex or co-twin (sex, birth year and familial factors), incident Type 2 diabetes with treatment by metformin monotherapy initiation compared with no diagnosis of diabetes was associated with increased mortality in both singletons (IRR = 1.52, 95% CI: 1.37, 1.68) and discordant twin pairs (IRR = 1.90, 95% CI: 1.35, 2.67). After adjusting for co-morbidities and social indicators, these associations were attenuated to 1.32 (95% CI: 1.16, 1.50) and 1.64 (95% CI: 1.10, 2.46), respectively. Increased mortality was observed across all levels of cumulative use and invariant to a range of study designs and sensitivity analyses. - https://academic.oup.com/ije/article/51/6/1886/6775037?login=false
[62] Treatment initiation by metformin monotherapy in Type 2 diabetes was not associated with survival equal or superior to that of the general population without diabetes. Our contrasting findings compared with previous research are unlikely to be the result of differences in epidemiological or methodological parameters. … One line of epidemiological evidence has been particularly influential in generating support for this hypothesis, originating from a 2014 study by Bannister et al. … Given the widespread attention this study has received, we set out to reassess its findings.
[63] Within the first three years, metformin therapy showed a benefit over matched controls, but this reversed after five years of treatment. … The results revealed that T2D patients treated with metformin had significantly greater survival times than non-diabetic controls in the first year (STR = 1·237, p = 1·06 × 10− 10). However, this became non-significant after three years, and reversed after four years (STR = 0·972, p = 0·049), with survival time ratio decreasing further with longer study periods.
[65] https://www.fda.gov/food/gras-notice-inventory/agency-response-letter-gras-notice-no-grn-000635 . The agency has not, however, made its own determination regarding the GRAS status of the subject use of NR.
https://www.fda.gov/food/dietary-supplements/information-select-dietary-supplement-ingredients-a
nd-other-substances#category4 4. Ingredient is excluded from the dietary supplement definition under section 201(ff)(3) of the FD&C Act
[66] StatPearls: Metformin, an antidiabetic agent, was approved by the U.S. Food and Drug Administration (FDA) in 1994 for treating type 2 diabetes
[67] Metformin is generally considered safe and well-tolerated. However, adverse GI effects, such as diarrhea, nausea, and vomiting, are relatively common, affecting up to 30% of patients who take metformin
In 2019, added to WHO list of essential medicine: in 2019, the EMA included soluble and isophane (ie, regular and neutral protamine Hagedorn) insulin, gliclazide, and metformin for people with diabetes. (2023 list)
Since the introduction of metformin to T2DM therapy, countless number of patients have been treated successfully with this globally available medication having a favorable risk/benefit profile recommended by IDF guidelines as first line drug [31]. Hence, it is not surprising that metformin is still the most commonly prescribed oral antidiabetic medication worldwide with the prescription rate of 45–50% of all prescriptions and taken by over 150 million people each year
[68] StatPearls: Metformin is generally considered safe and well-tolerated. However, adverse GI effects, such as diarrhea, nausea, and vomiting, are relatively common, affecting up to 30% of patients who take metformin
[69] The team found that infants whose fathers filled metformin prescriptions in the three-month window before conception were more likely to have birth defects (5.2%, or 75 out of 1,451 infants) when compared to: infants whose fathers were not prescribed diabetes drugs (3.3%, or 36,326 out of 1,109,750 infants); infants whose fathers were prescribed insulin in the three-month window (3.3%, or 174 out of 5,298 infants) https://pubmed.ncbi.nlm.nih.gov/35344380/
[70] RCT: https://www.nejm.org/doi/full/10.1056/nejmoa1800389
In a multicenter trial in Spain, we assigned 7447 participants (55 to 80 years of age, 57% women) who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat).... The primary end point was a major cardiovascular event (myocardial infarction, stroke, or death from cardiovascular causes). In this study involving persons at high cardiovascular risk, the incidence of major cardiovascular events was lower among those assigned to a Mediterranean diet supplemented with extra-virgin olive oil or nuts than among those assigned to a reduced-fat diet.
[71] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408672/#:~:text=In%20this%20systematic%20review%20of,fish%2C%20and%20lean%20meat%20or In this systematic review, consuming a nutrient-dense dietary pattern was associated with reduced risk of death from all causes.Evidence suggested that dietary patterns in adults and older adults that involved higher consumption of vegetables, fruits, legumes, nuts, whole grains, unsaturated vegetable oils, fish, and lean meat or poultry (when meat was included) were associated with a decreased risk of ACM. These healthy patterns were also relatively low in red and processed meat, high-fat dairy, and refined carbohydrates or sweets.
[72] https://www.nejm.org/doi/full/10.1056/NEJMoa1613502 Among participants who maintained a high-quality diet over a 12-year period, the risk of death from any cause was significantly lower — by 14% (95% CI, 8 to 19) when assessed with the Alternate Healthy Eating Index score, 11% (95% CI, 5 to 18) when assessed with the Alternate Mediterranean Diet score, and 9% (95% CI, 2 to 15) when assessed with the DASH score — than the risk among participants with consistently low diet scores over time…. Common food groups in each score that contributed most to improvements were whole grains, vegetables, fruits, and fish or n−3 fatty acids.
[73] “Is physical activity a cause of longevity? It is not as straightforward as some would believe. A critical analysis” Therefore, based on the current evidence, exercise-based rehabilitation for cardiac conditions cannot be recommended to reduce all-cause mortality, although it can be recommended in terms of other health benefits.
[74] Another critical review: https://onlinelibrary.wiley.com/doi/full/10.1111/joim.13353#:~:text=The%20results%20show%20that%20exercise,RCTs%20comprising%20%E2%88%BC50%2C000%20participants. The results show that exercise does not reduce all-cause mortality and incident CVD in older adults or in people with chronic conditions, based on RCTs comprising ∼50,000 participants.
[75] https://jamanetwork.com/journals/jamacardiology/fullarticle/2530563 RCT: LIFE study https://jamanetwork.com/journals/jamacardiology/fullarticle/2530563 Among participants in the LIFE Study, an aerobically based, moderately intensive PA program was not associated with reduced cardiovascular events in spite of the intervention’s previously documented ability to prevent mobility disability.
[76] Observational study https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2767517 In this cohort study of 765 patients with new symptoms of peripheral artery disease, higher stress levels in the year after diagnosis were independently associated with higher risk of mortality in the subsequent 4 years.
[77] https://www.ahajournals.org/doi/10.1161/01.CIR.0000028145.58654.41 Perceived mental stress was associated with increased mortality from stroke for women and with CHD for men and women.
[78] https://www.sciencedirect.com/science/article/pii/S0735109712030306?via%3Dihub AMI [acute myocardial infarction] patients with moderate/high stress had increased 2-year mortality compared with those having low levels of stress
[79] Transcendental Meditation (TM) - 2006 review https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1482831/ Patient data were pooled from 2 published randomized controlled trials that compared TM, other behavioral interventions, and usual therapy for high blood pressure. There were 202 subjects,... The duration of the intervention was 3 months.
Compared with combined controls, the TM group showed a 23% decrease in the primary outcome of all-cause mortality after maximum follow-up (relative risk 0.77, p = 0.039). Secondary analyses showed a 30% decrease in the rate of cardiovascular mortality (relative risk 0.70, p = 0.045) and a 49% decrease in the rate of mortality due to cancer (relative risk 0.49, p = 0.16) in the TM group compared with combined controls.
[80] Another TM study https://www.ahajournals.org/doi/10.1161/CIRCOUTCOMES.112.967406?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed A selected mind–body intervention, the TM program, significantly reduced risk for mortality, myocardial infarction, and stroke in coronary heart disease patients.
[81] Loneliness is a risk factor for all-cause mortality [pooled HR = 1.22, 95% CI = (1.10, 1.35), p < 0.001] for both genders together, and for women [pooled HR = 1.26, 95% CI = (1.07, 1.48); p = 0.005] and men [pooled HR = 1.44; 95% CI = (1.19, 1.76); p < 0.001] separately.
[82] Here we show that, in the general population, both social isolation and loneliness were significantly associated with an increased risk of all-cause mortality (pooled effect size for social isolation, 1.32; 95% confidence interval (CI)
[84] Life expectancy among smokers who quit at age 35 exceeded that of continuing smokers by 6.9 to 8.5 years for men and 6.1 to 7.7 years for women.