The Overlooked Side of Autophagy Causing Aging Part 2

Foreign. Welcome back to Biohacking Beauty. I'm Amitay Eshel.

0:00

I'm Anastasia Hojayeva.

0:07

And today we are going to give you the part two of the of the autophagy school, school of self eating. Okay. And how your skin can eat itself back into a youthful state. Without further ado, let's continue. So last time we kind of broke down what autophagy is, why it won a Nobel Prize, the switches, everything around that. Now we're going to talk specifically about skin.

0:09

Yeah. So skin has a few characteristics that make autophagy uniquely important here versus some other body parts.

0:41

Okay. What makes it different?

0:48

First, skin has two very different cell populations living together. You have rapidly renewing cells such as keratinocytes in the epidermis, and they turn over about every 28 days in young adults. And that's kind of like why we often hear that soul cycle is about 30 days. And a lot of the times you also, when you judge skincare products, it doesn't really make sense to judge before that, you know, before that time period. But. And not a lot of people know that you also have very long lived cells and those are fibroblasts and melanocytes that can sit in the dermis for decades.

0:51

Yeah, yeah.

1:27

Those long lived cells are the ones that really depend on autophagy for quality control, if you think about it.

1:28

Yeah. Because they don't get replaced. Right. Again, that's why I'm a little bit irked by the, the hyper focus on mitophagy right now. Because when we talk about skin health, a lot of the times it's not about destroying, for example, something like the mitochondria and then replacing it with new. It's a lot about the maintenance. And specifically when we talk about mitochondria, there are other pathways for mitochondrial health. Actually that's only one out of five that are important because there is a capacity, as we say, to the amount of different types of autophagy you can do. So maintenance, aside from replacement, is extremely important.

1:34

Absolutely. Yeah.

2:19

So basically, because they don't get replaced just to hammer in the point, they have to keep themselves clean.

2:21

Yeah, yeah. If you think about it, the melanocyte, let's say on your cheek is.

2:28

Oh, we're back to the cheek on your forehead.

2:34

The melanocyte on your nose, it can be older than your car. Like it's pretty crazy to think about.

2:38

Yeah.

2:45

And then if autophagy fails. Yeah, that cell is stuck carrying damaged mitochondria, oxidized protein, misfolded proteins. So like the machinery, broken machinery for. Brought for pigment for years.

2:46

So how does this. How. What does it mean visually?

3:04

Yeah, so when you think about melanocytes, they're also the ones that are giving pigment to your hair. So hair grain is considered to be one of, you know, like, issues with autophagy. So melanocytes lose function, pigment production drops again, gray hair appears, and then uneven pigmentation on your skin, like this age spots, kind of sunspots. That's all tied directly to autophagy. There was actually a Beautiful paper in 2013 by Journal of Investigative Dermatology showing that keratinocytotophagy is one of the mechanisms that dermatitis is, you know, rooted in, but also that determines skin tone because keratinocytes use autophagy to degrade the melanosomes transferred to them from melanocytes.

3:07

Yeah, that kind of blew my mind. There is an ingredient we were looking at, like, to replace all the vitamin Cs. It's going to take a while, but they have like a literal little video, little gif of pigment kind of traveling to the surface. They have this little thing that kind of stops the pigment from appearing in the surface, and then it gets into an autophagy cycle and kind of broken down. So this is, like, mind blowing to me.

4:06

Yeah. I mean, what you're describing is kind of like a more simplified illustration of it. But in a way, what you're describing is sort of what compounds like resveratrol do and how they prevent pigment formation. And there's another ingredient. I always stutter when I have to say it. It's isoliqui Ritigenin. Yes. And so the isoliqui. ISO. Liqui. Ritigenin, it goes by islt, is a key component in licorice extract, kind of known skincare ingredient. So it inhibits melanin production by controlling tyrosinase enzyme activity, and it effectively addresses hyperpigmentation caused by UV damage. And for those of the listeners who doesn't know what resveratrol is, resveratrol is a potent antioxidant, polyphenol, known to reduce hyperpigmentation and dark spots by inhibiting melanin production. Again, kind of like similar to what you were describing. And resveratrol, of course, we've been using in our skincare for a while.

4:36

We use the patented form, the one that actually has a patent on hyperpigmentation reduction. Two things that are really cool with what you're saying. Number one, One.

5:46

Yeah. With fermented resveratrol.

5:54

Fermented resveratrol. But the thing is this, like I am dealing with, with melasma. I can tell you that it, it's, it's, it's a crazy difference if, if, for example, if I am not a good boy and I don't use, don't use the products and when I do. And something about resveratrol that's interest. It's interesting. It really coincides with how your body is, as we say here, targets like pigmentation. Very different from things, for example, like obviously like sunscreen or vitamin C, which are, which are less congruent with how the body does it normally. This is very, very known process as far as how the body looks at it. So that's a very good ingredient that you can, you know, that you can confidently add to your routine if you are someone who suffers or dealing with hyperpigmentation.

5:55

Yes. And then. So since today we're talking more about autophagy that's related to skin health, we should also talk about mitophagy and fibroblasts, I think.

6:48

Yes. Okay, so walk me through it.

6:59

Fibroblasts are your collagen factories, basically. They also have the highest mitochondrial demand of any cell in the dermis because making collagen is very metabolically expensive. When fibroblasts, mitochondria started leaking reactive oxygen species from UV exposure, from blood sugar spikes, from inflammation. Mitophagy tags those bad mitochondria with the tags. We talked about parking and pink one, pink one and parking and hopefully recycles them. That's mitophagy. So when mytophagy fails, the fibroblast accumulates what is called zombie mitochondria. They can't make ATP, so they're useless, but they're still producing and leaking reactive oxygen species. And that reactive oxygen species goes on to damage the collagen those fiber plasts are trying to make.

7:01

Yeah, you know, that's what I call splayed state mitochondria or leaky mitochondria. And we talked a lot about that. I mean, we talked around that with Dr. Scott Scher and you know how. And how blue peptide spray works. But more than that, like how methylene blue works.

7:55

Right.

8:14

That's kind of the main, one of the main functions of methylene blue.

8:14

Yeah, the psychologist.

8:17

What?

8:20

The psychologist, you said it's like methylene blue. Remember you had the analogy that it's like a psychologist, like your usual antioxidant. You know, it has to sacrifice itself. So Imagine now the mitochondria is leaking like a lot of reactive oxygen species. So you have, you have to have a lot of antioxidants and they all like sacrifice themselves for each reactive oxygen species versus mertiline blue. It kind of recycles itself so it can save you from a lot more reactive oxygen.

8:20

It saves the mitochondria from self sabotage, whatever it's called in whatever. Ask Carl Jung or whoever or Freud. Anyway, so mitophagy. Mitophagy failure, if you would, is literally why photoaged skin makes bad collagen.

8:52

Yeah, it's one of big reasons. And there is a paper to back this up. So There is a 2024 paper in biogerentology. They show that resveratrol activates AMPK in human dermal fibroplast and the UVA irradiated mouse skin active. Basically they saw that there is a triggering of autophagy, reduced ROS production and visibly reversed. They were able to visibly reverse roughness, redness and wrinkling from the UV exposure.

9:14

So the same SIRT1, the same Sirtuin genes gene, resveratrol, Resveratrol autophagy kind of axis that shows up in the longevity. Longevity conversation, longevity literature more generally as well. It's a very important component and obviously we talk a lot about it when we talk about nad. It's a very important component as far as like the operating the machinery of skin health.

9:44

Am I correct? Yes, yes. And so that 2024 paper complements an older foundational paper. And that's while we were kind of talk about talking about SIRT 1 and longevity space for over like 16 years now. So yes, there was a paper published in 2010 which established that resveratrol activates autophagy through SIRT1 and that if you knock out SIRT1, resveratrol can't induce autophagy anymore. So we know that resveratrol works through SIRT 1.

10:14

Okay, so third mechanism you mentioned is a mechanism that's extremely hot right now, which is senescent cells. Right. You call zombie mitochondria zombie cells, kind of as a play on zombie cells, which are senescent cells, right?

10:48

Yes, yes. And I mean that one could be arguably the most important for visible skin aging. So senescent cells are the cells that stop dividing and similar to how we were describing zombie mitochondria, that is does not produce in ATP, so it doesn't serve and is useless. So are the senescent cells. They're kind of like they are no longer functioning. And usually in your body, if cell cycle is done, you know, the cell is being recycled. But this particular. And there is like, different mechanism. Let's say there's. There could be apoptosis, where the cell actually dies. You know, it was sent to die. But these particular cells, they refuse to die, they refuse to be recycled. And worse, they secrete something called sasp, the senescence associated secretary phenotype. So that's a cocktail of inflammatory cytokines and matrix degrading enzymes, and they just release it around them and they basically like, why they're also called zombies, like zombie. You know, they're. They're making other humans zombie. Right. So this bad cells not dividing, cells that refuse to die, they're now affecting healthy cells. Make them the same through this sasp.

11:02

Yeah, that's what I kind of alluded to in the beginning when I said, you know, sometimes the problem, it's not that the cells stop working. The problem's actually worse than just cells stop working. So what does this, what you described right now, what does it do to the skin?

12:15

So some will damage collagen directly, some recruit inflammation. But as I mentioned, really the worst part of it all is that it spreads senescence to neighboring cells, which is called paracrine senescence. Paracrine is when something is close. So a small number of zombie cells can poison a large area of dormice all around them and spread.

12:29

Yeah, a paracrine is the worst. No, I'm kidding. They couldn't have just called it like adjacent senescence or neighbor senescence? No. Anyway, so how does autophagy intervene here?

12:52

It does it in two ways. First, when MTOR is suppressed, whether by rabomycin or by fasting or by caloric restriction, autophagy goes up and some cess production drops. So that's called a cenomorphic effect. You don't kill the zombie cell, but you at least stop the bad effect. You stop the damage, and then the second one will be the actual functional autophagy, which helps the immune system recognize those bad. Clear bad senescent cells and then effectively clear them out before they accumulate.

13:04

Interesting. And is there. So, yeah, that's something I think, important to understand. I think people think of senescent cells just like the fact that, you know, senescent cells drive aging. They are. They do. But not having. So there are studies showing that not having senescent cells or not having kind of knocking out the ability to have senescent cells doesn't actually. Actually, you might die faster. Like it's actually pro aging. Yeah. The issue is not having senescent cells. It is the process that leads to more senescent cells and then having more senescent cells. I had the talk. I'm just gonna name drop over here. A name that no one knows about. So I had the talk. I had a conversation with Dr. Pinchas Cohen, which is probably the most important mitochondrial researcher in the world. He owns a few patents. One is for moth C, which is a very popular peptide. Anyway, and we talked about name drop.

13:41

Oh, yeah, Name drop in our field. That's a name drop.

14:48

Yeah, exactly.

14:51

It's not like you were talking to Kim Kardashian or whatever.

14:52

He's the Kim Kardashian of mitochondrial health. That's how I call him. You know, head of the mitochondrial field in usc. But anyway, we talked about senescent cells becoming what kind of what telomeres were like a decade ago, where everyone were like. There was a craze also in skincare, by the way, on, like, reducing telomere shortening. Well, telomere shortening, which are the ends of your DNA, if they shorten, your cells can divide. It's not that if they're short, you're older. No, you're older because mechanisms are not working correctly. And now your theorems are short. Right. So that was a little bit of a tangent. But senescent cells are a big, big issue. Not because of themselves. It's because what led you to having those senescent cells? Right. Okay, you got.

14:55

Yeah, I got it. So 12 more minutes to break the rest of it down.

15:55

Okay, so let's be quick about that. One thing that I do want you to point out, many early things in longevity, we have data on skin cells or mice or rodent models. Right. Is there human data to what you're saying?

16:00

Yes, there is human data. This is one, I guess, we should really highlight. So, in 2019, Christina Chang and the team at Drexel University College of Medicine ran an explanatory randomized trial of topical rapamycin in the journal Geoscience. So participants were over 40. They applied rapamycin cream to one hand and a placebo cream to another hand. And they did that for, I think, six to eight months. Every day? Almost every day.

16:15

AKA contralateral design. So every person had their own control, which is quite cool.

16:45

Every person is their own control. Correct. So after six months, they biopsy the skin. The rapamycin had significantly fewer p16 positive senescent cells. Remember, we're using p16 as a tag Protein and then there will be a tough coming and the garbage bag will take out the improper cell.

16:50

Yeah.

17:13

So it had higher levels of collagen at the basement membrane. It had like overall, basically the. There was a significant reduction in fine wrinkles, skin tone, like improvement in skin tone and that kind of thing. So the rapamycin had like significantly looked better. So there was like biomarkers that we could attribute the effectiveness of topical rapamycin. And there was also visual effects.

17:14

Nice. So something cool is that rapamycin is pretty aggressive. It's a really nice study to show the relationship between like senescent cells aging, things like that. Of course, we talked about in the famous debunking of the guy talking about vampire exosomes. I talk about P16 and platelet derived exosomes and how they lower P16 as well. And we know spermidine also lowers that, which is pretty.

17:44

Yeah.

18:07

So just in the.

18:08

I mean, spermidine is the OG of like autophagy.

18:09

Yeah.

18:12

And all the different kinds of autophagy, not just like.

18:13

Yeah. So just to make sure that we're, that we're quick here, let's wrap things up and let's maybe talk a little bit about, you know, how, how to incorporate spermidine in, in a routine. Sometimes things are, you know, we talked a little bit about in the beginning about the fact that we don't always want autophagy running high. Right. And especially when we talk about rapamycin, because rapamycin is something, you know, important with rapamycin is that it's so suppressive to growth. It's also suppressive to the immune system. It's oppressive to healing. So using it consistently on the skin when we're young, when we're healthy, when we want other things aside from longevity, you know, optimal performance, resilience, things like that, it's a little bit of an overkill. The really cool thing about spermidine or platelet derived exosomes is that you could have, at least your skin can have a signal of longevity, of repair, can stop and repair morning and evening when you apply those things. But during the day, obviously you're eating, hopefully you're breaking your fast at some point. You're feeding those cells with the right nutrients and it flips back growth. Right. So we can have that seesaw motion we're looking for extremely better than with something as aggressive as rapamycin. Right.

18:16

Yeah. Yeah. Do you want to talk about how why would somebody need both spermidine in their regimen and platelet derived exosomes? Because you can't put them in the same product, for example.

19:37

No. So just. Yeah, exosomes are very, very tricky. They're very delicate ladies. Most 99.0.9999% of things you can't put them in, okay, needs to be in a special bottle, needs to be with very small amount of ingredients and things like that. So you can't use spermidine peptides, NMN for that matter. The way we boost NAD there is very unique because of that. But bottom line, exosomes are perfecting cellular function, cellular activity. So they themselves are not very good at or they're not mainly used to relay signals of renewal. They do have growth factors in them, but even those are supporting building of materials which would stimulate renewal in other ways. So they would just make autophagy work really well. But that's something that we didn't go over in 2024. There was a study, I think it was Frank Medeo, but I might be wrong. We'll try to have it in the show notes where they looked at spermidine and they found out that your genes that encode spermidine, remember we talked about those 15 genes, they rely on spermidine to be encoded. Meaning if you don't have enough spermidine, and I remind people that spermidine is something innate to your system, you have it, you, it lowers with age. Very similar to the NID story. If you don't have enough spermidine, autophagy doesn't happen. So they basically fasted, they knocked out spermidine out of, you know, a mouse model and they fasted these mice and, and, and autophagy didn't happen. So spermidine is at the base of what autophagy is. We're talking about, you know, reduction of senescent cells, things like that from exosomes. Spermidine is still an important factor for actions to even happen. So it's a very fundamental version of what that is. And spermidine induces autophagy separate from MTOR. So spermidine induced it through a different mechanism called EP300. So it's really good to cover something that you want to cover as far as cellular function goes in a few different pathways. Because for the most part, what we see by the way, for example, fasting isn't as effective at longevity, at expanding health span or lifespan, the more complex the animal is. So it's really, really good in, you know, in again C. Elegans or whatever. It's not that great in humans. It's like not as revolutionary. You can't like double someone's life by fasting. Right.

19:48

And also I think it depends on what health the person is in the health state.

22:32

But well, that to your point, what will happen is that you have different compensatory mechanisms. So there are more pathways that will compensate for each other. I'm trying to signal emergency for the body by not consuming leucine specifically or something like that to induce autophagy. There are other mechanisms that even mitochondria, by the way, if you really stress it energetically, it can diversify and can be. Instead of contributing energy, it, it can contribute different like nutrients. It's not really healthy, but it can happen. It's very new. It's like a year old field of study. A day old. Happened yesterday.

22:38

Anyway, so you are really in the know.

23:17

I know. Ooh, they called me mitochondrial.

23:20

You're in the pinhas Cohen, in the pinhascohen club.

23:23

Anyway, you got the point, right? Like we wanna cover many mechanisms to make sure there is no compensation. There is no like rewriting, uh, et cetera, et cetera, et cetera. Like a small thing that, that I'll, that I'll add, like, you know, if you're just as an example for a compensatory mechanism there, if you want to be like in ketosis, you shouldn't have really, really high protein and no fat and no carbs. Why? Because the body's like, oh my God, I have a lot of protein and I have no carbs. So what I'm going to do is I'm going to make sugars out of protein. That's why you need like high fat, moderate protein and then like you know, little to no carbs. It's because you really want to force the body to use the, the. Yeah. To use the fatty acids anyway. So that's a compensatory mechanism that you're, that you're hitting a few pathways in order to make sure that what you want to happen, happen. Same thing here. Ep 300 mtor, ampk, all the good stuff. But yeah, spermidine is really cool. We probably shouldn't do this podcast because in my opinion, spermidine is the new nad. Like in five years all the companies are going to be like releasing spermidine and now we're telling them what to do. But we're generous like that.

23:27

That makes it much more special that we are still the first and the only company to have spermidin in our skincare.

24:51

Yeah, actually not the only. There is one company called Rainbow that has spermidine in their product. Shout out to budding company that has a spermidine product. The difference is that we use sellviospermidine. So Selvi spermidine was really designed for cosmetics and spermidine is very tricky to kind of keep stable in cosmetic formulations. So we got really, we were very

24:57

lucky, lucky, you know that the University of Graph worked on incorporating it in their cosmetics and then we ended up getting all the knowledge and the ingredients.

25:24

The main researcher right now in the world is Medeo and he's on the board. He's one of the co founders of the company that patented Sellvio where the exclusive we have exclusivity for. So it's really cool to be there, to be in the bleeding edge, as I like to say.

25:35

I mean it's always about the source. Like it's we, we kind of. If people listen to our previous podcasts, they know a lot of the times when you look at skincare products and the label might say the same thing, like the key ingredient is let's say nad or the king within this permitine and the key ingredients, vitamin C whatever it may be, is the source of that ingredient is what's going to make a difference and determine the price.

25:55

So the last thing I want to say is this. I love how you tied it together with Resveratrol and SIRT1. Most of the skincare ingredients that people love and they think they're effective are going to get tied back to spermidine or to autophagy. Whether it is, you know, vitamin C as something that stops pigmentation, as we mentioned, whether it is things for barrier function. So there is another study that shows.

26:23

Yeah, it's really good for supporting skin barrier.

26:47

Yes, exactly. Specifically, specifically in humans studies showing spermidine is or autophagy is an integral part of a healthy skin barrier, which is

26:50

skin barrier is the foundation of health. You can't talk about anything, anything, anything. Be the procedures you want to do. If you don't have your skin barrier dialed in or like really potent ingredients too, you have to have your skin barrier.

27:00

Exactly. Collagen production we covered. You know, you can't, you can't. If you have old collagen, you can't like just like put new collagen there. For that matter, how do, how you create collagen, all of those things they rely on autophagy which relies on spermidine hyperpigmentation we mentioned. So mainly all of the things that you guys care, detoxification, all the Things that you guys care about as far as like how your skin looks, functions, et cetera, really goes back to autophagy and spermidine. And by the way, that's one of the hallmarks of aging.

27:16

Yeah, yeah.

27:48

So that's. I think we can leave it at that.

27:49

Yeah, I think that's really, really good. Before we wrap up, we need to read the review.

27:53

Review? Yes. The reason we need to read the review is this. Look, guys, if you like this podcast,

27:59

we like it too.

28:05

We like it too. And more people should like it. No more people.

28:05

And the way we know if you like us, if you read a review, leave a review. If you don't leave a review, you actually don like us.

28:10

Yeah. And you're not welcome here anymore. But we need to make sure people are educated, make sure people know what's good for their skin, how to turn their health around or to optimize their health. That's what we're about. And reviews help. So because they help us, we're going to help you. And anyone who we read the review, they're getting a free product. So if we're going to read your review now, either email us young goose serviceungoose.com or DM us on Instagram Young Skincare.

28:16

Yeah.

28:54

And let us know. We read your review and we're gonna send you a free product. So go ahead for the win.

28:55

Okay. So short and sweet. I love the way they explain the science behind skincare. I always listen on my way to work.

29:03

Very sweet and very short.

29:12

Yes.

29:13

Who's the person?

29:14

Catalina Milado.

29:15

Let's go.

29:17

Dear Catalina, I hope you're listening right now on your way to work. I hope you get there safe. I hope the work day is great, productive and fun at the same time.

29:18

And you're reviewing her review?

29:28

No, I'm just realizing that a lot of people probably right now listening on the weird on the way to work or commuting back home. And I just hope everyone makes it home safe. Okay. And yes, please reach out to us either as I'm going to explain DM or email. And we will send you, you know what? This one, we'll send you a body cream. Yes, we'll keep it interesting.

29:32

We'll keep it interesting. Just for you to know, we're going to have a companion booklet that you can download with actionable information about autophagy, skin related. That's going to be in the show notes. So look for it if you're interested, if you want to dive deeper, if you want to basically have actionable items after this podcast.

30:00

Yeah, yeah. This was more so a deep dive. So, you know, when you hear autophagy, and you'll be hearing autophagy, you know, from everywhere, you actually understand the mechanisms and the relevance.

30:25

So.

30:37

So we hope this was helpful.

30:37

We do. Bye.

30:38

Bye.

30:40