The Updated 12 Hallmarks of Aging and What Do they Mean

The Updated 12 Hallmarks of Aging and What Do they Mean
Dr. Anil Bajnath, MD

In this episode

In a previous episode, we discussed nine key aging mechanisms known as the classic hallmarks of aging. Emerging research is now proposing even more hallmarks, expanding our understanding of the aging process. But does this really change our approach to healthy aging? And if so, how does it impact what we can do for longevity on a daily basis?

Our guest today is Dr. Anil Bajnath, MD, a functional precision medicine physician and an expert in anti-aging and longevity.
We’ll start with an overview of the newly added hallmarks of aging, and then we’ll look into practical ways to incorporate this new information into our lives.

Also in this episode:

Dr. Patti Shelton, MD, LongevIQ medical communications officer
Amir Ginsberg, LongevIQ founder.

Main topics

(0:00:00) Podcast and episode intro, medical disclaimer
(0:03:08) Disabled macroautophagy
(0:04:50) Chronic inflammation
(0:06:52) Dysbiosis
(0:08:14) GMOS foods effect on gut dysbiosis and other hallmarks
(0:11:11) Combining the 3 new hallmarks of aging with the previous 9 hallmarks
(0:12:33) Disabled macroautophagy and fasting
(0:16:26) Additional potential hallmarks of aging
(0:18:28) Do we know what causes the hallmarks of aging?
(0:20:43) Precision medicine – individual factors that affect aging
(0:22:28) Building realistic anti-aging and longevity protocols
(0:25:59) It’s about balance, not perfection
(0:27:28) Everything is an experience – Final tips and thoughts

Transcript

This podcast episode was edited to improve readability.

Podcast and episode intro, medical disclaimer

[00:00:00] Dr. Patti: This is Dr. Patti Shelton and you are listening to the LongevIQ Podcast. We discuss anti-aging and longevity science and how to benefit from it so we can all live long, healthy, happy lives. Just before we get started, a quick medical disclaimer. This podcast is for informational purposes only. It is not intended to diagnose, treat, cure, or prevent any disease or to provide or replace medical advice.

Please use this information to educate yourself as much as possible and share this information with a qualified health practitioner that you trust.

If you aren’t familiar with the classic nine Hallmarks, we recommend going back and listening to that episode first for context.
Welcome back Dr. Bajnath. Thanks for being here with us again today.

[00:01:31] Dr. Bajnath: Thank you so much for having me. It’s always a pleasure to be a part of this conversation.

[00:01:34] Dr. Patti: And we’ve previously talked about the nine hallmarks of aging. This classic, maybe 10 or so year-old framework for thinking about aging in the various processes that are involved. But you’ve let us know there’s a recent paper that’s come out that actually adds to that theory some new hallmarks of aging.

[00:01:52] Dr. Bajnath: Yes, actually, as of January 19th of this year, 2023, the same group Dr. Carlos Lopez and his group with various universities, have basically updated their original publication that was released in 2013 with some updated hallmarks.

So we know that originally there were these nine fundamental agreed-upon hallmarks that have survived the essential criticisms of multiple specialists within the field of aging and essentially have evolved into what’s now the 12 hallmarks of aging. So we have a new paper that’s fresh off the press that is expanding on those original nine hallmarks that have weathered the time over the past 10 years with three new addition, which I think are really important and exciting to kind of unpack.

Now the same nine hallmarks are still there as a part of the original release, but again, these three new additions that we could unpack here a little bit further.

[00:02:47] Dr. Patti: Yeah. So let’s go ahead and start talking about that. Maybe just let us know what the three are, and then we’ll unpack each one a little bit more.

The 3 new hallmarks of aging

[00:02:53] Dr. Bajnath: The three new additions are essentially disabled macroautophagy, chronic inflammation, and dysbiosis. And it’s interesting where they’re positioned within these hallmarks and how they’re all intricately related and influencing one another.

Disabled macroautophagy

[00:03:08] Dr. Bajnath: Disabled macroautophagy was settled within the primary hallmarks of aging. Primary being genomic instability, telomere attrition, epigenetic alterations, and loss of proteostasis.

And the argument was, well, the loss of proteostasis kind of gave rise to disabled macro autophagy because it’s not just proteins that need to be removed and have lost their ability to achieve balance, but it’s all these other kinds of molecules including glycated end products, you know, so sugars, and also, lipofuscin granules and these different fat molecules or lipid-associated molecules that undergo maybe lipid peroxidation that accumulates within cells.

So autophagy as a whole is needed to help remove and clear those cells of those different other non proteinaceous structures and also the organelles within the cell or the little compartments within the cell. Adding on the macro autophagy or the disabled macro autophagy to this process, I think, is a very important component of the aging process because we lose that body’s ability to recycle and remove these accumulated metabolites and end products that could essentially accelerate the aging process.

Which feeds into the next set of antagonistic hallmarks, the deregulated nutrient signaling, the mitochondrial dysfunction, and then cellular senescence.

And as we know, cellular senescence is one of those major hallmarks that accelerates the biological aging process due to its ability to release these harmful proteins, as we’ve discussed before in previous podcasts and discussions. Which leads to the terminal hallmarks, which are the integrative hallmarks, and the two additions are chronic inflammation and dysbiosis.

Chronic inflammation

[00:04:50] Dr. Bajnath: I see this all day long clinically with chronic inflammation, and I think it’s important to look at what’s causing that inflammation. Identify the source of inflammation, right? Clinically, what I do is I actually use transcriptomic testing.

I use a test called GENIE from ProgeneDX that shows us not necessarily what genes you have but think about it in the context of, well, if your genes are the instruments to your personal symphony orchestra, we’re measuring the harmony coming off those genes. Are certain genes upregulated and playing too loud, or are they playing too soft and too low and downregulated?

So I use a test clinically to identify patterns associated with inflammation, and immune dysregulation, to look at how the genes are behaving clinically. To identify, Hey, what’s going on here? Is it viral? Is it from an environmental component?

For example, I’m seeing individuals that are exposed to these environmentally acquired illnesses. They have a genetic predisposition with their haplotypes, a set of DNA variants of their HLA genes. Next thing you know, there is a combination of insults that triggers this part of the immune system that leads to a dysregulated response, and it perpetuates this chronic inflammation in the body. So that’s from an environmental component.

And then we didn’t even talk about food. How many foods are inflammatory? My goodness! How they’re prepared? Where they came from? All the different secondary kinds of metabolites that they release into our system, if they’re prepared incorrectly, that could have downstream endocrine dysregulation or hormonal imbalances. The types of oils we’re cooking with, you know, releasing smoke into our cells if we’re eating these damaged seed oils. So there are so many different potential molecular targets and associations nd I like to look at things in the full context on a very deep molecular level. Which also leads to the next hallmark, dysbiosis.

Dysbiosis

[00:06:52] Dr. Bajnath: And Clinically, dysbiosis, I see that all day. I run a stool analysis on my patients at a certain point in time once we get a better handle clinically on the inflammation to see what’s going on in their gut. And that stool analysis oftentimes shows us that there are these dysbiotic microorganisms that are living in the intestinal tract. Those organisms have the ability to precipitate inflammatory reactions in the gut.

And you got to keep in mind that the gut houses approximately 70% of our immune system in the form of gut-associated lymphoid tissue (GALT), which is hidden within these Peyer’s patches that line the digestive system.

So there is this communication between the gut and the immune system that’s so intricately related. And if there’s an imbalance within the gut, that could lead to all sorts of issues. And one of the most notable things that I see from this dysbiosis and chronic inflammation is something called endotoxemia or metabolic endotoxemia, which is basically when we eat certain inflammatory foods, we have shedding of the gut microbiome into circulation.

And I see that with the microscope behind me. I see bacteria in the blood, especially after you eat. These little rod-shaped bacteria. It’s coming from the gut. So if we’re eating a lot of processed foods and all sorts of different things, that has the ability to alter the gut microflora.

GMOS foods effect on gut dysbiosis and other hallmarks

[00:08:14] Dr. Bajnath: One of the very fascinating papers published a few years ago that I saw was that with these genetically modified foods, there’s actually plasmid exchange from the food to the microbiome, and the microbiome is uptaking these plasmids.

What’s a plasmid? Plasmids are this extrachromosomal DNA material that’s used in genetically modified foods for the plant to use to take up and release resilience factors.

So when they’re spraying the crops down with these herbicides, fungicides, and pesticides, the plant has protein structures needed to resist those chemicals. When you eat these processed GMO foods, not only are you eating the food that has the toxin on it, but you’re also consuming that plasmid genetically modified material that, when broken down by the gut, your actual microbiome is taking up those plasmids and releasing now some of those inflammagens itself.

A very interesting, you know, full circle concept that a lot of people and scientists don’t really take into account. There is this plasma exchange from genetically modified foods into the gut microbiome that alters and feeds this dysbiosis. Not to mention the type of foods we’re consuming, right? Are we meatatarians or carnivores? There’s nothing wrong with a carnivore. Just know that it’s going to shift very delicate ratios of the resident microbiome towards bacteria that are producing cadaverine and putrescine, which are these metabolites of microbial fermentation.

And then think about those names, cadaverine, and putrescine? You’re literally putrefying the bowel and cadaverizing the bowel. Food for thought on how the foods we eat influence dysbiosis, and that dysbiosis could feed forward into a very common issue, an increased gut permeability and that leaky gut syndrome.

Guess what happens when you have increased gut permeability? Instead of selectively absorbing these foods that are short-chain amino acids and peptide structures, you’re absorbing large sugar molecules, large protein molecules, and fat molecules that shouldn’t have been absorbed.

And when your immune system sees this, it gets confused and says: hey, you shouldn’t be here. It actually ends up taking note of that food particle and molecule and tags it. It’s taken up by what’s known as antigen-presenting cells, and then it brings it back and programs a different adaptive part of the immune system with Th1, Th2, and Th17 cells.
And then this could lead into essentially food sensitivities and allergies. And now, it becomes a feed-forward system with dysbiosis, leaky gut, and dysregulated immune system that could lead into food sensitivities and then ultimately autoimmunity, which is a true altered intercellular communication, which is another integrative hallmark.

So they’re all interconnected here, you know, with the chronic inflammation and the dysbiosis and everything else.

Combining the 3 new hallmarks of aging with the previous 9 hallmarks

[00:11:07] Dr. Patti: Yeah, everything is connected. It’s such a fascinating system. Do you think with these new hallmarks, the new kind of framework for aging or the additions to it, does that change the way that most people should be thinking about anti-aging and longevity lifestyle and treatments, or do our previous treatments still fit into the same framework?

[00:11:27] Dr. Bajnath: I think it expands upon the framework that we think about, right? We always used to say instead of chronic inflammation, inflammaging, and there are multiple factors that mediate inflammaging as we just unpacked and going upstream to identify those root causes and factors is critical at unpacking what’s driving not just the inflammaging response, but also, how it’s all interconnected with all their hallmarks that accelerate the overall aging process.

Also, dysbiosis is critical because, as I just mapped out, this gives us new avenues to focus on from an aging perspective.
Hippocrates said that all disease begins in the gut. So this gives that a new kind of approach to individualizing care. Do we begin with the dysbiosis in looking at that? And it’s part of the equation, so assessing dysbiosis and inflammation is definitely a part of everything that I do.

And, you know, I always advocate for trying to up-regulate the autophagy in our system through intermittent fasting and various supplements and other interventions as well, pharmaceutically and nutritionally.

Disabled macroautophagy and fasting

[00:12:33] Dr. Patti: That’s such an interesting connection, the autophagy. You’ve mentioned it a lot before when we were talking about the previous hallmarks, and then there’s a new hallmark that says maybe autophagy is impaired by aging. So does that change how effective it is to do these things like intermittent fasting? Or do we just need to do more of them to stimulate autophagy even more? How does that work?

[00:12:53] Dr. Bajnath: So, that’s a great question. I think the reason why it’s disabled is because it’s not induced, right? It’s an induction that we need to kind of turn on that molecular master switch, so to speak, through fasting. And that opens up the conversation about, okay, why is it disabled?

How many people are undergoing routine fasting?
When you start getting into fasting and its association with different cultures and ethnicities, and religions around the world, fasting is a very important component in most major religions. Fasting for lent, fasting for Ramadan, or other faiths, traditions, or religions. All these different holidays are kind of centered around removing certain foods and going through this time of fasting. So I definitely think looking at the role of fasting, how it’s used traditionally in these different cultures and how maybe we’ve gotten away from that maybe in, you know, pockets of society here in the west is something that I think should be explored a little bit because, when we fast, that’s how we’re able to turn on that switch and how we could up-regulate, those recycling mechanisms within the body to induce autophagy.

This paper talks about disabled macroautophagy. There’s also microautophagy. And the microautophagy actually could break down into, you know, there’s autophagy for every single little organelle, including mitochondrial, which is known as mitophagy as well.
So all of these little organelles need to be recycled and cleaned. And I think that’s induced ultimately through the fasting process.

Is this something you need to take a bunch of drugs, medications, and supplements for? Or is it something that we just kind of say, Hey, we’re going to set the intention of going through this almost, I don’t want to say cleanse or purge, this induction of autophagy with the intentions of implementing a fast.

So I definitely think the fasting component is one of our strongest resources that we could do, and some research says 18:6 intermittent fasting helps promote this low-grade recycling process. But I ultimately think three days of a fast or a fasting-mimicking diet is going to have the greatest potential at turning on that switch.

So that’s what I think is one of the greatest factors that we could leverage to help promote and stimulate autophagy as a whole.

[00:15:13] Dr. Patti: And just to make sure people understand, by a three-day fast, do you mean three days with absolutely no calories? Do you mean three days of reduced calories? What do you do for those three days?

[00:15:23] Dr. Bajnath: That actually deals with another hallmark, deregulated nutrient sensing. And Nutrient sensing of the liver looking at some of these other enzymes that are turned on with glycogen synthesis, or the enzymes that break down the glycogen in the body. So those are some of the greatest signals of feasting or fasting. And there are certain foods that are not going to have a major glycemic or protonation influence on nutrient signaling.

Various broths and low glycemic types of foods and berries could be potentially used in this fast that could be low calorie, low glycemic, low fat, and low protein. This is better known as a fasting-mimicking type of diet that was presented by Dr. Valter Longo.

So with that being said, I definitely think that’s one way of doing it, but ultimately I think that no food kind of water fast is going to be one of the best opportunities to really induce the greatest recycling, taking out the trash.

Additional potential hallmarks of aging

[00:16:25] Dr. Patti: Very important. Yeah. It’s so interesting that we have these new hallmarks. We had this structure that had been there for a decade. Now we have some additions to it. Do you expect more additions to it in the future? Do you think there may be some more hallmarks yet to be discovered? At what point will we feel like we maybe have a handle around this?

[00:16:41] Dr. Bajnath: I definitely think that there’s more to come. As our understanding of the molecular mechanisms of aging expands, I think there’s going to be a lot more opportunity to dissect these kinds of larger 12 hallmarks into subsets.

You kind of see how they’re all interconnected, starting with genomic instability and looking at all these things that potentially lead to intrinsic and extrinsic DNA damage. And these different damages could include multiple different things, including point mutations, deletions, translocations, double-stranded breaks and chromosomes and defects, and nuclear architecture that are disrupting gene integration as a whole.

And then the role of viruses as well. So there are so many different things that influence genomic instability and could be broken down into further compartments. And I think we’re going to see these be further dissected into further sub-compartments within the 12 hallmarks.

And then, looking at telomere attrition, that’s another key hallmark that we unpacked before.

But essentially, as the telomeres continue to shorten, there are going to be multiple different opportunities to help with optimizing and enhancing the telomerase factor here. We went over some of that before, looking at the different nutraceutical compounds, exercise, and the role of hyperbaric oxygen therapy to help enhance that.

And one of the things not mentioned in the hallmarks of aging is essentially the immune system and the immune response and the involution of the thymus as we get older and how that influences our body’s ability to have that adaptive immune response. That kind of ties into immunosenescent cells and, you know, this weathered older immune response. But how do you rejuvenate that? How do you prime that?

So there’s a lot of opportunity to unpack that further as we move forward.

Do we know what causes the hallmarks of aging?

[00:18:28] Dr. Patti: Is it the case that as we get older, the body is intrinsically more sensitive to some of these things that cause damage? Or are we just accumulating so much damage over time, and then as we get older, it starts to become more obvious? Or do we not know that from the research yet?

[00:18:45] Dr. Bajnath: As we get older, our ability to respond to adversity dampens. How we recover from exercise, I think, is one of the greatest examples. I’m in my thirties, and I train Brazilian jiu-jitsu. I grapple with college wrestlers and those college wrestlers. I’m telling you, it’s like riding a bull, and then the rate of recovery sometimes isn’t what it used to be. That’s, unfortunately, a natural phenomenon right now until we figure out ways to recover quicker, better, and keep up with things. But I think that’s a clear example of our body’s ability to adapt to that adversity and stress.

If you were to ask me what is health? You know, and I don’t think health is merely the absence of disease, but your adaptive capacity to have this homeodynamic, autoregulatory kind of process, meaning your body’s not in a state of stasis. It’s always oscillating. Whether that’s our pH, our body temperature, our auto-autonomic nervous system tone, our heart rate variability, whatever it might be, we’re always in a state of oscillation. So we’re not static. We’re in a homeodynamic state, and this homeodynamic state, based on these different signals and inputs, is going to influence our adaptive capacity.

When we lose that adaptive capacity in whatever system we’re looking at, whatever omic we’re looking at, due to all these different signals and inputs, that’s kind of when we start losing our health. So again, health to me is not necessarily the absence of disease but the loss of the homeodynamic adaptive capacity to auto-regulate.

[00:20:18] Dr. Patti: And essentially, you’re saying it’s both. It’s the aging process and the damage that we accumulate over time.

Precision medicine – individual factors that affect aging

[00:20:43] Dr. Bajnath: The thing is, aging is a phenomenon, right? We see it, and there are hallmarks that have been well-established. But, when we start really dissecting things from an N of 1 perspective, there are so many different signals and inputs that could come about, even potentially transgenerational, primordial, epigenetic imprinting.

For example, looking at the thrifty genotype, and people that were born during famine and the Great Depression having very unique epigenetic kind of signals and genetic predispositions towards obesity and holding on to fat because of that maternal programming.

So this is pretty well established in the literature as well known as the thrifty genotype and associated with times of famine that influence that programming in utero and the offspring or the child’s weight management. It’s very interesting.

So I always look at things in the context of N of 1 medicine and N of 1, essentially signaling that whoever you’re speaking to in front of you is a very unique person and being and that we can’t take these large clinical studies that have, N values in the thousands and try to apply it to this person sitting in front of you clinically.

As an MD and a precision medicine practitioner, I’m taking into account multiple different factors. Starting with your DNA blueprint. What hand were you dealt? What are the cards that you were dealt with genetically? Did you win the lottery, or, unfortunately, have been dealt a poor hand? And that poor hand on a molecular level or a genetic level could be polymorphisms or variants in gene expression.

So I always think of things in regard to the omics of medicine and connecting those molecular dots.

Building realistic anti-aging and longevity protocols

[00:22:28] Dr. Patti: A lot of people listening to this might be thinking, okay, now I’ve got even more things that I have to pay attention to every day for my longevity, and more will be likely added in the future. It could start to seem overwhelming for a lot of people. So how can we use this research effectively in our lives?

[00:22:46] Dr. Bajnath: It would be great to have this ideal roadmap and blueprint of what you need to do to target all the aspects of aging, and we have that, and we could try to execute that with precision and perfection.

But the reality is, oftentimes, life has another, you know, purpose and intention for you. And we could only do so much.
When you’re sitting down with somebody, and they’re telling you, hey, my mom just died, right? And the six months leading up to it, I couldn’t do anything. I was their caretaker. The amount of stress it put on me and the family burden because we didn’t want to put her in a home was really significant. My diet went to crap, I didn’t exercise, and everything went out the window.
Those things, those bumps in the road, happen, right? And oftentimes, Hey, I just lost my job, my kid, you know, is going through this issue. I don’t know what’s going on with them.

Life happens, right? Maybe, hey, right now, your sleep is going to be compromised because you got a newborn like myself, so what do you do to buffer that? Exercise gets compromised. Your social engagements get compromised, and your yoga might get compromised. All these different things kind of oscillate with the rhythms of life.

[00:24:04] Dr. Bajnath: And I think what we need to do for a healthy longevity program is stay to the pillars, focus on nutrition, exercise, and movement. Stress reduction, meaning and purpose, and great relationships so that we could always come back to that foundation.

And once we come back to that foundation, we’re going to be able to ride that wave or take on that bull, you know, in grappling in jiu-jitsu and just try your best, whatever it is. So I really think that from my clinical experience, it’s not always linear, and there are multiple bumps in the road.

When I speak to my patients, whether I spoke to them two to four weeks ago or three to three to six months after the facts, and getting caught up in between the stories that they share and they’re like, Hey, I couldn’t do that test because of this issue, or whatever it is.

It’s quite fascinating to hear, and I think that’s the difference between petri dish lab rat kind of studies and speaking to the human. And that human element is totally different, right? There are so many variables in that exposome in that environment. What’s penetrating your bubble and influencing those signals and inputs?

[00:25:12] Dr. Patti: That’s such an important message. There’s perfect, and then there’s real life. There’s a laboratory, and then there’s the real world. And just understanding that it’s okay that things aren’t always perfect and lining up just exactly right. We just respond.

[00:25:26] Dr. Bajnath: Yeah. And translating that information from bench to bedside is very unique. Just because you take resveratrol, is that going to have an influence on your sirtuin activity? So far, I don’t know. Research hasn’t really panned out on that, or it’s mixed. But at the same time, does resveratrol have profound benefits on hormone optimization and antioxidant capacity? Absolutely. There are so many different ways to look at how to navigate that, but translating this information from bench to bedside into actionable, meaningful outcomes so that it’s not daunting.

It’s about balance, not perfection

[00:25:58] Dr. Bajnath: Because one of the things is that if we get wrapped up in perfectionism, and we’re so obsessed with living in this bubble, I think that causes more damage and good.

I also believe in hormesis. I think a little bit of low-level stress will induce resiliency. So if we strive for perfection, and then God forbid, you eat a piece of fried food, you can’t tolerate it because you’re so pure inside.
You have a french fry, and all of a sudden, your world’s, you know, turned upside down. You, my friend, lacked resilience. And that’s not good either, right?

And we’ve had conversations about this. I try my best to eat a whole food plant-based diet, and I’m essentially riding that wave of being a vegan, but I want to be able to adapt and accommodate when and if needed. If I am stranded on a deserted island, I’m going to look for some fish to eat. I’m going to forge for some food and hunt, you know, I don’t think coconut water and berries will cut it. But that’s the thing, being able to be flexible with everything.

I can tell you stories all day long, I’ve had the honor and privilege of sharing in this therapeutic relationship with my patients, that are longevity enthusiasts, but they’re human. And it’s just amazing to hear the trials and triumphs that these individuals go through and what they try to do to accommodate these disruptions in their routines.

[00:27:16] Dr. Patti: Fantastic message. Like, On the one hand, yes, you can influence your aging process. You can have an impact on these things. On the other hand, you don’t need to be perfect. Remember to enjoy your life.

Everything is an experience – Final tips and thoughts

[00:27:28] Dr. Patti: Do you have any last words of advice or tips you’d like to give people out there as they think about these new hallmarks of aging?

[00:27:36] Dr. Bajnath: I definitely think the greatest opportunity is what’s in front of us at this given moment in time, which is our thoughts, words, actions, and behaviors. It’s important to have really well-meaning thoughts. If our thoughts and words that follow are that of the divine with good meaning, love, and intention, then our actions and behaviors will reflect that. Think about the cause-and-effect relationship on how that’s influencing ourselves and our gut microbiome, right? Because we’re actually outnumbered by those guys by order of magnitude, and we have more bacteria that habitat our system and our being than we do what we have perceived cells that make us, that’s a part of us per se.

Everything’s interconnected. We can’t get away from nature, and we need to work with nature, not against nature, to harness the power of that to unlock the healing mechanism within us by removing those obstacles and being very mindful with everything we do. But at the same time, have fun doing it.

Everything is an experience. We need to experience, you know, the flavors of life. In certain agricultural practices and winemaking, they call it the terroir of the experience, which is essentially what goes into the soil and the minerals and all the different factors that go into cultivating that planter product or wine, giving its unique experience. Everything is an experience because that wine that you consume will influence everything. The resveratrol content, the alcohol content, the flavonoids and polyphenols, and all the other things found within it. That’s enriching to our experience.

And don’t forget the concept of hormesis. We need a little bit of stress to make us a little bit more resilient. Pressure makes diamonds, yeah.

[00:29:24] Dr. Patti: Thank you for sharing so much helpful, interesting information about the aging process.

[00:29:29] Dr. Bajnath: It’s always a pleasure. Thank you guys so much.