The Hallmarks of Aging - LongevIQ Podcast with Dr. Bajnath

The Hallmarks of Aging: What Happens to Our Body as We Age?

Dr. Anil Bajnath, MDThe Hallmarks of Aging: What Happens to Our Body as We Age?
Dr. Anil Bajnath, MD

In this episode

In this episode, we’ll go over some of the key aging mechanisms that play a major role in the way that we age. Known in the literature as the hallmarks of aging, these changes represent our most current understanding of the aging process and how it affects our bodies.
But do we know enough yet to benefit from all of this research? Can we slow down or even reverse any of these processes? And if so, where do we get started?

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 hallmarks of aging, and then we’ll look into practical things we can all do that can influence these aging processes.

Also in this episode:

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

Related podcast episodes and articles with Dr. Bajnath

Main topics

  • (0:00:00) Podcast and episode intro, medical disclaimer
  • (0:01:28) The hallmarks of aging overview

Primary hallmarks

Antagonistic hallmarks

  • (0:13:12) Deregulated nutrient-sensing
  • (0:15:05) Mitochondrial dysfunction
  • (0:19:22) Cellular senescence

Integrative hallmarks

  • (0:21:37) Stem cell exhaustion
  • (0:23:29) Altered extracellular communication
  • (0:24:51) Quick recap of the nine the hallmarks of aging

Targeting the hallmarks of aging

  • (0:26:26) Factors that affect the hallmarks of aging
  • (0:31:31) Testing the hallmarks of aging
  • (0:35:45) How long does it take to reduce biological age?
  • (0:38:28) Symptoms that may be associated with the hallmarks of aging
  • (0:41:36) Intermittent fasting
  • (0:42:18) Dr. Bajnath personal healthy aging and longevity routine


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.

In this episode, we’ll go over some of the key aging mechanisms that play a major role in the way that we age. Known in the literature as the hallmarks of aging, these changes represent our most current understanding of the aging process and how it affects our bodies.
But do we know enough yet to benefit from all of this research? Can we slow down or even reverse any of these processes? And if so, where do we get started?

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 hallmarks of aging, and then we’ll look into practical things we can all do that can influence these aging processes.

Also joining us today, as always, is Amir Ginsberg, the founder of LongevIQ.
Welcome, Dr. Bajnath. Thank you so much for joining us today.

[00:01:26] Dr. Bajnath: Thank you so much for having me.

The hallmarks of aging overview

[00:01:28] Dr. Patti: We wanted to talk today about the hallmarks of aging, and this is something that you discussed really in detail in your book and in some of your work at the university. So we would love it if you would give us an overview of what are these hallmarks of aging.

If we look at aging as a whole process, there are multiple different factors that influence the body’s ability to, number one, accumulate the damage over a lifetime and, number two, repair the damage. And as we get older, sometimes those checks and balances are dysregulated, and we start accumulating more damage, and we lose the ability to repair.

[00:01:44] Dr. Bajnath: All right, thank you. Yeah. The hallmarks of aging refer to a consensus amongst the scientific literature that’s mapped out these nine fundamental hallmarks that regulate the biological aging process. And as we know, there are multiple different factors that contribute to age-related chronic diseases. And what we have found is that there are different levels of these hallmarks that influence each and every clinical disease imbalance or pathology. And these hallmarks are all intertwined.

And this kind of stems from a paper that was published back in 2010 with Lopez et al. in, I believe it’s cellular biology. He and his team mapped out and gathered the literature and synthesized all this into what is now conventionally accepted as the hallmarks of aging. And these hallmarks are broken down into different subcategories and are all interrelated like I said to one another.

We have these four core primary hallmarks, which cause the bulk of the damage. And we have a couple of antagonistic hallmarks that lead into integrative hallmarks, each compounding and leading into one another. If we look at aging as a process as a whole, there are multiple different factors that influence the body’s ability to, number one, accumulate the damage over a lifetime and, number two, repair the damage. And as we get older, sometimes those checks and balances are dysregulated, and we start accumulating more damage, and we lose the ability to repair. Looking at this through the lens of the hallmarks of aging, I think, is important, and it’s a fun topic of discussion because it’s the foundation of aging as a whole.

And as we know, we also have this concept of biological age versus chronological age, where our biological age is what’s happening on the inside, and chronologically or calendar age, we could be in our thirties, forties, or whatever, but biologically we could be even younger than that just because we’ve done our homework to really help with the self-preservation, mitigating exposure to damage and undoing some of the damage that we are exposed to over a lifetime.

Primary hallmarks

Genomic instability

[00:03:53] Dr. Bajnath: Now, just starting off with one of the primary hallmarks of aging is looking at what is known as genetic instability. So as we get older, we accumulate genetic damage throughout our lives, and it’s very important to understand where this damage comes from. This could be endogenous (from within), and sometimes it can come from exogenous.

For example, endogenous genetic instability could come from free radical damage that leads to reactive nitro nitrogenous species in our system that is pretty genotoxic.
Also, another pretty genotoxic commonly found metabolite is 4-Hydroxyestrone. As estrogen is metabolized in the liver, it could lead to these different estrogen metabolites. And the 4-Hydroxyestrone is most noted for being genotoxic and the one that is behind driving cancer formation. There are multiple different factors that lead to genetic instability, and it’s important to look at that and try to identify these different endogenous, and exogenous factors, to mitigate that exposure.

Generally speaking, genomic instability and its root cause for aging goes into basically the DNA structure. If you were to look at DNA, the double helix, it’s basically, as we all know, a complete set of instructions that we’re all born with 50% inherited by our biological mother and the other 50% from our biological father. And we know that there are approximately 3 billion base pairs that comprise approximately 25,000 genes.

Now, as we get older and our cells replicate, the ability to repair DNA when it’s exposed to these different reactive oxygen and nitrogenous species and other chemicals that we’re exposed to becomes a little bit tax. We have what’s called DNA proofreading repair enzymes that are very important for the cell cycle checkpoints and to make sure that before the cell moves into the next phase of replication, it has not accumulated too much damage and it’s able to repair any of those nucleotide bases that might have occurred through mutation.
So, the primary hallmark, again, starting off with genomic instability. And there are multiple different factors that could lead to those genotoxic exposures.
[00:06:05] Dr. Patti: So starting with those four primary hallmarks. The first one being genomic instability. What’s the next one?

Telomere attrition

[00:06:10] Dr. Bajnath: Well, the next one is telomere attrition. If you’re to picture your DNA as shoelaces, and at the end of our shoelaces, we know there are these little caps at the end.
Now as we get older, every year, our telomeres, the little caps on the end of our DNA, begin to weather and frail, and we actually lose telomerase activity at a very notable rate.

And that rate of telomere attrition or shortening of the telomeres plays a very important role because telomeres, in general, are very important for keeping the DNA structure, function, and integrity intact.
There are various proteins and enzymes that are involved that are responsible for just making sure that there is no accumulated damage taking place on those ends of the telomeres. So a telomere starts to fray and become shorter. They start to resemble broken DNA. As they become more broken, they’re more likely to be targeted by a process known as DNA damage response, which ultimately could lead to cell death.

Shorter telomeres are associated with accelerated aging and disease.
The enzyme that we try to preserve is known as telomerase. That basically helps maintain chromosomal length, and it’s found in various cells and tissues. It’s most notably found in lower concentrations in somatic cells, which are any cells other than reproductive cells, and in higher concentrations in stem cells and germ cells, like eggs and sperm.

Telomerase activity support

[00:07:38] Dr. Bajnath: As we get older, there are multiple different factors that influence our telomere activity. And there are some things that we could do to maintain our telomere length with pretty strong evidence.

Most notably, exercise. Exercise is one of those things that has been shown to really help support telomere structure, function, and integrity.
Stress reduction, maintaining a healthy weight, healthy diet, and smoking cessation are all different interventions that could be used to help preserve our telomerase activity. Additionally, there was a very fascinating publication that came out two years ago from Israel that looked at the role of hyperbaric oxygen therapy at boosting telomerase activity. And that’s been fairly reproducible in human clinical trials.
And then, there are other compounds promoted for helping with telomerase activity, and that includes a compound known as TA-65. TA-65 is an alkaloid derived from a Chinese medicine herb called astragalus. And astragalus is a herb known as an adaptogen, but it also has different benefits for the pulmonary systems in the lungs used traditionally in Chinese medicine. And that’s a compound that has some evidence to support that. It’s been shown to increase telomerase activity as a whole.

Epigenetic alterations

[00:08:52] Dr. Bajnath: And that leads into another primary hallmark, which is looking at what’s known as epigenetic alterations. Now, epigenetics is basically the gene environmental interface.

So far, these primary hallmarks are all centered around the structure, function, and integrity of the genome. So making sure that there’s no instability, that the ends of the genome and the telomeres are maintained, and then looking at what leads to epigenetic alteration.

Epigenetics literally means above the gene, and it’s not necessarily changing your DNA, but it has the potential to influence how your genes are being expressed. It’s almost like the volume control of how certain genes are upregulated or downregulated and expressed due to various environmental signals, and there’re various signals that could drive various gene expressions.

Epigenetics literally means above the gene, and it’s not necessarily changing your DNA, but it has the potential to influence how your genes are being expressed. It’s almost like the volume control of how certain genes are upregulated or downregulated and expressed due to various environmental signals, and there’re various signals that could drive various gene expressions.

On a molecular level, this has to do with methylation, acetylation, deacetylation, and all those other factors that could potentially influence the gene’s ability to wrap around what’s known as these histone proteins. Histones are these little arginine-rich bases that basically allow the gene to wrap around, and sometimes, as the gene needs to upregulate a specific signal, it will unravel and then get to the point where the gene needs to be expressed. Either deacetylate, methylate, or acetylate that specific gene for various functions and response to whatever signal it’s responding to.

I definitely think that epigenetics is one of our greatest abilities to harness the ability to really influence how our genes behave based on the various signals and input that our body is receiving.

This could lead to something known as chronobiology and looking at various peripheral signals in the environment that influence our body’s internal clock regulation.
But generally speaking, with epigenetics, there are so many different factors that could influence it, diet, nutrition, stress, and exercise. All these have the ability to influence our gene expression and turn up and down various forms of genetic regulation and volume control.

Again, one of the greatest opportunities for us on a daily basis is to try to feed ourselves healthy quality information so that we can enhance our favorable gene expression. A classic example is gonna be diet. If a diet is rich in pro-inflammatory foods, it’s gonna have the ability to influence these different nuclear response elements.
Nuclear factor kappa B (NF-κB) is going to be upregulated with inflammatory signaling due to some of the foods we eat. And that can have a whole host of downstream inflammatory cytokine responses. So again, there’re multiple different factors that could influence how our bodies respond to these different stresses, with food being one of our greatest opportunities to enhance our favorable gene expression.

Loss of proteostasis

[00:11:40] Dr. Bajnath: Which leads to the last primary hallmark, loss of proteostasis. And this has to do with a decline in the quality of proteins that keep our cells doing what they need to do.

After decades of toxins from the environment in our food assaulting our cells, they could become damaged. And your body has a natural defense against these damaged cells, and that’s called autophagy. Autophagy really helps remove some of these damaged accumulated proteins.

Another important factor that leads to the removal of these accumulated proteins is sleep. So at nighttime, when we go to sleep, we have this internal hydraulic pump that lives within our cerebral spinal fluid, known as the glymphatic system. And the glymphatic system wipes away and washes away from the neuron, all the alpha-synuclein, beta-amyloid, and tau-tangled proteins. And it’s been shown that just one night of sleep disruption could lead to higher concentrations of these protein metabolites that could accumulate and lead to loss of proteostasis in the body.
And this is most notably involved with neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

And this is actually the last primary hallmark in our list before we get into the next phases of the hallmarks, the antagonistic hallmarks.

Antagonistic hallmarks

[00:12:57] Dr. Bajnath: The antagonistic hallmarks are the responses to the damage from the primary hallmarks. So the primary hallmarks are the ones that really cause the damage, the antagonistic hallmarks of the defensive mechanisms that come into response due to that.

Deregulated nutrient-sensing

[00:13:12] Dr. Bajnath: The first antagonistic hallmark is known as Deregulated nutrient sensing. Your body has this built-in nutrient-sensing system, that its only job is to make sure that you’re eating enough healthy nutrients.
As you age, these systems start to break down, and have a hard time determining what you need. Years of eating processed foods and unnatural foods put added stress on these nutrient sensors and cause us to age faster. Our hypothalamus can be affected, causing us to become hungrier than normal and eat too many calories, further degrading our nutrient-sensing systems.

One of these deregulated nutrient signaling could be linked to leptin resistance, for example. With chronic inflammation, our body produces this neuropeptide known as leptin, and it binds to the arcuate nucleus in the hypothalamus and signals feelings of satiety or feeling full.
And sometimes, with chronic inflammation in our system, our body starts to become resistant to leptin, and we no longer have that signal saying: Hey, stop eating, right? So that’s one example of how deregulated nutrient signaling could influence our body’s ability to respond to normal cues to feeding.

Other signals also include IGF signaling regarding different growth factors in the body, either being fed or fasting. And when we’re in a fed state, there are different molecules that upregulate different proteins in the liver and everything else, and different signals, including IGF, which could be upregulated in response to being in a fed state. Being in a fasting state, as we’ve spoken before in previous discussions, could influence our mTOR signaling, the mammalian target of rapamycin. And when we’re in a fasting state, it’s been shown that we upregulate something called AMP kinase, which has the ability to inhibit the mTOR, and the mTOR turns on that molecular master switch to signaling autophagy.

Mitochondrial dysfunction

[00:15:05] Dr. Bajnath: Another very important antagonistic hallmark is mitochondrial dysfunction. As we know, mitochondria are the powerhouses of the cell. And we actually inherit our mitochondrial DNA from our mother. It’s where we generate the energy to carry on with the normal job of our body. The ATP production or energy production coming from these organelles is what keeps us going.

Time and free radical damage could lead to damage accumulation to the mitochondria and leads to less energy production, making you slower and more lethargic. This decline is most often seen first in tissues with high energy demand, like the brain and heart.

This is one of the reasons our mental function faculties decline as we get older. And this hallmark has become a major focus of anti-aging research. If we can keep ourselves powered, they can keep doing their jobs for longer and keep us healthier in this process.

And that leads to inflammaging. And inflammaging could be coming from multiple different factors. In my clinical practice, we use a form of testing called transcriptomic testing, which looks at how the DNA is behaving through assessing RNA function and looking at what genes are upregulated or downregulated.

And one of the things that I see all day with this test, unfortunately, is molecular hypometabolism, which has to deal with something called cell danger response. And cell danger response in the literature refers to when a cell perceives some sort of environmental threat, it takes on a defensive posturing where the allocation of energy and the triaging of energy has shifted away from being healthy, vibrant cells and manufacturing enough ATP to keep us healthy and vibrant. But it goes in towards becoming little battleships. And those little battleships take on that defensive posturing because of this perceived threat in the environment.

So again, if we’re living and being exposed to these different environmental threats, whether there’s infections or viruses or mold, most often is what I see. The mold could cause this cell danger response, and it could lead to a host of sequelae of dampening mitochondrial function.

Also, one of the things that I think is really important as we discuss autophagy is the concept of mitophagy, right? Mitophagy is basically the recycling of the mitochondria, and going in there and turning on that molecular master switch of triggering autophagy and the recycling of these various organelles. Organelles are basically the little structures within the cell.

And there are so many different things that could lead to mitochondrial dysfunction and uncoupled and mitochondrial damage. Just chemicals and toxins in the environment. And there’s a whole laundry list of different toxins that that we all know of. From the cosmetic products that we use topically to the cleaning products in our home, the cooking utensils that we have, the way our food is grown and harvested and prepared, preserved, and so forth. All of those could have an effect on mitochondrial function.

So that’s a very important hallmark. And again, there are so many different things and supplements out there that’s been shown to help with mitochondrial structure, function, and integrity. That’s a whole nother lecture that I could get into looking at PQQ and CoQ10 lipoic acid and, you know, looking at the different complexes within the mitochondria that are needed for ATP production. We’ll save that for another deeper dive, another day on mitochondrial structure function.

What’s also really interesting about mitochondria is that it’s higher in cells that have the most metabolic machinery, So our heart and our brain are loaded with mitochondria as well. And time could lead to dampening mitochondrial function leading to symptoms of fatigue and neurocognitive issues.

But another very interesting concept from an evolutionary biology perspective is what is known as the endosymbiotic theory of how we acquired mitochondria from a theoretical, evolutionary perspective.
It is said that these mitochondria used to be a bacteria that was living in an environment of cyanobacteria. More specifically and eons ago, somehow, our cells engulfed that bacteria, and since then, there’s been this symbiotic relationship between the mitochondria and the rest of the cell to help with energy production. This is very interesting because some of the subunits found within the mitochondria get damaged with certain antibiotics, for example. Very interesting stuff.

Cellular senescence

[00:19:22] Dr. Bajnath: The last antagonistic hallmark, which is my favorite topic, deals with cellular senescence. As we’ve spoken about this before, cellular senescence refers to cells that have reached their end mitotic division or accumulated enough damage over time where the cell is no longer able to divide appropriately and is not removed from circulation through programmed cell death or apoptosis, and it is not removed through the immune system.

And as these cells accumulate, they release these different proteins known as SASP proteins or senescent-associated secretory proteins or phenotype. And those proteins accelerate the aging process, hence the zombie effect that it’s spewing out these toxic metabolites, accelerating the conversion of other cells in the neighborhood to transform into senescent cells. We could find these cells accumulated in every single organ in tissue. Our immune system, our brain, our heart, our lungs, and our kidneys. Everywhere.

And this is an area of research where researchers are really trying to take a deeper dive into to see if removing these cells aggressively through pharmacological interventions will have an age reversal effect. So far, the studies are quite promising but should be used very responsibly.

And as we know, there are different lifestyle factors that we could implement right now to empower ourselves to help remove these senescent cells. That includes, as we discussed before, intermittent fasting or fasting as a whole, to turn on that upregulation of AMP kinase, which inhibits the mTOR and then turns on the autophagy, and autophagy is that cellular recycling pathway that we’ve discussed today. It’s good to turn on the garbage disposal switch, right? To clear out all the debris that’s accumulated in the system. We’ve discussed different compounds that could help support AMP kinase signaling, including berberine, fisetin, and quercetin, and there are different pharmaceutical agents, including dasatinib and rapamycin, that are being used to help with turning on that switch, so to speak. So that’s cellular senescence which is the last of those antagonistic hallmarks.

Integrative hallmarks

[00:21:23] Dr. Bajnath: This leads to the last two hallmarks, the integrative hallmarks. These lead to the culprits of a pathophenotype, meaning once these are kind of in motion, it really leads to disease and dysfunction.

Stem cell exhaustion

[00:21:37] Dr. Bajnath: The first integrative hallmark deals with stem cell exhaustion. As we know, stem cells are like a blank slate, and they are able to give rise to any other form of cells. They have the ability to go into different forms and lead to growth and regeneration.

There’s very interesting research behind various factors of these stem cells as we get older. And research right now on rejuvenating some of these factors has been shown to help turn on stem cells once again endogenously without having to take other stem cells.
It’s still in its infancy, but this refers to the Yamanaka factors, and the Yamanaka factors are basically these series of genes that have been shown to be downregulated, influencing stem cell exhaustion.

But there are different things that could help with stem cell mobilization.
And I think a lot of this has to deal with the microenvironment. Taking more of a philosophical approach to aging, sometimes, we need to look at the body as a micro-ecosystem or terrain. If that terrain is nurtured and we remove all the excess sugar, fat, salt, protein, and so forth, and we keep the microorganisms happy, there’s no overgrowth, and we’re doing enough physical activity and exercise to stimulate stem cells, repair and growth, there’s a nice homeodynamic balance between degeneration and regeneration.

There are multiple different things, pharmaceutical agents, and interventions that are being investigated right now for helping with stem cell exhaustion, with Yamanaka factors being the highest level.
That’s a whole nother conversation and definitely worth looking into for a deep dive. But again, stem cell exhaustion leads to our inability to repair ourselves. That accelerates the body’s aging process and inability to recover from any damage that’s been accumulated.

Altered extracellular communication

[00:23:29] Dr. Bajnath: Which leads into the last hallmark, altered extracellular communication. Altered extracellular communication has to deal with how cells communicate with one another. If there’s dysregulation in communication due to signaling molecules that are upregulated, for example, SASP proteins, those senescence-associated proteins, or they’re inflammatory cytokines, and there’s a pro-inflammatory cytokinetic milieu or environment – that’s going to have an ability for these cells to miscommunicate.

When there’s miscommunication, there are all sorts of things that could go awry, including the potential for cancer and autoimmunity. So this is where we lose the ability to recognize self, you know, in autoimmune conditions, where now all of a sudden our immune system is like, oh, we’re attacking these different tissues that are ourself, and we’ve lost the ability to differentiate between self and not self which is not good.

And once we have that altered extracellular communication and we don’t have the ability to recognize self from non-self, and we lose the additional autoregulatory capacity to remove damaged cells from our system, and they escape apoptosis or program cell death, and they now gain some oncogenic (* causing the development of tumors) activity, or they have a loss of tumor suppressor activity, now we’re concerned about cancer growth and proliferation. So there are a lot of different factors that come out of this hallmark.

Quick recap of the nine the hallmarks of aging

[00:24:51] Dr. Patti: That is fantastic. Wow. So much information. Let me see if I can just summarize really quick, you know, the hallmarks that you’ve just shared to kind of remind everybody, and then we can talk about how they’re all related to each other.

So you had the primary hallmarks. The genomic instability. So damage to the DNA coming from inside and outside cells. You had telomeres, the little caps on the ends of chromosomes, kind of wearing away slowly over time. You had epigenetic changes, so changes in how genes are expressed in the body, and then changes in proteostasis or loss of proteostasis. So abnormal proteins building up and causing damage, right? So those are our primary hallmarks.
And then there were the antagonistic hallmarks. So where the body’s protective mechanisms are being damaged or lost. So, nutrient sensing is no longer functioning well. We might eat too much food. We might not get enough nutrients into the right cells in the body.
Changes in the mitochondria. The little power factories in the cell are no longer able to do what they need to do. And then cellular senescence, so like old zombie cells that can’t divide anymore, building up in the body. And then we led into the integrative hallmarks where everything comes together, which is exhaustion of the stem cells. So the cells that are like the sources of healing and rejuvenation for tissues, those are no longer there for us, no longer able to do what they need to do. And then changes in how cells communicate with each other. So, cells are no longer able to work together and function well as a whole. Yeah. Is that a good kind of summary of what we’re all talking about?

[00:26:52] Dr. Bajnath: Absolutely.

Targeting the hallmarks of aging

Factors that affect the hallmarks of aging

[00:26:26] Dr. Patti: We can see how these things might interact with each other. But maybe talk a little bit about how an action on one hallmark might feed both backward and forward into different ones or how the hallmarks are related.

[00:26:39] Dr. Bajnath: I think it has to deal with a lot of lifestyle factors. You know, aging is very integrally related to diet and lifestyle. I’ve spoken about historically the unitary theory of the fundamentals of aging, which highlights the interdependence among the hallmarks of aging. Intervening in one fundamental aging process will influence and impact all other processes.

For us to sit here and say we’re gonna target stem cells and telomeres and everything else through specific isolated nutrients, I think, is myopic in perspective and approach to graceful aging. I think that when it comes down to it, a lot of this is going to be lifestyle-driven.

Mitigating environmental factors

Making sure we’re mitigating any potential exposure or damage that could lead to genomic instability, accelerate telomere attrition, epigenetic alterations, and ultimately loss of proteostasis on those primary causative factors. So, mitigating exposure to these different environmental factors is critical.

And that’s where it’s like, all right, maybe we should eat certain foods organic. I don’t wanna get too crazy with it, but, you know, there’s a clean 15 and the dirty dozen put out by the Environmental Working Group, and I know there’re criticisms on how reliable that is, and the accumulation of these different herbicides, fungicides, pesticides that leads to endocrine disruption. But one thing to take into consideration is how was your food grown and harvested? Additionally, if you do eat meat, was that grass-fed, grass-finished? Was there a hormone or antibiotics in the life of that animal that kind of carries over?

Environmentally acquired illnesses

I’m seeing individuals that are exposed to these environmentally acquired illnesses. Mold with mycotoxins and endotoxins from bacteria. And even a very ubiquitous bacteria that I find quite often in my testing called Actinomyces. So looking at the relationship between our environment, the immune system, and the potential infectious process. Do we have stealth infections festering below our normal immunological surveillance capacity to address this issue?

Chronic Epstein–Barr virus, which could also have an effect on all of this, right? In terms of mitochondrial function and dysregulated immune response with accelerating immunosenescence. So infections have the ability to accelerate that.

Healthy eating, fasting, exercise, and other modalities

Epigenetics, again, I think diet’s going to be your greatest opportunity.
Eating organic, and eating healthy, is very important.
Eating across a rainbow with different flavonoids, polyphenols, and so forth, and those different phytonutrients actually affect cellular function. You know, those phytonutrients bind to G protein-coupled receptors and actually influence signal transduction on a molecular level to influence gene expression.

Doing things like fasting could help with dysregulated nutrient signaling, cellular senescence, and loss of proteostasis.

Targeting one of these hallmarks through supplements could have some benefits. There’s research now that’s emerging that’s looking at different types of drugs and medications that could be used to help deal with senescent cells. There are different medications and supplements that could help with mitochondrial function.

Exercise, right? And its effect on telomeres.

Hyperbaric oxygen is another really great tool. I have a hyperbaric oxygen chamber in my practice. That’s one of those tools that could really help out with increasing oxygenation of the tissue, which thereby leads to an upregulation in our bodies’ endogenous antioxidant systems.

And then, on the horizon, different stem cell interventions are to come, whether it’s actually going for stem cells, therapy on yourself, Autologous or otherwise, or exogenous stem cells.

Biological rhythms

Looking at your chronobiology (* the study of biological rhythms) and Chrono rhythm, which deals with how your body is feeding, fasting, sleeping, and all these different light cues and signals. And that discordance, I think, is the beginning of triggering these downstream hallmarks when there’s an environmental gene mismatch from the chronobiology and the stress and the accumulation of that stress and that dysregulation that could ultimately just make our reserve less vital.


Also, genetics plays a very important role.
Everybody has dealt their own unique hand of gene inheritance patterns. Some people have won the genetic lottery, and others have not. And it’s very interesting how that influences aging as a whole. There has been a couple of genes that have been mapped out that have been associated with longevity.
So there are multiple factors there.


And then, looking at how we could help decrease or turn down the inflammatory volume control of all those inflammatory proteins because inflammaging could be linked to every single hallmark here as well.

Dr. Patti: What you’re saying is the nine hallmarks of aging aren’t actually the nine causes of aging, but more like nine mechanisms by which things in our environment and our body are impacting how aging shows up ultimately in our lives.

Testing the hallmarks of aging

[00:31:31] Dr. Patti: So what if somebody said, okay, there’s nine hallmarks of aging. How do I test where I am in each and every one of these nine? Do we need to test every single one of them? Is that even meaningful to do since they impact each other? Is there a way to do that?

[00:31:50] Dr. Bajnath: No. I use a test, no affiliation with this company, and I have no financial interests or anything, but I like to get the TruDiagnostic TruAge test for my patients that are going through my longevity program. It establishes a really nice biological age baseline, and it also looks at the rate of stem cell replication per year and your telomerase activity. It gives you an idea of immunosenescence, and it also looks at epigenetic alterations. So it kind of really hits on a lot of these different hallmarks.

Looking at these different commercially available tests, TruAge from TruDiagnostic is the one that I personally really love using because they actually break down methylation patterns on various specific genes and those different factors, which could tell you if there are any epigenetic alterations and key CpG island (CpGI) that are influencing specific pathways.

I really like looking at the biological age to see if we’re accelerated in our aging process. I also like to look at the Telemere and the stem cell replication components. Those tell us where we fall based on averages of the population and the rate of aging and everything else.
So to me, that’s probably the best test that I have. But I also use that in conjunction with another software in my practice. We actually get a Phenotypical age report card where we measure your lung function and look at arterial stiffness to get your biological age on your different tissues.

So that’s kind of like the baseline of how I like to map and see where my patients are at. The goal is, all right, let’s have fun at reversing our biological age objectively, and we have data to support that. All those different tools are what I use clinically to assess hallmarks of aging surrogates of hallmarks and age as a whole to establish that baseline.

Dr. Patti: And do you normally see that all nine hallmarks are roughly proceeding at the same rate? Or might somebody see, for example, their telomeres are still really long, but their epigenetic aging has proceeded super rapidly. Might there be a mismatch like that?

Dr. Bajnath: There are mismatches, and again, these are more so composites and comparisons to the general population. The stem cell mitotic number tells you the rate compared to others.
Same thing with the telomerase activity. It gives you kind of a percentile number of how you compare to cohorts of a similar age and where you land in that process. And ideally, you wanna maintain really good stem cell activity and really good telomerase activity and so forth.
But there is some discordance where I’ve seen people with really dampened stem cell function pretty darn good telomerase function and still accelerated aging on an epigenetic level. There are all sorts of different mismatches. Then you look at the lifestyle of this individual, and you’re like, all right well, you know, you’re 64 years old, but you’re biologically 71, your stem cells seem to be really pooping out on us, and we need to look at well, are you active? For example, grip strength is one of the most important things, fitness wise, and a very important surrogate marker for longevity.

And again, you got to look at also the different wellness wheels. Sleep, diet, nutrition, exercise, meaning and purpose, relationships – all those different factors need to be optimized.
And if one of those is dysregulated, it’s going to have a downstream effect on everything else. If you stop exercising, you find yourself restless in your sleep, or if you eat very poorly and you start gaining weight, and you lack motivation, or there’s a high stress day, and alcohol consumption, which leads to poor sleep and then caffeine the next day, all these different things, it’s super dynamic.
And it’s interesting to see how that is also further captured with wearable data and biometrics, like an aura ring or something of that nature. I love my aura ring. And I use this with my patients as well to look at the HRV and some patterns over time.

And you could oftentimes link these different lifestyle stress factors into patterns of dysfunction, which leads to behaviors that lead to patterns of dysfunction that sometimes could have rippling effects that could take days to undo that damage.

How long does it take to reduce biological age?

[00:35:45] Dr. Patti: On that kind of a note, when somebody discovers that their biological age is higher than their chronological age and they want to address that and slow down that aging, how quickly can we impact the rate of aging? How quickly could somebody’s changes in lifestyle or supplements or things like that actually begin to bring down that biological age so that it’s maybe in line with, or even less than, the chronological age?

Dr. Bajnath: There are two, three major studies out there right now that really broke that down.

Dr. Greg Fahy and his trial looked at a couple of different interventions, including growth hormone, DHEA, vitamin D, and Metformin, and their effect on the biological aging process. Then there was Dr. Kara Fitzgerald’s publication on biological aging in regard to using nutritional interventions. And all of them are studying a smaller population.

My approach to things is – everything is individualized N of 1. With research right now in medicine, everything is like, what’s the end value? How many people are participating in this study?

What kind of outcomes do we get collectively? And you’re just trying to mash up all sorts of data and end points when it comes down to it, looking at the person in front of you, your genetics is completely different, and the way you clinically respond to even drugs and medications is going to be different than the other person.

So I like to use these age related tests to paint that baseline. And then, I take a deep dive by looking at your genetic blueprint. I also look at sometimes that transcriptomic blueprint. I look at proteomics, metabolomics, microbiome, and all of that data and put it together. So my private practice with the Institute for Human Optimization is kind of a clinical manifestation of the courses that I teach at George Washington University.

The course director of the Omics of Medicine class. I’m teaching other fellows that are going for their boards in integrative medicine how to connect the molecular dots from genome to pathophenome. So I like to use this data to personalize a protocol for people.

To answer your question, you could sometimes see a shifting of the needle within six months. And it’s not one thing that we’re going to do, but a combination of things that we could do objectively. But I would not recommend doing the TruAge diagnostic test less than six months in between interventions to see a notable signal.

[00:37:52] Dr. Patti: And do you normally then check it every six months? Or, once you see it sort of stabilized, maybe you just don’t need to test again for a while?

[00:37:59] Dr. Bajnath: It’s very individualized because this testing is not cheap, and it’s not covered by insurance. So it really just depends on the individual. I like to at least get a baseline and then try to check it at a very minimum annually. Certain individuals have access to more resources than others, and they’re proactive with their health, and they want to get ahead of the curve and wanna make sure that the intervention has a positive signal. But I typically recommend every six to 12 months.

[00:38:24] Dr. Patti: Amir, do you have any questions you’d like to add to the mix here?

Symptoms that may be associated with the hallmarks of aging

[00:38:28] Amir: We mentioned a lot of testing, but are there any common symptoms that are associated with some hallmarks, for example, low energy and mitochondria problems, et cetera?

[00:38:39] Dr. Bajnath: When it comes down to determining whether there are cause and effect relationships with the specific hallmarks in a clinical manifestation or a symptomatic manifestation, like you said, one of the things that I see molecularly is downregulated mitochondrial function or mitochondrial dysfunction and fatigue. And that could be on a neuronal level and symptomatically manifest as early neuro fatigue, inability to focus, decreased assimilation of new knowledge, confusion, and disorientation. Mitochondria, as a whole, could be associated with that.

Also, stem cell exhaustion. You go to the gym, and you just can’t recover. You’re not mobilizing and recovering and regenerating like you used to. It could also be a manifestation of brittle bones and all sorts of osteoblastic-like activity on a bone level or fibroblastic activity on a tissue level. Even aches and pains could be associated with some of those hallmarks.

Dysregulated nutrient sensing. I mentioned leptin resistance, the role of feeding and fasting, and diabetes or Diabesity (* indicates both diabetes and obesity) is another classic example of an accelerated aging process. Literally, when you’re measuring hemoglobin a1c, you’re measuring the advanced glycated end products or AGES. It’s not a hallmark of aging those AGES, but it’s actually a mechanism of aging where it’s looking at the cross-linking of various sugars and proteins on a cellular level leading to insulin receptor site resistance, not good. And that also further shifts the body’s ability to triage and process energy appropriately.

Epigenetically, it’s hard to say, oh, this is an epigenetic symptom. But what I see on a transcriptomic level looking at specific genes that might be potentially upregulated due to inflammaging. I sometimes see a HIF1A upregulated, and that is very important for the cardiopulmonary circuitry. And people with HIF1A upregulation, their transcriptomic profile is more susceptible to decreased exercise tolerance, shortness of breath, and pulmonary hypertension because they’re clamping down on the vasculature.

It’s multifactorial on the symptomatic manifestation. There are multiple hallmarks of aging that influence disease manifestation. So if you were to take a disease like diabetes, there could be at least eight of these hallmarks that are involved and could be connected to the pathophysiological processes of type two diabetes. Same thing with Alzheimer’s. You can connect some of those dots there and see how each hallmark could have a role in disease development.

Top lifestyle options

[00:40:57] Dr. Patti: As we’ve talked, you’ve mentioned a few lifestyle factors or ways that people can impact lots of these hallmarks all at once. Exercise impacts many different ones. Sleep impacts many different ones. I know this is a huge, huge, huge topic, but maybe a little summary of how a few really high-impact activities might act on various hallmarks of aging. Some things we can do that might impact maybe multiple different hallmarks all at once or ones that might impact even one specific one really strongly.

Intermittent fasting

[00:41:26] Dr. Bajnath: A lot of this has to deal with diet and lifestyle, right? And I think that’s going to be one of our greatest opportunities to have the greatest impact on some of these hallmarks of aging.

And I got to say that there’s really great evidence about intermittent fasting. New England Journal of Medicine had a wonderful publication that looked at 18:6 intermittent fasting and its association with longevity and cancer reduction. It’s not every day that the New England Journal of Medicine discusses that. So right off the bat, adapting intermittent fasting kind of lifestyle, 18:6 at baseline. It shouldn’t be too hard to do. You finish dinner around 6 PM. You have your first meal around 12 the following day. It shouldn’t be that difficult. Maybe you squeeze in some gentle exercise and activity in the morning while fasting to have a greater thermogenic effect. It’s gonna work on dysregulated nutrient signaling and loss of proteostasis. It has an effect on epigenetics and also cellular senescence.

Dr. Bajnath personal healthy aging and longevity routine

[00:42:18] Dr. Bajnath: And back to the food conversation. Eating foods that are colorful and across the rainbow.


I’m sipping on a smoothie right now that has every single color in it.
If you were to actually break down these different foods and, more so, phytonutrients, you’re gonna see that every single pigmentation has a different alkaloid that has a different therapeutic clinical benefit. And the only way we could get these alkaloids into our system or these phytonutrients is through consuming these foods.

And I know some will say, oh, but the sugar. I’ve seen other things spike my blood glucose on CGM versus a smoothie. When I am tracking my continuous glucose monitor, this is not spiking my blood sugar at all, so I’m maintaining a nice flat curve.

What I put in my smoothie – blackberries and blueberries, and we know those berries are loaded with phytonutrients that have been shown to help with all sorts of age-related changes, blueberries for the brain, and all sorts of stuff. Raspberries, you know, raspberries are a really rich source of Ellagic acid. And Ellagic acid is really important for protecting the blood vessels in the vascular system. Strawberries so more darker, red pigmentations and purples and black. And then I put in there two oranges and a banana, so some orange and yellow. And then I have a green powder that has all sorts of grasses in there that I like to use. And then I put in a really clean veggie protein I get from Whole Foods market. No flavor. And I put the base of coconut water, and I love coconut water. Coconut water is essentially doing a liquid IV. It’s loaded with magnesium and potassium. I do the unsweetened Açaí, so there’s no sugar in that. I also put spinach in it. But yeah, that’s the foundation of the smoothies that I have. Almost daily. I just feel good doing this. It supercharges me. And then, you know, dinner comes around five o’clock, and I have my first meal.

My pattern so far today. I woke up, and I was able to get a little bit of sleep. I have a newborn. I went to the gym, had an incredible workout, and then that carried on to about 18 hours of fasting because I finished dinner around 6 PM yesterday.

Diet and supplements

And then I had my nutrient-rich smoothie, and then I’m gonna have a meal this afternoon. I try to lean into a kind of whole food, plant-based meal.

I will infuse some fish and seafood into my diet because if you’re to look at the blue zones and the centenarians and the research around that, they’re eating primarily a whole food, plant-based diet. They will infuse some fish here and there. They will do some meat here and there. They’re not rigid or incredibly restrictive, but there’s a strong emphasis on whole food and plant-based dieting. So that’s something that I do personally.

I also recommend supplements. I really like CoQ10. I do like the Omega 3’s. Are there supplements that I take to help with targeting some of these hallmarks? I take berberine. I find it has tremendous benefits with improving insulin sensitivity and other metabolic benefits, as well as helping with cholesterol, and it’s been shown to have some mild pcsk9 inhibition.


Sleep is critical, right? Clearing out those accumulated proteins that have lost their structure, function, and integrity. Sleep is one of the things that I try to prioritize, and now that I have the newborn, what I’m doing is just trying to get to bed even earlier, knowing that the sleep is gonna be disrupted throughout the night. So that’s how I’m trying to gauge it, and I’ve got the aura ring data to support that I’m not crashing horribly, you know, I used to hit optimal levels regularly. Now it’s very seldom, but it’s not horrible in the sleep number comparatively.

Movement and activity

I like to lift weights a few times a week. I do my sauna a couple times a week. Sauna’s been shown to help with all sorts of benefits, including BDNF, mobilizing toxins out of your system, and cardioprotective benefits as well. So I do sauna three to five times a week, generally speaking. I love to train in Brazilian Jiu-Jitsu. That’s something that I’ve been doing since I was in high school, and it’s just my personal passion.
So I’ve infused Jiu-Jitsu, weightlifting, and sauna as part of my physical activity on top of other things I have in my garage, rowing and boxing, and all sorts of other fun stuff. So movement and activity are critical.


Mindfulness-based practice is also very important. So I typically do some pranayama breathing exercises when I’m in my sauna for a period of time. I think meditation gratitude’s very important. All those things will help just overall wellness.

Community, finding your tribe

Community’s very important; that’s another big thing with the Blue Zones. Having your tribe is important, and your tribe should be pushing you to further yourself so that you can learn and grow. I personally strive to surround myself with individuals that I could just learn and grow from and that push me, whether it’s at the gym or intellectually with a medical conversation or socially with various topics, whatever it might be.

So those are some of the things we could adapt quality of life-wise that I think that we could do to improve our aging trajectory as a whole. And there’s a whole bunch of other toys that I could get into for biohacking, but that’s a whole nother conversation.

[00:47:13] Amir: I think it’s a really important takeaway for those interested in healthy aging. It’s not just the body. Our whole life, even our emotional state and our sense of community impact the hallmarks and our aging process.

[00:47:26] Dr. Bajnath: I agree. And I think that removing obstacles to unlock that healing process is what we should be striving for daily.
Once we get out of the way of ourselves, our body knows what to do to restore and get back to some level of homeodynamic balance.

[00:47:43] Dr. Patti: Wonderful message. Such an empowering message too. We have a lot more control over these processes than sometimes we might think that we do.

[00:47:51] Dr. Bajnath: Oh yes. It’s what we surround ourselves with, you know, the environment. We have these little antennas that connect to our DNA that receive these various signals and inputs from the environment, zeitgebers, and other signals, that influence how our body responds. It’s very fascinating.

[00:48:07] Dr. Patti: Thank you for sharing so much wisdom, so much really helpful, interesting information. I think this will help a lot of people connect the dots in different things that they’re hearing about the aging process in different places. And I know we’ve only just scratched the surface here. There’s just so much more to dive into and to know about each of these things. So we look forward to doing a few of those deep dives with you into some of these specific topics.

[00:48:32] Dr. Bajnath: Would love to.

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