If you spend a few hours daily steeped in NIH research, occasionally you'll come across something that really gets your attention.

It's happened a few times for us:

• Vitamin D - the steroid we get from the sun
• Psilocybin - will eat up mental health over the next few years
• Metformin/Berberine and AMPK pathways for aging
• Dr. Sinclair's Yamanaka Factor research

 

We have massive reviews on all of these simply because of the scale of suffering reduction they represent in health..now!

The latter one may be new to some people but it's probably as big a discovery as CRISPR (gene editing tech we borrowed from bacteria).

We're officially adding carnosine to that list of breakthrough health tools and the Yamanaka Factor research figures in prominently. 

Let's get started on these topics: 

• A quick intro to carnosine
• The problem with sugar
• AGE's and health
• Histone glycation and aging
• Carnosine's role with glycation
• Carnosine and diseases tied to aging
• Carnosine for senescent cells and mitochondria
• Studies on carnosine and aging
• Benefits of carnosine in the body
• Practical questions around carnosine supplementation

 

Let's get started! 

A quick intro to carnosine 

There are plenty of sites that go into the chemistry of carnosine but we're going to flesh out the vitals.

Carnosine is made in the body by combining two amino acids, alanine, and histidine.

It's abundant in muscle and the brain…actually any body area that is highly energy-intensive which is a big clue to our story.

The root "carn" means flesh and we consume most of our external carnosine from meat.

Again, think back to how we ate 40,000 years ago.  Meat, fish, a few vegetables we could come across (no real ag yet) and very limited berries depending on the area.

The energy piece is really our key focus.

Around 1.5 BILLION years ago, a predecessor hijacked bacteria to make energy for our cells.

They are called mitochondria and they power everything you do.  They even have their own DNA separate from ours.

Making energy is a messy business whether at an oil derrick or in a cell.

The waste material of cellular energy is primarily in various forms of oxygen called oxidants.

Oxygen acts like little chemical scissors (think of bleach or even water) that cut right through organic material like our cells or even our DNA.

In fact, when the body wants to kill off a cell (the immune system does this), it jacks up oxidative stress inside the faulty or virally infected cell.

Radiation and chemo are just massive doses of oxidative stress!

Clearly, the body must have pathways to clean this up or we would quickly degrade from the inside out.

Hello, carnosine.

We actually have lots of pathways that address ROS (reactive oxygen species) with glutathione being the dominant one (see glutathione or oxidative stress reviews).

Carnosine, however, has a special ability that makes it very important…and it all comes down to sugar 

The problem with sugar 

We have a big review on how glucose is A root of aging evil.

You could survive on protein and fat alone.  Sugar is not "needed" per se.  It's a bonus that plant life figured out to get us (and our brethren) to propagate their seeds.

Okay, stumbled on is more appropriate with evolution but the same result.

Even grains, the mainstay of our diet for the past 10,000 years is basically sugar in a different form.

Needless to say, that ship has sailed and sugar (and sugar in carb's clothing)  is a larger percentage of our total caloric intake than ever before.

A bowl of pasta is about the same as a candy bar in terms of our body's take.

So…what's the big deal?

We all hear that sugar is bad for us but why?

We're going to focus on one aspect of it…glycation.

Essentially, when sugar is found free-range in the body, it's chemically "sticky" much like the actual substance when wet.

It will attach to proteins and fats (lipids) to form new structures.

These proteins and/or fats are then no longer very useful for what they originally were intended to do.

Remember…our body runs on proteins and fats!  Proteins carry out the orders and fats make up the scaffolding (cellular walls, etc).  

All our steroidal hormones come from LDL (the supposed "bad" cholesterol) and we already looked at longevity and steroidal hormones specifically.

Sugar gums up the works of our cellular machinery via this glycation effect.

It gets worse.

They then start to connect these "clumps" to each other in what is called cross-linking glycation.

The result of all this is AGEs - advanced glycation end products.

Yes, they picked AGE for a reason as you'll see shortly.

Introduce carnosine.

This is carnosine's secret weapon: 

Carnosine has been shown to prevent AGE formations through reduction of blood glucose, prevention of early glycation, and even reversing previously formed AGEs.  

https://ift.onlinelibrary.wiley.com/doi/abs/10.1111/1541-4337.12376

It's easier to get to this root of carnosine's action since it affects so many (if not all) pathways in the body especially tied to aging. By the way, almost every health issue is tied to age 

AGE's and health 

The key takeaway is this….glycation is system-wide!

Brain.  Hearth  Immune system.  Bone/Muscle.  Everywhere.

Again, it's going to be more prominent in high-energy production sites like the brain and heart.

Let's just take a few examples to understand why this "gunk" of sugar is so destructive. 

We'll focus on: 

• AGEs and the brain
• AGEs and the heart
• AGEs and metabolic function
• AGEs and the immune system

 

Let's get started… 

AGEs and the brain 

Let's start with neurogenerative diseases like Alzheimer's.

Increased AGE levels explain many of the neuropathological and biochemical features of AD such as extensive protein crosslinking (ß-amyloid and MAP-τ), oxidative stress and neuronal cell death. 

https://www.sciencedirect.com/science/article/abs/pii/S0165017396000161

We have a massive review on Alzheimer's here.

The hallmark of Alzheimer's called amyloid plaques are…clumps of cross-linked material via…glycation!

What about mental health (see CBD and mental health)?

A brand-new study looked at AGEs levels in fingertip tests and connections with psychotic episodes.  The results: 

Altogether, fingertip advanced glycation end products potentially predicted the trajectory of psychotic symptoms among drug-naive adolescents, which indicated its involvement in the pathophysiology of early psychosis.  

https://www.nature.com/articles/s41537-021-00167-y

Goodness…we did a big review on schizophrenia here but this study is fascinating.

AGE levels predicted psychological stress!

Oxidative stress is tied to all mental health issues (see oxidative stress review).  It's basically a storm in the brain.  

 

 

We've done deep dives on the immune system (where oxidative stress is managed) and mental health since this is the future here.

Speaking of oxidative stress…what about anxiety?

A study looked at cortisol levels (our stress hormone) and AGEs: 

Morning cortisol values and AUCG correlated with AGEs, anxiety, and depression. 

https://www.sciencedirect.com/science/article/abs/pii/S0306453020301281

We could go on and on.  Big reviews on the pathway of depression here or anxiety here.

We'll look at carnosine specifically below.

What about the most intensive muscle and energy user there is. 

AGEs and the heart 

First, the headline: 

A number of studies have shown a correlation between serum AGE levels and the development and severity of heart failure (HF).  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342583/

So what's going on?

Newer research is digging into the process further to tease out what's going on: 

The present results suggest that intracellular TAGE are generated in cardiomyocytes and directly damage them, resulting in CVD. 

https://www.nature.com/articles/s41598-019-39202-5

So..a specific type of AGE is made by the cells that manage heart contraction and causes accumulating damage.

Again, glycation is system-wide and just more pronounced in heavy energy-using areas (like the heart!).

Let's turn to the big one. 

AGEs and metabolic function 

This is the pathway that has garnered all the attention with a focus on diabetes.

AGEs form intra- and extracellular cross-linking not only with proteins but with some other endogenous key molecules including lipids and nucleic acids to contribute to the development of diabetic complications. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951818/

All the nasty outcomes of diabetes: 

• Cataracts
• Neuropathy
• Vision loss
• Kidney loss
• Heart disease

 

Levels of AGEs correlate in lockstep with signature markers of diabetes:

The correlation between the SR-AI scavenging receptors concentration and the fluorescence of AGEs as well as diabetes biological markers: GFR, creatinine concentration and HbA1c was demonstrated. 

https://www.nature.com/articles/s41598-021-92630-0

Of course, excess sugar is an ignition switch they both share.

Let's turn to a marker of our true age. 

AGEs and the immune system 

The saying goes…you're as old as your immune system is.

Researchers now know that we slowly generate an inflammatory state as we get older.

It's called inflammaging.

During aging, chronic, sterile, low-grade inflammation — called inflammaging — develops, which contributes to the pathogenesis of age-related diseases. 

https://www.nature.com/articles/s41574-018-0059-4

Look at AGE's effect there:

The dietary AGEs induced TNF-alpha secretion of human macrophage-like cells.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315629/

Interestingly, this inflammation stimulating effect wasn't from the food-derived (the "browning" of food; high heat generally) AGE itself but from when it is bound to other proteins (the cross-linking).

The immune system is tasked with recognizing these errored constructions just as well as external bacteria or viruses!

Simply put: 

a variety of stimuli sustain inflammaging, including pathogens (non-self), endogenous cell debris and misplaced molecules (self) and nutrients and gut microbiota (quasi-self).  

https://www.nature.com/articles/s41574-018-0059-4

Remember that the immune system is in charge of removing faulty cells and material.

"Cell debris".

AGE's are large floating chunks of debris.

One note…the amyloid-beta plaques (a form of AGE) is actually composed of individual immune response cytokines designed to literally stab bacteria.

They can accumulate like fishing wire to form the plaques.

Let's go one level down…to our actual DNA! This is where it gets very exciting. 

Histone glycation and aging 

Let's set the stage first.

DNA gets all the headlines but it's remarkably static.  Barring mutations (and we have error corrections for that), it doesn't change much, and yet, we're constantly changing.

Think of early childhood or puberty alone. What about the brain maturation up till age 25.

Clearly, static DNA can't account for this.

Sitting "on top" of the hard code of DNA is our epigenome.  This is a set of instructions for which genes to turn on, when, and for how long.

That's the interface between nature (DNA) and nurture (outside influences and timeline).

Now…here's the rub…DNA stretched out would be about 6 feet long.

That same continuous strand is somehow fits into a cell's nucleus… too small to see.

Talk about jumbled fishing wire!

Here's the beautiful part.

We have an entire system called histones that "unpack" sections of this giant strand to be read.

This is the "which gene, when, and how long" manager.

So far so good.  What's the connection with aging?

Dr. Sinclair (and others) are testing a revolutionary theory that aging is actually the accumulation of errors (or changes) at THIS level…histones and the epigenome.

Basically, the difference between your 25-year-old self and your 50-year-old self is the "efficient and effective" management of gene expression.

It makes sense since your DNA is probably not changing much.  Any error would have to reside in the "turntable", not the record (I date myself).

Sinclair and researchers found that when you "wash" this machinery with 3 Yamanaka factors (early genes that turn any gene brand new), they go back to their youthful state but KEEP their identity (skin cell is a skin cell).

We did a full review here because it's probably the biggest thing we've seen since CRISPR.

Crushed optic nerves repairing themselves.

Blind mice due to aging seeing again

Just crazy sci-fi results.  Bezos just invested heavily in Altos Labs to explore the same path.

You're talking about resetting age in the body.  Point. And it's years away, not decades.

So, what's the connection with carnosine?

The question is…what is gunking up histones to created the damage that Yamanaka factors are stripping away.

Well…it's hopefully obvious after everything you've read.

Glycation is part of it!  

Histone proteins are particularly susceptible to NECMs due to their long half-lives and nucleophilic disordered tails that undergo extensive regulatory modifications 

https://www.nature.com/articles/s41467-019-09192-z

NECM is just a long way to say glycation cross-linking.

Turns out the histone proteins are especially susceptible to this damage due to their structure and how long they stick around.

It's especially prevalent in cancer cells: 

Finally, we detect intense histone glycation and DJ-1 overexpression in breast cancer tumors. 

 

Dr. Sinclair's work looked deep into the histone control of DNA reading and found that a "recipe" for a given type of cell is recorded by little markers called methyl groups.

Read here.  Stop here.  Go here.  Etc on the DNA code.

Our cells retain an original copy of this recipe even if errors accumulate.

Does glycation affect this process of methylation (literally the clock of aging)?

Newer research is showing this directly such as with diabetes-based osteoporosis: 

Advanced glycation end products inhibit the osteogenic differentiation ability of ASCs by activating DNA methylation and inhibiting Wnt/β-catenin pathway in vitro.  

https://onlinelibrary.wiley.com/doi/full/10.1111/cpr.12834

It's a sophisticated study but basically, the AGE was affecting the methylation pattern which resulted in certain pathways turning on too much and others not turning on enough.

This is cutting-edge research and we expect more to flow from every corner of the body and brain.

The overlap between aging-related diseases and AGEs is almost exact.  

• Diabetes
• Heart issues
• Brain degenerative issues
• Immune response failures

 

We said almost just in case there's an outlier but we're not aware of it.

So…let's finally turn to carnosine. 

Carnosine's role with glycation 

Since glycation is destructive to the very machinery of our DNA, you would think the body naturally has some mitigating pathway.  

It does!  Carnosine and GLO-2 are the relief squad here.

GLO-2 is a more complicated pathway but carnosine is easy and safe to support so let's focus there.

Essentially, carnosine acts as a scavenger of glycation products in the body:

Carnosine has been shown to prevent AGE formations through reduction of blood glucose, prevention of early glycation, and even reversing previously formed AGEs. 

https://ift.onlinelibrary.wiley.com/doi/abs/10.1111/1541-4337.12376

Goodness.  

Can we actually affect its level with supplementation?

l-Carnosine supplementation attenuated fasting glucose, triglycerides, advanced glycation end products, and tumor necrosis factor-α levels in patients with type 2 diabetes: a double-blind placebo-controlled randomized clinical trial 

https://pubmed.ncbi.nlm.nih.gov/29420997/

Okay… 

• Reduced sugar
• Reduced triglycerides (triglycerides are just a different, condensed means of storing sugar)
• Reduced AGE's  (ding ding ding)
• Reduced inflammation (TNF-a)

 

This is the holy grail.

That's all great but does this mechanism actually reflect in health and longevity?

Let's look at the main areas again with two more important ones added in: 

• carnosine and the brain
• carnosine and the heart
• carnosine and metabolic function
• carnosine and the immune system
• carnosine and skin

 

First, the brain: 

• carnosine and the brain

 

We'll look at the following for brain function: 

• Carnosine and Stroke
• Carnosine and Alzheimers
• Carnosine and  Depression

 

All hallmarks of aging.

First, stroke. 

 

A study on stroke in mice: 

We found that wild type (WT) C57BL/6 mice, subjected to hind limb ischemia (HLI) and supplemented with carnosine (1g/L) in drinking water, had improved blood flow recovery and limb function, enhanced revascularization and regeneration of myocytes compared with HLI mice placed on water alone. 

https://www.frontiersin.org/articles/10.3389/fphys.2019.00751/full

Ischemia is tech talk for stroke.

So much of the damage from stoke is the immune response afterward and the inability to repair scar tissue.  

"Revascularization and regeneration" are the two most important words there.

Another study in the brain: 

Carnosine significantly decreased infarct size and neuronal damage when administered at time points both before and after the induction of ischemia. 

https://www.ahajournals.org/doi/10.1161/STROKEAHA.107.488502

And here: 

In both permanent and transient ischemic models, carnosine treatment exhibited significant cerebroprotection against histological and functional damage, with wide therapeutic and clinically relevant time windows 

https://www.ahajournals.org/doi/10.1161/STROKEAHA.112.673954

The most important takeaway: 

Carnosine was well tolerated and exhibited no toxicity. 

 

Next up…the immune hyperactivation angle. 

Carnosine and Alzheimers 

Remember how the tell-tale signals of Alzheimer's and dementia are the "plaques" of amyloid-beta (an immune cytokine jumble)?  

Hello, carnosine: 

Atomic force microscopy revealed that carnosine in a dose-dependent fashion reduced amyloid beta peptide 1-42 (Aβ1-42) polymerization and decreased the number of deposited aggregates in a model of the amyloidogenic peptide fragment Aβ1-42, which suggests that carnosine may inhibit Aβ1-42 fibrillogenesis. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627134/

Can we drop the mic now?

Not yet.

What about practically speaking effects: 

After 3 months of supplementation, the carnosine/anserine group had better verbal episodic memory performance and decreased connectivity in the default mode network, the posterior cingulate cortex and the right fronto parietal network, as compared with the placebo group. 

https://www.frontiersin.org/articles/10.3389/fnagi.2015.00219/full

And…

Furthermore, there was a correlation between the extents of cognitive and neuroimaging changes.

So…carnosine supplementation showed positive changes in the brain then translated into positive effects on thinking.

Let's turn to more common issues tied to aging in the brain. 

Carnosine and Depression 

First, the headline: 

Dietary supplementation with carnosine has been shown to suppress stress in animals, and improve behavior, cognition and well-being in human subject

 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567213/

A study looked at adding carnosine to an SSRI and found the following: 

In the 52 completers at 6 weeks, L-carnosine, compared with placebo, was associated with significantly greater rates of response (100% vs. 77%) and remission (73% vs. 35%), with groups seperating statistically at 6 weeks. 

https://www.jwatch.org/na50942/2020/02/24/adjunctive-l-carnosine-depression

We've gone deep into how SSRIs work here and the issue is that they build tolerance.

Carnosine does not!  It's a basic building block of the body.

100% response?  Drop remission in half?

Again, mental health requires an entire review as big as this one. We're focusing on aging-related issues here.

Next up…the heart.

Carnosine and the heart 

A study looked at effects on carnosine for people with heart failure: 

Compared with controls, diet supplementation with orodispersible L-carnosine was associated with an improvement in peakVO2 (P < 0.0001), VO2 at anaerobic threshold, peak exercise workload, 6 MWT and quality-of-life assessed by the EQ-5D test and the VAS score. 

https://pubmed.ncbi.nlm.nih.gov/25287762/

The interesting piece is the "qualify of life" score.  Other attributes all speak to cardiovascular fitness.

Carnosine also protected vascular function from lack of oxygen: 

After culturing VECs with camosine (10 to 20 mmol/L) for 6 hours, the decrease in VECs activity induced by 12 and 24 hour hypoxia was inhibited. The release of LDH was also inhibited, and the integrity of cell structure remained. 

https://pubmed.ncbi.nlm.nih.gov/20476559/

The heart is one of the biggest users of carnosine which makes sense due to its energy consumption.

Let's turn to the most researched area directly tied to aging. 

Carnosine and metabolic function 

Look…metabolism is all about energy and glucose is a primary player there.

A study looked at carnosine supplementation for people who were obese but non-diabetic:

Two-hour glucose and insulin were both lower after carnosine supplementation compared to placebo in individuals with impaired glucose tolerance (P < 0.05). 

https://onlinelibrary.wiley.com/doi/full/10.1002/oby.21434

The conclusion: 

These pilot intervention data suggest that carnosine supplementation may be an effective strategy for the prevention of type 2 diabetes.

 

This is fascinating since diabetes is a breakdown in our metabolic process.

What about after diabetes is already established?

The resulting injury from excess glucose in the blood appears to come down to AGEs: 

AGEs, which were largely thought as oxidative derivatives resulting from diabetic hyperglycemia, are increasingly seen as a potential risk for islet β-cell injury, peripheral IR and diabetes. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3903318/

So… 

• Damage to the cells that make insulin (which then becomes a vicious circle)
• Damage to body tissue (kidney, nerves, brain, heart, etc).

 

Carnosine is the body's primary removal of AGEs!

Let's turn to the immune system. 

Carnosine and the immune system 

Carnosine directly affects multiple facets of inflammation that we noted is tied to aging: 

This carnosine antioxidant activity was accompanied by the attenuation of the PMA-induced Akt phosphorylation, the down-regulation of TNF-α and IL-6 mRNAs, and the up-regulation of the expression of the anti-inflammatory mediators IL-4, IL-10, and TGF-β1.  

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720685/

Goodness.  Learn more at our review on oxidative stress or autoimmune.

Remember that AGE's trigger immune response (i.e. inflammation) since they're seen as faulty products that need to be removed.  

There's one more important piece.

Carnosine naturally chelates metals or keeps them from accumulating.  This is especially important in the brain and the thymus.

The hypothalamus in your brain controls the entire hormone complex and it can atrophy with age.

Carnosine's role there: 

Previously, we found that carnosine inhibits trace metal-induced death of immortalized hypothalamic neuronal GT1-7 cells. 

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240448

Hormones drive immune function, especially estrogen and testosterone with progesterone as a buffer.

The thymus is the control hub of your immune system and it shrinks as we get older (called thymus involution).

A study looked at carnosine's role of protecting the thymus when under stress: 

Carnosine prevents necrotic and apoptotic death of rat thymocytes via ouabain sensitive Na/K-ATPase

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3481008/

One very important side note…the immune system is tasked with removing faulty cells (pre-cancerous, virally-infected, etc).

Cancer risk is definitely tied to age.

We would expect effects there if it's a true longevity player.

Okay.

Carnosine (1) inhibits breast, ovarian, colon, and leukemic cancer cell proliferation; (2) upregulates expression of pro-inflammatory molecules; (3) modulates cytokine secretion; and (4) alters U937 differentiation and phenotype. 

https://pubmed.ncbi.nlm.nih.gov/3380949/ 

What's with the upregulation of inflammation?

Remember…the immune system uses inflammation (oxidative stress) to kill cancerous cells!  So…a different response depending on the state of the system.  Reminds us of CBD!

One of many studies.  

More…

Cancer cells exposed directly to L-carnosine displayed reduced viability, increased frequency of apoptosis and unaltered proliferation 

https://ar.iiarjournals.org/content/36/2/665

This was a study of preventing cells from becoming cancerous under strain!

Let's turn to something we can actually see. 

Carnosine and skin 

Everything we've talked about before is internal…it's hard to see the state of your heart or brain.  

The skin is living, breathing reflection of our inner health…and age.

We can measure carnosine's effect there because all of this is just a waste of time if we don't see improvements at this basic level.

First, skin and AGEs:   

AGEs production in skin cells is known to promote stiffness and loss of elasticity through their buildup in connective tissue. 

https://www.nature.com/articles/srep27848

Basically, the hallmarks of aging skin.

What about carnosine and skin?

During oral supplementation with stabilized from enzymatic hydrolysis carnosine (Can-C Plus® formulation), the skin parameters investigated showed a continuous and significant improvement in the active group during the 3 months of supplementation as compared to placebo.  

https://pubmed.ncbi.nlm.nih.gov/21756141/

The net net…

Visual investigation showed improvement of the overall skin appearance and a reduction of fine lines. 

 And most importantly…

No treatment-related side effects were reported. 

A study looked at actual AGE levels in skin after treatment: 

Antiglycation effect for AQ-CARN was CML: –64 and –41%, 

https://www.karger.com/Article/Fulltext/492276

CML is a particular AGE.

This is important…we can actually see the results of AGEs in our skin and carnosine doesn't just stop additional damage but reverses it!

That's also the histone piece!

This brings us to an interesting piece…cancer.

Cancer risk is definitely tied to age (all other things being equal).

There's a direct tie between AGEs and cancer risk…

Finally, we detect intense histone glycation and DJ-1 overexpression in breast cancer tumors. 

https://www.nature.com/articles/s41467-019-09192-z

So…not damage to DNA but damage to the controller system (histones) right above!

We would then expect that carnosine exhibits anti-cancer effects if any of the above holds water.

Okay.

Carnosine (1) inhibits breast, ovarian, colon, and leukemic cancer cell proliferation; (2) upregulates expression of pro-inflammatory molecules; (3) modulates cytokine secretion; and (4) alters U937 differentiation and phenotype. 

https://pubmed.ncbi.nlm.nih.gov/33809496/

Technically, carnosine is called antineoplastic which just means… anti-tumor.

Pick a cancer and then google it with carnosine.  Remember, the immune system is in charge of detecting and killing cancer (the pro-inflammatory piece above).

Okay…let's start to dive into carnosine's effect on aging directly.

First, a quick detour on that route.

Carnosine for senescent cells, mitochondria, and telomeres 

What about other known players in longevity?

We need to introduce three major players with the process of aging.

• Senescent cells - zombie cells that are broken and leak out inflammation
• Mitochondria - our cell's power plants that may be the weakest link for aging
• Telomeres - DNA shoe-ends that shorten with age

 

The big longevity push right now is centered around removing senescent cells.

Cells that no longer function correctly but aren't being cleared out by the immune system.

The accumulate with aging and are highly destructive to surrounding tissue.

There's a whole class of senolytics like fisetin (see review here) and triggering the AMPK pathway (see AMPK and longevity) to boost the clearances of this debris.

If the above is true, carnosine should have an effect there as well.

Hello…

Carnosine Stimulates Macrophage-Mediated Clearance of Senescent Skin Cells Through Activation of the AKT2 Signaling Pathway by CD36 and RAGE 

https://www.frontiersin.org/articles/10.3389/fphar.2020.593832/full

Macrophages are literally the "mouths" of our immune system that eat up and remove bad actors.

Remember how Dr. Sinclair's theory is that histone error is the key to returning cells back to their youthful state?  

Goodness:

We have shown that late-passage HFF-1 cells retain a juvenile appearance in medium containing 50 mM carnosine, and revert to a senescent phenotype when carnosine is removed.  

https://europepmc.org/article/med/10197726

We can drop the mic there.  

Basically, carnosine removed the "gunk" from cells so they retained youthful function and when removed from carnosine, they proceed to their senescent state.

Okay…what about mitochondria?

Here's the deal…mitochondria have their own DNA and the error correction is not nearly as robust as our cellular machinery.

When energy production goes awry, it leaks out oxidative stress which causes damages and even further impairs mitochondria function.

A vicious cycle.

There's a range of studies in different settings that show carnosine's effect here.

Such as this one with Alzheimer's…

We found that carnosine supplementation in 3xTg-AD mice promotes a strong reduction in the hippocampal intraneuronal accumulation of Aβ and completely rescues AD and aging-related mitochondrial dysfunctions. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058055/

"Completely rescues".

Or this one in the brain: 

It was found that carnosine (1, 5, 10 and 20 mM) alleviated ammonia-induced mitochondrial dysfunction.  

https://www.sciencedirect.com/science/article/abs/pii/S2213434416300780

This review here is a monster of studies on carnosine across the entire energy complex: 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874395/

What about telomeres, the shoelace end that keeps DNA bound tight.

First, the aging piece: 

Telomeres shorten with age and progressive telomere shortening leads to senescence and/or apoptosis. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3370421/

And carnosine?

Cells continuously grown in 20 mM carnosine exhibited a slower telomere shortening rate and extended lifespan in population doublings.

https://pubmed.ncbi.nlm.nih.gov/15474517/

Okay…we've danced around it…let's get to aging directly. 

Studies on carnosine and aging 

Believe it or now, the early studies on carnosine's ability with aging go back quite a bit.

Such as this 1994 study: 

These late-passage cultures preserve a nonsenescent morphology in the presence of carnosine, in comparison to the senescent morphology first described by Hayflick and Moorhead. Transfer of these late-passage cells in medium containing carnosine to unsupplemented normal medium results in the appearance of the senescent phenotype.  

https://pubmed.ncbi.nlm.nih.gov/8187813/

This is the study where they put human cells in a solution of carnosine and they retained their youthful function and when removed, proceeded towards a senescent (old) functioning.

413 days lifespan for the cells versus 126-139 days without carnosine.

Then there are the levels and associations with aging: 

Free carnosine concentrations in rat skeletal muscles also showed a significant negative correlation with the ages of the rats. A decline in free carnosine concentration of 63% takes place between age 10 and age 70 in human subjects, and in rats a continuous decline is observed, amounting to about 37% on average between the third and the 23rd month of life. 

http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.617.8181&rep=rep1&type=pdf

Interesting that this pattern matches the steroidal hormone complex (see pregnenolone or testosterone or steroidal hormones and aging).

Just earlier.  Age 10 versus say 20.

Interestingly, a study looked at carnosine's effect with hypogonadism (low testosterone production) and it offsets some of the key deficits: 

Carnosine and β-alanine are strongly reduced resulting in increased fatigue and mental confusion.  

https://www.nature.com/articles/s41419-018-0587-9

That's a story for another day but maybe the damage of sugar drives the loss of steroids!!

What about animal studies on the usual suspects?

A study looked at mice who are genetically programmed to age faster.

Results: 

A 50% survival rate of animals treated with carnosine increased by 20% as compared to controls. 

https://www.liebertpub.com/doi/abs/10.1089/rej.1.1999.2.337

Remember the skin study above?

Carnosine distinctly improved the appearance of the aged mice, whose coat fullness and color remained much closer to that of young animals. Significantly more carnosine-treated mice had glossy coats (44% vs. 5%), while fewer had skin ulcers (14% vs. 36%).

 

We need more studies the researchers take away: 

carnosine-treated animals can be characterized as more resistant to the development of features of aging

 

So…a quick synopsis of what carnosine does in the body before practical questions 

Benefits of carnosine in the body 

We're just going to hit the highlights.  

Since carnosine is a scavenger of damage at the genetic (and epigenetic) level, it's systemic.

A few key takeaways:

• Reduces sugar and sugar-caused damage across the body (glycation and AGEs)
• Anti-inflammatory
• Reduces oxidative stress
• Manages metal levels via chelation (to avoid build-up)
• Supports metabolic pathway (triglycerides, lipids, glucose, insulin, etc)
• Supports immune function (T cells,  thymus, etc)
• Improves mitochondrial function (more and more efficient energy production)
• Removes or reverts senescent "zombie" cells
• Supports neurotransmitters and hormones y reducing MAO (which breaks down neurotransmitters and hormones)

 

Okay..we have to stop somewhere.  

We look forward to further trials.

SO…practical.

Practical questions around carnosine supplementation

Let's touch base on when, how much, and what.

First, what.

There are two ways to go: 

• Carnosine
• Beta-alanine

 

B-Alanine is one of the components of carnosine and it's thought to be a rate-limiting element in levels.

A study on exercise and endurance: 

β-ALA supplementation (e.g., 2-6 grams/day) has been shown to increase carnosine concentrations in skeletal muscle by 20-80%.  

https://pubmed.ncbi.nlm.nih.gov/23657886/

A standard supplement is around 2000mgs (2 grams).  

Never buy supplements on Amazon!  

The standard take is that b-alanine is for efficient but they primarily focused on exercise-related effects (athletes are all over carnosine).

Then there's carnosine directly.  

The standard dose referenced in research is between 500mg - 1500mg daily.

This is what we take:

Carnosine  (after lunch)
Beta-Alanine (after breakfast)

Some studies point to improved sleep but that was with autism (known sleep issues).

Carnosine calms the HPA axis (fight or flight) and supports GABA in the brain (target for benzos - see CBD versus benzos).

Serotonin and dopamine also figure into sleep and both are positively affected by carnosine.  

Test and see how you feel.

What about safety?

We really focus on longevity supplements that don't build tolerance and have strong safety profiles.

For example:

• Magnesium glycinate
• CBD isolate (new study on longevity effects here)
• Siberian rhubarb (supports housekeeping side of estrogen)
• Berberine - gut inflammation and gut barrier - interesting effect on AMPK for aging
• Vitamin D - get tested but many people are deficient
• Fisetin - interesting senolytic (remove zombie cells and cancer protection)
• NAC - powerful antioxidant effects (interesting connection with carnosine below)

 

This limits the field quite a bit.

Carnosine is now our favorite on that list (beyond CBD of course - more on how CBD works for longevity).

Carnosine's safety profile is very strong.

The only thing we can find is that it calms blood pressure so if you're on blood pressure meds, be aware and work with your naturopath.

We take NAC along with carnosine for a very specific reason.

Carnosine is breaking apart cellular debris essentially.  NAC supports glutathione, our primary detox system which is critical for removing debris!

Glutathione also supports GLO2 which is the other big anti-glycation pathway so it's a win-win!

More on NAC here.

As new info comes in, we'll keep an eye out.

If we were betting people, we would go heavily on the fact that the glycation (AGE) reducing effect is going to be revolutionary in future studies.

Till Yamanaka factor research is full tilt.

Carnosine might be the discount Yamanaka factor we can use right now!

Be well. Take care of each other. Take care of yourself.

Related Research:

Yamanaka Factor

CBD and SIRT for longevity

The problem with glucose

 

 

Always work with a doctor or naturopath with any supplement!

The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.