The curious case of l-carnosine

I became fascinated with l-carnosine about ten years ago.  Back then, this substance seemed capable of doing more or less what telomerase activators are hoped to be doing now – greatly extending the replicative life spans of certain body cells.  So I started studying l-carnosine intensively and also taking it as a supplement.  And I am still doing that.  The substance clearly has significant anti-aging powers but some of the ways in which it works are still shrouded in mystery. 

L-carnosine does a number of very good things for health and longevity.   I wrote a review of the substance in 2002 and there I said, listing multiple literature citations, “Carnosine can inhibit non-enzymic glycosylation of proteins.  Carnosine blocks the formation of AGEs  protecting against cross-linking of proteins in the eye lense and skin collagen, cross-linking of proteins to DNA molecules, and formation of other abnormal proteins.  Carnosine promotes wound healing, and has numerous anti-oxidant properties including the quenching of  singlet oxygen.  Carnosine traps peroxyl radicals, inhibits damage due to gamma irradiation, binds transition metals rendering them unable to participate in the toxin-producing Fenton’s reaction.  Carnosine may go beyond scavenging ROS to reducing the production of ROS.  It protects against and promotes healing of stomach ulcers and reduction of brain damage due to accumulation of beta amyloid and possibly due to malondialdehyde or hypochlorite anions.  It can very likely be used as an anti-ischemic drug.  Carnosine is an efficient chelating agents for copper and other transition metals, and Carnosine appears to protect neurons from zinc- and copper-mediated neurotoxicity.  Carnosine appears to expand the resistance of rats to various induced stresses.  It can be used in the treatment o severe gingivostomatitis.  Carnosine  is an immunostimulant.  Carnosine is reported to have an ability to up or down-regulate cellular and enzymatic processes to bring them into normal range.  For example, Carnosine can decrease platelet aggregation in patients with low clotting indices.  The list goes on and on.  One study by Egyptian researchers even suggests that Carnosine could be used to correct metabolic disturbances induced by schistosomiasis.”

But the one reported fact about carnosine that really attracted my attention was that it could significantly delay or reverse cellular senescence.  This was long before the days of telomerase activation.  I wrote “Research studies by Mcfarland and all going back to 1994 indicate that Carnosine can delay senescence and promote formation of a more juvenile phenotype in cultured human fibroblasts, extending the Hayflick limit for reproduction of such cells by up to ten doublings.  Late-passage fibroblasts from lung and foreskin tissues were switched back and forth a number of times between Carnosine-enhanced and non-enhanced culture media.   Mcfarland and his colleagues consistently observed that the Carnosine culture medium restored the juvenile cell phenotype within days, whereas immersion in the standard culture medium brought back the senescent cell phenotype(ref).  The life span of cells immersed in the Carnosine medium was also increased, even for old cells. When late-passage lung fibroblasts at 55 PDs (population doublings) were transferred to the Carnosine medium, they lived to 69 to 70 PDs, compared to 57 to 61 PDs for the fibroblasts that were not transferred. Further, the fibroblasts transferred to the Carnosine medium attained a life span of 413 days, compared to 126 to 139 days for the control fibroblasts.  Finally, it appears that when cells in the Carnosine medium eventually enter into cellular senescence, they nevertheless retain a normal or less-senescent morphology.“  

On a cellular level, l-carnosine extended the lifespan of the fibroblasts by a factor of about 3, and this fact really grabbed me. And now that I start to think about it again, it still grabs me.

This led me back then to conjecture that perhaps l-carnosine caused the expression of telomerase or some other telomere-protecting protein and therefore had extraordinary anti-aging power.  But other experts in longevity I consulted at the time, having their own fish to fry, had no patience for that idea. 

A 2004 publication L-carnosine reduces telomere damage and shortening rate in cultured normal fibroblasts  confirmed the earlier Mcfarland observations.  “In this work, we studied the effect of carnosine on the telomeric DNA of cultured human fetal lung fibroblast cells. Cells continuously grown in 20 mM carnosine exhibited a slower telomere shortening rate and extended lifespan in population doublings. When kept in a long-term nonproliferating state, they accumulated much less damages in the telomeric DNA when cultured in the presence of carnosine.  We suggest that the reduction in telomere shortening rate and damages in telomeric DNA made an important contribution to the life-extension effect of carnosine.” 

On the one hand, this capability of carnosine to greatly extend the number of cell doublings excited me greatly at the time and still intrigues me.  Even today, precious few substances seem to have that kind of anti-aging potential.

On the other hand, how carnosine works to extend the number of cell doublings so greatly was then and is still now a mystery.  I further wrote “The mechanism by which Carnosine can extend the Hayflick limit appears to be unknown, though in my mind at least it is possibly the most central issue with respect to Carnosine and longevity research.  Various  possibilities appear to exist, including:  1.  The ROS-scavenging properties of Carnosine significantly reduce damage of telomeric DNA thus extending the maximum number of divisions possible. 2.  As put by Hipkiss “Perhaps the carbonyl binding activity of Carnosine (or the released histidine) might mask any deleterious effects of the aberrant (carbonyl) protein on proteasome function as well as facilitate degradation  to allow the extras cell divisions;” and, 3.  Through some sequence of Carnosine-induced gene transcription and protein release, telomerase is expressed in the cells involved leading to longer telomeres and consequently more extended cell replication cycles.”

As I became more engaged in other areas of anti-aging research around 2003, this unusual capability of l-carnosine slipped to the back of my mind.     However, I just ran across a 2009 publication that brings the enigmatic character of this substance up again.  The publication is appropriately titled On the enigma of carnosine’s anti-ageing actions“Carnosine (beta-alanyl-L-histidine) has described as a forgotten and enigmatic dipeptide. Carnosine’s enigma is particularly exemplified by its apparent anti-ageing actions; it suppresses cultured human fibroblast senescence and delays ageing in senescence-accelerated mice and Drosophila, but the mechanisms responsible remain uncertain. In addition to carnosine’s well-documented anti-oxidant, anti-glycating, aldehyde-scavenging and toxic metal-ion chelating properties, its ability to influence the metabolism of altered polypeptides, whose accumulation characterises the senescent phenotype, should also be considered. When added to cultured cells, carnosine was found in a recent study to suppress phosphorylation of the translational initiation factor eIF4E resulting in decreased translation frequency of certain mRNA species. Mutations in the gene coding for eIF4E in nematodes extend organism lifespan, hence carnosine’s anti-ageing effects may be a consequence of decreased error-protein synthesis which in turn lowers formation of protein carbonyls and increases protease availability for degradation of polypeptides altered postsynthetically. Other studies have revealed carnosine-induced upregulation of stress protein expression and nitric oxide synthesis, both of which may stimulate proteasomal elimination of altered proteins. Some anti-convulsants can enhance nematode longevity and suppress the effects of a protein repair defect in mice, and as carnosine exerts anti-convulsant effects in rodents, it is speculated that the dipeptide may participate in the repair of protein isoaspartyl groups. These new observations only add to the enigma of carnosine’s real in vivo functions.”

So the enigma remains unresolved.  In fact the author AR Hipkiss has been an important leader in l-carnosine research all along, having also published some 30 documents having to do with l-carnosine in the last 10 years, including:

Chapter 3 carnosine and its possible roles in nutrition and health. (2009) “Physiologically carnosine may help to suppress some secondary complications of diabetes, and the deleterious consequences of ischemic-reperfusion injury, most likely due to antioxidation and carbonyl-scavenging functions.”

Carnosine, diabetes and Alzheimer’s disease (2009)

Could carnosine or related structures suppress Alzheimer’s disease? (2007) “Protein oxidation and glycation are integral components of the AD pathophysiology. Carnosine can suppress amyloid-beta peptide toxicity, inhibit production of oxygen free-radicals, scavenge hydroxyl radicals and reactive aldehydes, and suppresses protein glycation.” – “Carnosine stimulates proteolysis in cultured myocytes and senescent cultured fibroblasts. These observations suggest that carnosine and related structures should be explored for therapeutic potential towards AD and other neurodegenerative disorders.”

Would carnosine or a carnivorous diet help suppress aging and associated pathologies? (2006) “Carnosine has the potential to suppress many of the biochemical changes (e.g., protein oxidation, glycation, AGE formation, and cross-linking) that accompany aging and associated pathologies. Glycation, generation of advanced glycosylation end-products (AGEs), and formation of protein carbonyl groups play important roles in aging, diabetes, its secondary complications, and neurodegenerative conditions. Due to carnosine’s antiglycating activity, reactivity toward deleterious carbonyls, zinc- and copper-chelating activity and low toxicity, carnosine and related structures could be effective against age-related protein carbonyl stress.”

Does chronic glycolysis accelerate aging? Could this explain how dietary restriction works? (2006) {VG comment: To the extent that chronic glycolysis does accelerate aging, then perhaps l-carnosine’s powerful anti-glycating action could explain some of its anti-aging capability.}

On the mechanisms of ageing suppression by dietary restriction-is persistent glycolysis the problem? (2005) {Same VG comment}

Could carnosine suppress zinc-mediated proteasome inhibition and neurodegeneration?   Therapeutic potential of a non-toxic but non-patentable dipeptide. (2005)

Glycation, ageing and carnosine: are carnivorous diets beneficial? (2005) {VG comment:  Meat-eating has a bad reputation in health circles today.  In this and other articles, Hipkiss points out that meat-eating has some good things going for it too.}

Other researchers have continued to publish about l-carnosine. However the mechanism of how l-carnosine can so greatly extend the replicative life of certain cell cultures and extend the life of lower organism has never been satisfactorily explained as far as I am concerned. In 1999 leading l-carnosine  researchers wrote in the publication Carnosine as a Potential Anti-senescence Drug “Anyway, the question “How could such a small molecule have such profound effects?” remains unanswered, though we hope through increased global scientific collaboration that we shall have the answers sooner rather than later.”  Now, ten years later, the question still remains unanswered.

One thing is for sure though.  L-carnosine will continue to be part of my suggested anti-aging Supplement Regimen and I will continue taking it, currently 500mg twice daily.

About Vince Giuliano

Being a follower, connoisseur, and interpreter of longevity research is my latest career, since 2007. I believe I am unique among the researchers and writers in the aging sciences community in one critical respect. That is, I personally practice the anti-aging interventions that I preach and that has kept me healthy, young, active and highly involved at my age, now 93. I am as productive as I was at age 45. I don’t know of anybody else active in that community in my age bracket. In particular, I have focused on the importance of controlling chronic inflammation for healthy aging, and have written a number of articles on that subject in this blog. In 2014, I created a dietary supplement to further this objective. In 2019, two family colleagues and I started up Synergy Bioherbals, a dietary supplement company that is now selling this product. In earlier reincarnations of my career. I was Founding Dean of a graduate school and a full University Professor at the State University of New York, a senior consultant working in a variety of fields at Arthur D. Little, Inc., Chief Scientist and C00 of Mirror Systems, a software company, and an international Internet consultant. I got off the ground with one of the earliest PhD's from Harvard in a field later to become known as computer science. Because there was no academic field of computer science at the time, to get through I had to qualify myself in hard sciences, so my studies focused heavily on quantum physics. In various ways I contributed to the Computer Revolution starting in the 1950s and the Internet Revolution starting in the late 1980s. I am now engaged in doing the same for The Longevity Revolution. I have published something like 200 books and papers as well as over 430 substantive.entries in this blog, and have enjoyed various periods of notoriety. If you do a Google search on Vincent E. Giuliano, most if not all of the entries on the first few pages that come up will be ones relating to me. I have a general writings site at www.vincegiuliano.com and an extensive site of my art at www.giulianoart.com. Please note that I have recently changed my mailbox to vegiuliano@agingsciences.com.
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12 Responses to The curious case of l-carnosine

  1. Res says:

    But it increases lipofucin. So it is advised to take along with ALcar. I know you do take alcar. Just a reminder.

  2. admin says:

    Res. Right on the lipofuscin. In my treatise I say “Several of the antioxidants already mentioned function so as to reduce levels of lipofuscin accumulation in brain and other cells, including alpha-lipoic acid, CoQ10 and curcumin. Piracetam, another firewall component, appears to significantly decrease the formation of lipofuscin in neurons. I take two supplements which have a capability to pump lipofuscin out of cells. One is meclofenoxate (centrophenoxine) a ‘smart drug” used in Europe to treat symptoms of senile dementia and Alzheimer’s disease. The other is acetyl-l-carnitine, a pluripotent antioxidant also useful for mitochondrial health.”

  3. Res says:

    Hi Vince

    Just plain Carnosine had resolved the acid reflex and burning sensation in my wife. (it is quite an achivement. She had acid reflex for more than 4 years)

    But the literature says that this cure is provided by Zinc-Carnosine salt.(pepzin)

    But if she takes ALCar with Carnosine, the burning sensation returns albeit mildly. So she takes only Carnosine.

    Can you hypothesize why?

    With loving Regards
    Res

  4. admin says:

    Hi Res,

    Off the top of my head I don’t have an answer for you. Might have to do with the acetyl form of carnitine. It is one more thing for me to think about. I do both of course, but also take one omiprazole in the morning so notice no acid reflux.
    Vince

  5. Karen Mack says:

    Hi,

    Any possiblility of it being used topically?

    Thx Karen

  6. admin says:

    Karen
    Possibly. I am not up on research related to that.
    Vince

  7. Karen Mack says:

    Hi Vince,

    I have a condition in which scientists hypothesise is caused by fibroblast senescence …. I would like to start taking carnosine and DMAE. Would you be able to provide me with details of where I can purchase these products online.

    Thx Karen

  8. admin says:

    Hi Karen Mack

    L-carnosine and DMAE are substances available from most major online supplement houses like vitacost.com and swansonvitamins.com. Local health food stores will sell it too, but normally at high cost. I normally buy 500mg pills of l-carnosine.

    Vince

  9. Pingback: Age-related cognitive decline: focus on interventions | AGING SCIENCES – Anti-Aging Firewalls

  10. Cyanwolf says:

    Hello,
    I take L-Carnosine but I am wondering if it matters what brand you use. Are all brands equal? I just started using it a couple of months ago after reading a couple of books on Longevity. What brand would you recommend? Thanks! 🙂

  11. presuminged says:

    Do you know of any human data? Human safety data?

    • Presuminged:

      It ha been a while since I revisited l-carnosine. A quick scan of pubmed.org shows a number of newer publications since I wrote the blog entry but still none that examines human in-vivo impact of supplementation over time. Human cell-level data does exist. I have not seen actual safety data although some may exist. The substance is generally considered to be safe for genetically normal people for recommended dosages. However, for people with a genetically-determined deficiency in plasma carnosinase activity, clearance of ingested l-carnosine from the blood plasma may be insufficient leading to carnosinemia, a condition of excess circulating carnosine. See the April 2012 publication Low plasma carnosinase activity promotes carnosinemia following carnosine ingestion in humans, at http://www.ncbi.nlm.nih.gov/pubmed/22496410

      Vince

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