Life Extension Magazine®

Wide-Ranging Benefits of SAMe

SAMe has demonstrated a new anti-aging mechanism via its ability to improve DNA methylation. This adds to previously demonstrated effects of improved mood, reduced joint discomfort, and cartilage regeneration.

Scientifically reviewed by: Dr. Heidi Yanoti, DC, on February 2020. Written By Christian Mendez.

Since Life Extension® first introduced SAMe (S-Adenosyl-Methionine) back in 1997, it’s become popular for boosting mood.

In addition to fighting depression, SAMe also stimulates the production of new cartilage in animals and improves symptoms and functioning in osteoarthritis patients.1-3

In a recent study SAMe was shown to increase lifespan of yeast.4

What’s the common link between these benefits and SAMe?

SAMe is a cofactor involved in a process called DNA methylation, which regulates gene expression.5 In doing so, it can help fight against some of the causes of age-related disease—and it may prolong life itself.6,7

Understanding DNA Methylation

Genes are stretches of DNA that determine our traits, from hair and eye color to susceptibility to certain diseases and even lifespan potential.

Genes can also be active or inactive. The science of epigenetics studies how and why genes are expressed, or not.8

One of the main “switches” that modulates the way genes are expressed is DNA methylation, which occurs when methyl groups are added to the DNA.9

SAMe (S-Adenosyl-Methionine) is a nutrient found naturally in the body that serves as the primary methyl donor. That means it’s involved in practically all methylation reactions.9-12

If we don’t have enough of it, the body cannot methylate properly. That can lead to chronic inflammation, tissue damage, and age acceleration.13,14

One lab study showed that treating human cells with SAMe increased DNA methylation and modulated the expression of genes associated with inflammation.15

This has shown benefits in multiple disorders and has the potential to prolong life.

plants growing in a beaker

What You Need to Know

How SAMe Helps Our Genes Fight Disease

  • Humans have about 20,000 genes. Our bodies turn them on or off as necessary.

  • One of the main switches that modulates the way genes are expressed is a process called methylation, in which methyl groups are added to the DNA.

  • The nutrient SAMe (S-Adenosyl-Methionine) is the body’s preferred methyl donor.

  • If we don’t have enough of it, the body cannot methylate properly.

  • Two seemingly unrelated conditions, osteoarthritis and clinical depression, both involve improper methylation. In human studies, both are improved by treatment with SAMe.

  • Preclinical studies indicate that increased SAMe also contributes to longer life and improved health.

Osteoarthritis Improvement

plants growing in a beaker

Osteoarthritis is the most common and disabling joint disease.16 It can cause loss of the cushioning cartilage that eases joint movement, eventually damaging underlying bone.

It’s chronic and has no known cure.3,16 But there is new hope for treating it.

Scientists have discovered that abnormal methyl-ation in osteoarthritis patients affects genes that promote inflammation, which in turn promotes the painful swelling that typifies the disease.17,18

By donating methyl groups and getting the methylation cycle back on track, SAMe may modulate those genes and suppress inflammation.19

Improper methylation disrupts healthy cartilage cells’ activity, leading to cartilage damage that further erodes bone tissue.16,20

Numerous studies have shown that SAMe may help treat osteoarthritis. Among the results:

  • SAMe stimulates production of new cartilage in animals.3 This is crucial to slowing or reversing the progress of osteoarthritis.

  • In short- and long-term studies, patients reported improvement of symptoms.21,22

  • Osteoarthritis patients treated with SAMe experienced pain relief as strong as that delivered by non-steroidal anti-inflammatory drugs (NSAIDs), with improvement lasting longer after treatment.1,2,23

  • A meta-analysis of 11 studies showed that SAMe improved functioning in arthritis patients and was comparable to NSAIDs for pain, without the side effects common with NSAIDs.24

In one study, SAMe also reduced the depressive feelings associated with osteoarthritis.21 That is likely because it eased symptoms of the arthritis and because SAMe has a direct impact on mood disorders.

Depression

plants growing in a beaker

Clinical depression affects more than 16% of U.S. adults over a lifetime.25

Stress is a contributor to mood and anxiety disorders. Researchers have found that it drives epigenetic changes in the brain that can alter normal methylation patterns.26

In fact, abnormal methylation has been linked to depression and mood disorders in multiple ways:

  • Prenatal and early childhood exposure to a mother’s depression affects methylation patterns in the infant’s brain.27

  • Childhood trauma leads to methylation defects, which can be related to long-term mood and mental health problems.28

  • Altered methylation is seen in people at high genetic risk for mood disorders, including bipolar and major depression, even before they develop symptoms.29

SAMe helps regulate the production of neurotransmitters that produce feelings of well-being, potentially alleviating depression.30,31

Clinical trials have shown that:

  • SAMe improves memory-related cognitive symptoms in depressed patients.31

  • Over 12 weeks, SAMe (1,600 mg/day-3,200 mg/day) proved superior to both a placebo and the prescription antidepressant escitalopram (20 mg per day) at improving scores on the Hamilton Depression Rating Scale. Remission rates were 34% for SAMe, 23% for escitalopram, and 6% for a placebo.32(Later analysis suggested that the effects were only significant in men, and researchers are exploring the reason for that.33)

  • Adding 800 mg of SAMe to antidepressant medications improved results on standard measures of depression.34

Life Extension® encourages individuals interested in adding SAMe to their regimen to discuss it with their treating physician.

Prolonging Life

plants growing in a beaker

Methylation isn’t just linked to the development of age-related diseases. It also has a direct impact on lifespan itself.35,36

Studies show that aging is associated with alterations in DNA methylation.35,37

This causes pro-inflammation and disease-causing genes to be expressed and tumor-suppressor genes to be silenced, increasing cancer risk.

Studies of long-lived animal strains show that they use SAMe much more efficiently than their shorter-lived relatives, leading to activation of lifespan-extending genes, such as those involved in chemical stress defenses.38,39

Studies have demonstrated just how SAMe might extend life:

  • Stimulating SAMe synthesis in yeast extends their lifespan by activating the youthfulness-promoting enzyme AMP-activated protein kinase (AMPK).4 In humans, AMPK helps the body use calories more efficiently, reduces fat accumulation, and enhances cleanup of cellular “junk.”

  • Short-term SAMe use in tumor-prone mice prevented liver tumor development, in part by restoring methylation and turning on tumor suppressor genes.40

Summary

plants growing in a beaker

The way genes are expressed has a great impact on our health and longevity.

DNA methylation is a process that regulates gene expression.

SAMe (S-Adenosyl-Methionine) is an essential factor involved in DNA methylation.

Defects in methylation can lead to diseases.

Increasing SAMe intake provides the body with a critical methylation nutrient, which can help modulate the way genes are expressed.

SAMe has so far shown clinical success in treating osteoarthritis and depression. Early studies suggest SAMe’s status as the body’s preferred methylation nutrient may also protect against other diseases and contribute to longer lifespan.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

References

  1. Najm WI, Reinsch S, Hoehler F, et al. S-adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: a double-blind cross-over trial. BMC Musculoskelet Disord. 2004 Feb 26;5:6.
  2. Kim J, Lee EY, Koh EM, et al. Comparative clinical trial of S-adenosylmethionine versus nabumetone for the treatment of knee osteoarthritis: an 8-week, multicenter, randomized, double-blind, double-dummy, Phase IV study in Korean patients. Clin Ther. 2009 Dec;31(12):2860-72.
  3. Hosea Blewett HJ. Exploring the mechanisms behind S-adenosylmethionine (SAMe) in the treatment of osteoarthritis. Crit Rev Food Sci Nutr. 2008 May;48(5):458-63.
  4. Ogawa T, Tsubakiyama R, Kanai M, et al. Stimulating S-adenosyl-l-methionine synthesis extends lifespan via activation of AMPK. Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):11913-8.
  5. Mahmoud AM, Ali MM. Methyl Donor Micronutrients that Modify DNA Methylation and Cancer Outcome. Nutrients. 2019;11(3):608.
  6. Xiao F-H, Wang H-T, Kong Q-P. Dynamic DNA Methylation During Aging: A “Prophet” of Age-Related Outcomes. Frontiers in Genetics. 2019 2019-February-18;10(107).
  7. Johnson AA, Akman K, Calimport SRG, et al. The role of DNA methylation in aging, rejuvenation, and age-related disease. Rejuvenation research. 2012;15(5):483-94.
  8. Dupont C, Armant DR, Brenner CA. Epigenetics: definition, mechanisms and clinical perspective. Semin Reprod Med. 2009 Sep;27(5):351-7.
  9. Glier MB, Green TJ, Devlin AM. Methyl nutrients, DNA methylation, and cardiovascular disease. Mol Nutr Food Res. 2014 Jan;58(1):172-82.
  10. Luka Z, Mudd SH, Wagner C. Glycine N-methyltransferase and regulation of S-adenosylmethionine levels. J Biol Chem. 2009 Aug 21;284(34):22507-11.
  11. Lin H. S-Adenosylmethionine-dependent alkylation reactions: when are radical reactions used? Bioorg Chem. 2011 Dec;39(5-6):161-70.
  12. Laurino P, Tawfik DS. Spontaneous Emergence of S-Adenosylmethionine and the Evolution of Methylation. Angew Chem Int Ed Engl. 2017 Jan 2;56(1):343-5.
  13. Rotondo JC, Bosi S, Bazzan E, et al. Methylenetetrahydrofolate reductase gene promoter hypermethylation in semen samples of infertile couples correlates with recurrent spontaneous abortion. Hum Reprod. 2012 Dec;27(12):3632-8.
  14. Rotondo JC, Selvatici R, Di Domenico M, et al. Methylation loss at H19 imprinted gene correlates with methylenetetrahydrofolate reductase gene promoter hypermethylation in semen samples from infertile males. Epigenetics. 2013 Sep;8(9):990-7.
  15. Pfalzer AC, Choi SW, Tammen SA, et al. S-adenosylmethionine mediates inhibition of inflammatory response and changes in DNA methylation in human macrophages. Physiol Genomics. 2014 Sep 1;46(17):617-23.
  16. Monteagudo S, Cornelis FMF, Aznar-Lopez C, et al. DOT1L safeguards cartilage homeostasis and protects against osteoarthritis. Nat Commun. 2017 Jun 19;8:15889.
  17. Shen J, Abu-Amer Y, O’Keefe RJ, et al. Inflammation and epigenetic regulation in osteoarthritis. Connect Tissue Res. 2017 Jan;58(1):49-63.
  18. Reynard LN. Analysis of genetics and DNA methylation in osteoarthritis: What have we learnt about the disease? Semin Cell Dev Biol. 2017 Feb;62:57-66.
  19. Miranda-Duarte A. DNA Methylation in Osteoarthritis: Current Status and Therapeutic Implications. The open rheumatology journal. 2018;12:37-49.
  20. Jeffries MA, Donica M, Baker LW, et al. Genome-Wide DNA Methylation Study Identifies Significant Epigenomic Changes in Osteoarthritic Subchondral Bone and Similarity to Overlying Cartilage. Arthritis Rheumatol. 2016 Jun;68(6):1403-14.
  21. Konig B. A long-term (two years) clinical trial with S-adenosylmethionine for the treatment of osteoarthritis. Am J Med. 1987 Nov 20;83(5A):89-94.
  22. Bradley JD, Flusser D, Katz BP, et al. A randomized, double blind, placebo controlled trial of intravenous loading with S-adenosylmethionine (SAM) followed by oral SAM therapy in patients with knee osteoarthritis. J Rheumatol. 1994 May;21(5):905-11.
  23. Maccagno A, Di Giorgio EE, Caston OL, et al. Double-blind controlled clinical trial of oral S-adenosylmethionine versus piroxicam in knee osteoarthritis. Am J Med. 1987 Nov 20;83(5A):72-7.
  24. Soeken KL, Lee WL, Bausell RB, et al. Safety and efficacy of S-adenosylmethionine (SAMe) for osteoarthritis. J Fam Pract. 2002 May;51(5):425-30.
  25. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003 Jun 18;289(23):3095-105.
  26. Hing B, Gardner C, Potash JB. Effects of negative stressors on DNA methylation in the brain: implications for mood and anxiety disorders. Am J Med Genet B Neuropsychiatr Genet. 2014 Oct;165B(7):541-54.
  27. Babenko O, Kovalchuk I, Metz GA. Stress-induced perinatal and transgenerational epigenetic programming of brain development and mental health. Neurosci Biobehav Rev. 2015 Jan;48:70-91.
  28. Jaworska-Andryszewska P, Rybakowski JK. Childhood trauma in mood disorders: Neurobiological mechanisms and implications for treatment. Pharmacol Rep. 2019 Feb;71(1):112-20.
  29. Walker RM, Sussmann JE, Whalley HC, et al. Preliminary assessment of pre-morbid DNA methylation in individuals at high genetic risk of mood disorders. Bipolar Disord. 2016 Aug;18(5):410-22.
  30. De Berardis D, Orsolini L, Serroni N, et al. A comprehensive review on the efficacy of S-Adenosyl-L-methionine in Major Depressive Disorder. CNS Neurol Disord Drug Targets. 2016;15(1):35-44.
  31. Levkovitz Y, Alpert JE, Brintz CE, et al. Effects of S-adenosylmethionine augmentation of serotonin-reuptake inhibitor antidepressants on cognitive symptoms of major depressive disorder. J Affect Disord. 2012 Feb;136(3):1174-8.
  32. Sarris J, Papakostas GI, Vitolo O, et al. S-adenosyl methionine (SAMe) versus escitalopram and placebo in major depression RCT: efficacy and effects of histamine and carnitine as moderators of response. J Affect Disord. 2014 Aug;164:76-81.
  33. Sarris J, Price LH, Carpenter LL, et al. Is S-Adenosyl Methionine (SAMe) for Depression Only Effective in Males? A Re-Analysis of Data from a Randomized Clinical Trial. Pharmacopsychiatry. 2015 Jul;48(4-5):141-4.
  34. Targum SD, Cameron BR, Ferreira L, et al. An augmentation study of MSI-195 (S-adenosylmethionine) in Major Depressive Disorder. J Psychiatr Res. 2018 Dec;107:86-96.
  35. Xiao FH, Kong QP, Perry B, et al. Progress on the role of DNA methylation in aging and longevity. Brief Funct Genomics. 2016 Nov;15(6):454-9.
  36. McEwen LM, Morin AM, Edgar RD, et al. Differential DNA methylation and lymphocyte proportions in a Costa Rican high longevity region. Epigenetics Chromatin. 2017;10:21.
  37. Bacalini MG, D’Aquila P, Marasco E, et al. The methylation of nuclear and mitochondrial DNA in ageing phenotypes and longevity. Mech Ageing Dev. 2017 Jul;165(Pt B):156-61.
  38. Uthus EO, Brown-Borg HM. Methionine flux to transsulfuration is enhanced in the long living Ames dwarf mouse. Mech Ageing Dev. 2006 May;127(5):444-50.
  39. Dziegelewska M, Holtze S, Vole C, et al. Low sulfide levels and a high degree of cystathionine beta-synthase (CBS) activation by S-adenosylmethionine (SAM) in the long-lived naked mole-rat. Redox Biol. 2016 Aug;8:192-8.
  40. Stoyanov E, Mizrahi L, Olam D, et al. Tumor-suppressive effect of S-adenosylmethionine supplementation in a murine model of inflammation-mediated hepatocarcinogenesis is dependent on treatment longevity. Oncotarget. 2017 Dec 1;8(62):104772-84.

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