Thymosin Beta 4: Genetics & Supplemental Peptides

Key takeaways:

~ Thymosin Beta 4 (Tβ4) is a naturally occurring peptide involved in wound healing, inflammation reduction, tissue regeneration, and is produced in nearly all cell types.
~ It is encoded by the TMSB4X gene, with higher levels during fetal development and important roles in brain, lung, and eye health.
~ Thymosin beta 4 is also available as a peptide supplement – usually as a fragment that is both active and more easily absorbed.

What is thymosin beta 4:

Thymosin beta-4 (Tβ4) is a peptide produced in most tissues of the body (except red blood cells). It was initially discovered to bind to actin, which is part of the cytoskeleton, and influence cell migration for wound healing.[ref]

Thymosin beta 4 was initially isolated from the thymus in calves, which is why it was named thymosin. In the 1970s, doctors used thymosin fraction 5 (containing Tβ4 plus other thymosins) to treat children with genetic conditions that cause immune deficiency.

Tβ4 has since been found to be in most cells and is specifically beneficial for reducing inflammation and promoting tissue regeneration. In the 1990s and early 2000s, studies in animals clearly showed that TB4 promotes tissue repair in the skin and increases blood supply to damaged tissue.[ref][ref]

What is a peptide?

Before we go any further, I want to explain that a peptide is a broad term for a class of molecules made up of a short chain of amino acids. Longer chains of amino acids (usually more than 50-100) are called proteins. Peptides are created by the body, usually through chopping up proteins, and peptides are naturally found in food.  Peptides are also produced as medications or research chemicals.

A lot of the time when you see “peptides” mentioned online, it refers to synthesized peptides used for various health conditions. In the case of thymosin beta 4, it is a peptide that is made in the body and one that you can get as a supplement. Other peptides that the body makes include insulin, substance P, neuropeptide Y, ghrelin, CCK, leptin, leuteinizing hormone, thyroid-stimulating hormone, and more.  Semaglutide, which is sold as Wegovy and Ozympic, is also a peptide.

Endogenous (in the body) production of thymosin beta 4 (Tβ4):

Thymosin beta-4 contains 43 amino acids. It is encoded by the TMSB4X gene as a longer protein and cleaved to the 43 amino acid peptide. In the fetus, it is important for development. Researchers have found that levels of thymosin beta 4 in newborns are about 20 times higher than in adults. It plays an integral role in fetal development.[ref]

Thymosin beta 4 is found throughout the body in all tissues, including in the nervous system, where it plays a role in the development of the brain and helps to promote neuronal survival.[ref][ref] In the lungs, thymosin beta 4 plays a protective role against damage and is anti-fibrotic.[ref] In the eyes, Tβ4 is essential in ocular repair.[ref]

However, overexpression of TB4 in cancerous cells may be a negative factor and help the tumor to survive.[ref[ref] In cancerous tumors, there is an increase in Tβ4 for certain types of cancer. Tβ4 helps to promote angiogenesis, or the formation of new blood vessels needed by fast-growing tumors. It is also thought that Tβ4 may increase cell migration, which could increase metastasis.[ref] For example, thyroid cancers often have higher TMSB4X expression.[ref]

Peptide fragment: Ac-SDKP
Thymosin beta 4 can be broken down into a shorter peptide called Ac-SDKP, which is an active peptide that reduces inflammation and fibrosis. Interestingly, the Ac-SDKP is broken down by ACE (angiotensin-converting enzyme). A common class of blood pressure medications is ACE inhibitors, and one benefit of ACE inhibitors (beyond blood pressure regulation) is that Ac-SDKP levels increase.[ref][ref]

Gene expression:
MiRNAs can affect gene expression of TMSB4X. Mir-153 decreases TMSB4X expression, but a circular RNA called PIP5K1A can inhibit miR153 and thus affect the expression of TMSB4X.[ref]

Clinical trials with TB4 peptide supplements:

Thymosin beta 4 is available as a full-length peptide that is usually injected or as a fragment of the peptide that is available orally. The fragmented peptide is referred to either as TB-500 or as TB4 Frag. TB4 Frag is usually Ac-SDKP, while TB-500 contains the actin-binding motif LKKTETQ.

Note that TB-500 and TB4 Frag are sold as wellness products and not as an FDA-approved therapeutic drug in the US.

Safety trials:

• Recombinant human thymosin:
  A phase I clinical trial assessed the safety of multiple doses of injectable recombinant human thymosin in healthy adults. The results showed no toxicities or serious adverse events.[ref]
• Synthetic thymosin beta 4:
  A phase I safety trial using synthetic thymosin beta 4 at doses from 42 to 1260 mg for 14 days showed no toxicity or serious adverse events.[ref]

Human clinical trials for specific conditions:

Venous ulcers:
Wounds that don’t heal, such as venous ulcers, are a significant problem in older patients with limited mobility. A clinical trial found that thymosin beta 4 applied topically helped to accelerate wound healing.[ref] Other studies show that it accelerates wound healing by up to a month faster than without TB4.[ref]

Dry eyes:
Eye drops containing thymosin beta 4 were trialed in a “multicenter, randomized, double-masked, placebo-controlled 56-day phase 2 clinical trial including a 28-day follow-up at 2 US sites”. The results showed that the Tβ4 eye drops improved ocular discomfort and increased tear volume compared to placebo.[ref]

Bacterial eye infection:
Using Tβ4 along with an antibiotic improved the healing of infections in the cornea.[ref]

Microneedle patch:
An interesting clinical trial used TB4 in extracellular vesicles along with stem cells for healing diabetic wounds. The extracellular vesicles were injected using a microneedle patch. [ref]

Stem cells with Tβ4:
Endothelial progenitor cells with added Tβ4 were transplanted into the hearts of patients who had had a heart attack. The Tβ4 group had improved walk time and cardiac function after 6 months.[ref]

Animal Studies:

Studies on TB4 in animals show:

• In a mouse model of pulmonary hypertension, treatment with Tβ4 attenuated the blood pressure problem and heart hypertrophy.[ref]
• Animal studies show Tβ4 helps repair the damage from a heart attack and also improves the vasculature of the heart.[ref][ref]
• In the liver, Thymosin beta 4 injections prevent liver damage and fibrosis from alcohol.[ref]
• Animal studies also show that TB4 prevents lung fibrosis by alleviating inflammation.[ref]
• TB4, plus the enzyme that creates the TB4-frag, was shown in mice to reduce kidney fibrosis and repair kidney health.[ref]

What is TB-500:

Another form of thymosin beta 4 available as a peptide is called TB-500. It is described as a “N-terminal acetylated 17-23 fragment of human thymosin beta 4” which is a synthetic version that promotes tissue repair, regeneration, and muscle growth. The peptide chain is LKKTETQ. Most of the peer-reviewed research studies on TB-500 focus on how to detect it as a doping agent for sports or in horse racing.[ref] It is a banned substance for horse racing and by the World Anti-Doping Agency for competitive athletes.[ref]