Increasing Oxytocin and Inhibiting TGF-beta to Extend Lifespan

In mice - the combo holds promise for extending lifespan and healthspan.

A new study¹ published in the journal Aging shows that a combo of two drugs extends lifespan in old mice. I don’t usually pay all that much attention to lifepan studies in old mice, but this one is interesting and has a two-pronged approach that seems like a good idea.

The study looked at restoring the levels of oxytocin, which decline in aging, and inhibiting TGF-beta, which increases in aging.

The results of the study showed that male mice given the oxytocin + TGF-beta inhibitor in old age had an increased median lifespan of 14%. Female mice didn’t have the same lifespan extension, but they did have an extension of reproductive span and healthspan.

Screenshot from https://www.aging-us.com/article/206304/text

The researchers also looked at healthspan; they noted that the treated mice looked and acted much younger than the placebo-treated mice.

Let’s take a look at why oxytocin and a TGF-beta inhibitor help with healthspan.

Oxytocin in aging:

Oxytocin is commonly called the love hormone. It’s a neuropeptide hormone that promotes parent-child bonding, social bonding, and emotional regulation. Studies in aging animals also revealed that oxytocin plays an important role in maintaining skeletal muscle mass by enhancing stem cell activation in aging muscles.²

A 2024 study showed that higher oxytocin levels corresponded to better memory and larger hippocampus volume in elderly adults.³ Interestingly, higher overall oxytocin levels also correlate with younger-looking skin.⁴ clinical trial showed that intranasal oxytocin four times a day in older adults increased muscle mass by about 5 lbs and decreased fat mass.⁵

TGF-beta in aging:

TGF-β (transforming growth factor beta) is a cytokine produced by white blood cells that comes in three forms: TGF-β 1 to 3. It binds to TGF-β receptors to activate several different types of immune cells.

In general, TGF-β is involved in growth, cell signaling, and the immune response to cancer. TGF-beta receptor activation has a bunch of different effects, depending on the cell type and situation. In aging, TGF-beta overactivation is linked to fibrosis, arthritis, and neurodegeneration. TGF-beta plays a role in cellular senescence, ROS, DNA damage repair, telomere regulation, unfolded protein response, and autophagy. So TGF-beta has a bunch of functions that are important. However, you don’t want excess TGF-beta signaling.⁶

Higher levels of TGF-beta are found in aging and cause tissue fibrosis. Fibrosis occurs with the accumulation of extracellular matrix proteins (e.g. collagen, fibronectin), and this is the process that causes scar tissue after a wound. In aging, a gradual excess of fibrosis can decrease lung function and liver function. Excess TGF-beta signaling also plays a role in osteoarthritis.⁷

The endothelium is the type of tissue that lines the blood vessels and lymphatic vessels. It’s a dynamic and adaptable barrier that is essential for moving blood, oxygen, CO2, and lymph throughout the body.

Where does TGF-beta come into play? Endothelial cells are flexible and resilient to allowing things like white blood cells and stem cells to move through them.⁸ However, this adaptability also means that they can transition to another cell type - called endothelial to mesenchymal transition. Mesenchymal cells are a cell type that can migrate, produce extracellular matrix, and possibly differentiate into multiple cell types, such as fibroblasts or smooth muscle cells. Endothelial to mesenchymal transition is helpful in wound healing, but causes problems in atherosclerosis, pulmonary hypertension, and fibrosis in the heart, lungs, and liver.

What causes endothelial to mesenchymal transition? TGF-beta signaling.

Normally, TGF-beta is suppressed in the endothelium due to low levels of the receptor (ALK5). However, inflammatory cytokines can increase ALK5 levels and initiate TGF-beta signaling. It’s a feed-forward loop with endothelial to mesenchymal transition, then causing more inflammation, more TGF-beta signaling, and more transitioning — resulting in fibrosis, stiffening in the arteries, and decreased vascular function.[ref]

Circling back: The study on extending healthspan and lifespan in mice used a TGF-beta inhibitor medication, along with supplemental oxytocin. Inhibiting TGF-beta at the right level prevents the fibrosis and endothelial dysfunction seen in aging.

Natural alternatives: Oxytocin nasal spray and TGF-beta inhibitors

Oxytocin is available online as a nasal spray. It’s a small peptide hormone that can cross the nasal epithelial cells. There are a few options on Amazon, but I don’t know what the quality is like.

If you’re interested in trying supplemental oxytocin, shop around with some of the peptide suppliers that offer it. Oxytocin nasal spray is used for autism (to increase social bonding), weight loss, and for nursing mothers who need help with letting down.

For inhibiting TGF-beta, a number of natural supplements have been shown to act on the pathways that induce TGF-beta production.

Natural inhibitors or modulators of TGF-beta signaling include: Cryptotanshinone, Resveratrol, Oximatrina, Ligustrazina, Osthole, coumarin, Codonolactone, Betanin, Tannic acid, Cinnamomum cassia extracts Cairicoside E, Gentiopicroside, Genistein, Paeoniflorin, Gambogic acid, Arctigenin, Curcumin, Baicalin and baicalein.[ref]

Several of these are readily available supplements that are well studied with multiple roles in longevity and healthy aging. As always, talk with your doctor if you have any medical questions.

• Resveratrol is the polyphenol found in grapes and wine. It is available in capsules⁹ and as a powder. It has little taste and can easily be added to a drink, yogurt, or smoothie if you don’t want to take more capsules.

• Tannic acid is a component of black tea, and genistein is found in soy.

• Cinnamomum cassia is cinnamon. You can get it as an extract in capsules or up your cinnamon intake. One concern with supplementing with cinnamon is the possibility of lead contamination. ConsumerLab.com does lab testing of supplements and spices. They found that Badia brand cinnamon had higher than acceptable levels of lead. Swanson Cinnamon was the top pick in capsules based on price and passing the testing.

• Baicalin is a component of Chinese Skullcap, an herb used in traditional chinese medicine. It is also available as a supplement.

• Curcumin is readily available as a supplement in capsules. Be sure to check for interactions with any medications that you’re on. This is the brand that I’m currently using, but read reviews and choose one that works for you.

To be honest, I don’t know whether natural supplements have a large enough effect size to move the needle on TGF-beta and fibrosis in aging. There are multiple therapeutics under development right now, so there may be more effective options available at some point. More studies on this are needed!¹⁰

Conclusion:

This new study is pretty impressive in mice, and it mechanistically makes sense in humans — but we need actual human trials to know effect size, dosing, timing, etc. A prior study in mice showed that inhibiting TGF-beta and supplementing with oxytocin brought positive benefits when combined with exercise. The combo prevented the inflammation and fibrosis seen in the elderly with exercise.¹¹

I’m intrigued by TGF-beta, the endothelial-to-mesenchymal transition, and reversing fibrosis. So I’m going to follow this up next week going more indepth on those topics.

1. Sex-specific longitudinal reversal of aging in old frail mice. Kato, et al. https://www.aging-us.com/article/206304/text

2. Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration. Elabd, et al. https://www.nature.com/articles/ncomms5082

3. https://www.sciencedirect.com/science/article/pii/S2950307824000870

4. https://www.dermatologytimes.com/view/clinical-study-points-to-oxytocin-s-antiaging-benefits

5. https://pubmed.ncbi.nlm.nih.gov/34029521/

6. https://www.mdpi.com/1422-0067/20/20/5002

7. https://pubmed.ncbi.nlm.nih.gov/23685840/

8. https://rupress.org/jcb/article/201/3/449/37290/Release-of-cellular-tension-signals-self

9. Amazon affiliate link as an example — please read reviews and choose what works best for you.

10. https://pubmed.ncbi.nlm.nih.gov/34560077/

11. https://pubmed.ncbi.nlm.nih.gov/40536399/