Rapamycin cream, also called topical rapamycin or topical sirolimus, is a hot topic in longevity and anti-aging communities. Rapamycin is an old prescription drug that has traditionally been used as an immunosuppressant, but researchers have become interested in its effects on mTOR, a cellular signaling pathway involved in growth, metabolism, cellular repair, and aging. Now, compounded rapamycin creams and other topical formulations are being used as a treatment for wrinkles, skin laxity, and other signs of skin aging.

There are  no controlled trials looking at its effects on aged skin- so we do not know much about it.
I am addressing the topic of topical sirolimus because my patients are asking me about it and because topical rapamycin has become a popular topic in skincare and longevity communities. 

My goal is to separate the science from the hype and explain what we actually know about the potential benefits, side effects, contraindications, drug interactions, concentrations, and long-term safety of topical rapamycin. 

The use of topical rapamycin to "slow skin aging" spurred development of a new rapamycin-related compound that selectively targets mTORC1 and is now available as a skin care product called ReQ.

This article will discuss use of the topical prescription form of rapamycin for skin aging.

Rapamycin affects pathways involved in how cells age, so the idea is that it may help older skin cells function more like younger, healthier cells.

Early research has found some encouraging changes in markers of skin aging, but we do not yet know how much these changes translate into visible improvements in the skin.

Many of the benefits people describe, such as increased radiance, firmness, and smoother-looking skin, are still anecdotal and have not been proven in large, well-controlled clinical trials.

People who have used topical rapamycin on their skin have reported:

• Brighter, more radiant skin
• Smoother skin texture
• Firmer-feeling skin
• Improved elasticity
• Fewer visible fine lines and wrinkles
• More even skin tone
• Healthier-looking skin
• An overall more youthful appearance

Topical rapamycin can cause skin side effects, and there are still unanswered questions about the safety of using it long-term for cosmetic anti-aging purposes. Rapamycin (sirolimus) is an immunosuppressive prescription drug, so it should not be treated like a typical over-the-counter skincare ingredient. Although much less sirolimus reaches the bloodstream with topical use than with oral sirolimus, some systemic absorption can occur.

The only info we have on topical rapamycin side effects are anecdotal reports. These are the side effects I have heard form patients or from Reddit conversations:

• Dryness
• Redness and irritation
• Peeling or flaking
• Itching
• Acne or acne-like breakouts
• Application-site reactions
• Potential systemic absorption

Keep in mind that people are making their own topical cream or ointment by crushing up the oral drug, or pharmacies are compounding it. There is no standard "topical rapamycin cream" so it is very difficult to know the true risks. Some of the risks may be due to the vehicle used in compounding.

One of my biggest concerns with topical rapamycin for anti-aging is not that we know it is unsafe—it is that we do not yet have enough long-term safety data in healthy people using it cosmetically. 

These are the unknown potential issues:

• Increased susceptibility to infection due to its immunosuppressive effects
• Drug interactions
• Unknown effects of long-term use
• Lack of established dosing, concentration, and application frequency to treat skin aging
• Systemic absorption
• Activation of mTORC2 and its long term effects

Because rapamycin has immunosuppressive effects, I would avoid applying topical rapamycin to skin with an active infection. This includes herpes simplex (cold sores), bacterial infections, fungal infections, and infected acne lesions. I would also use caution in people who are prone to recurrent HSV outbreaks or other frequent skin infections because local immune suppression could theoretically make it more difficult for the skin to control infection. The effects of long-term topical rapamycin on the skin microbiome have not been adequately studied, so we do not yet know whether chronic use alters the balance of bacteria, fungi, and other microorganisms that normally live on healthy skin. These concerns are particularly relevant when topical rapamycin is being used electively for anti-aging rather than to treat a medical condition.

Rapamycin works by temporarily changing the signals that tell cells when to grow, divide, make proteins, and respond to nutrients and growth factors. After entering a cell, rapamycin first binds to an intracellular protein called FKBP12 (FK506-binding protein 12). Together, rapamycin and FKBP12 form a complex that binds to the FRB domain of mTOR, primarily inhibiting mTORC1. Rapamycin does not directly inhibit mTORC2 in the same way. However, prolonged exposure can interfere with the formation of new mTORC2 complexes in certain cell types, so chronic rapamycin treatment may ultimately suppress both pathways.

Basically, topical rapamycin may help “reset” aging fibroblasts by giving them a temporary rest from growth signaling, helping preserve their function and reducing their tendency to become senescent.

mTOR stands for mechanistic target of rapamycin, a cellular signaling pathway involved in growth, metabolism, repair, and aging. Topical rapamycin has been studied as a way to reduce cellular senescence and improve signs of aged skin. However, its potential use for skin aging is limited by concerns about systemic exposure and, with prolonged treatment, unwanted inhibition of mTORC2.

mTORC1 promotes cell growth and protein production, but persistent overactivity is associated with reduced autophagy and cellular senescence. For antiaging purposes, the antiaging goal is to temporarily reduce excessive mTORC1 activity, allowing cells time for autophagy and repair.

mTORC2, in contrast, supports cell survival, cytoskeletal organization, migration, and normal tissue function. We generally do not want to inhibit mTORC2 when targeting skin aging because these functions are important for healthy cells and tissue repair. This is one reason a more selective mTORC1 inhibitor such as Dioxothiazetidinyl demethoxyrapamycin is interesting.

he science behind rapamycin and skin aging, combined with encouraging clinical findings and anecdotal reports, has led some physicians and patients to use prescription topical rapamycin off-label to treat wrinkles and other signs of skin aging. Research into the mTOR pathway also led to the development of RLX-201 (Dioxothiazetidinyl demethoxyrapamycin), a derivative of rapamycin designed to selectively inhibit mTORC1 while preserving mTORC2 activity.(1) RLX-201 is now found in Re-Q Pro-Longevity Face Serum, a new antiaging serum designed to target this pathway without the broader mTOR inhibition associated with rapamycin. Studies of RLX-201 show selective mTORC1 inhibition without suppressing mTORC2, while testing of the finished Re-Q formulation reportedly found no detectable systemic absorption. This targeted approach may offer an important advantage over topical rapamycin, although more clinical research is needed to establish its long-term efficacy and safety.

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