Sirolimus works via different pathways as compared to other skincare ingredients such as retinoids. Sirolimus or rapamycin targets senescent cells (old cells that don’t function at optimal levels), whilst tretinoin & retinoids work by upregulating receptors found in all cell ages. 

Sirolimus reverses skin aging at a cellular level; namely keeps fibroblasts (cells that produce collagen) at optimal efficiency by reversing the cell’s aging process & removing old cells. 

Retinoids such as tretinoin merely makes the cell work harder by asking it to produce more collagen (via RAR receptors). It makes sense to combine both pathways for more powerful anti aging effects.

Application guidelines have not been determined, however can be extrapolated via recent studies.  

Sirolimus should be used once daily to dry skin. It has a low irritant potential, which means in many cases it can be mixed with retinol, retinoids & selected skincare products. It can be used on aging areas of the face, neck & hands. Though there is no advice on the maximal surface area permissible, 4-5 palms (represents 5% of the surface area) seems safe & sensible. 

Studies have shown that results are visible at 4 months, & continue to improve beyond one year. More clinical research is required to understand optimal timeframes. 

Let’s extrapolate the scientific evidence with oral rapamycin. Starting sirolimus rapamycin in one’s late 20s or early 30s may optimize both healthspan and lifespan compared to starting in later decades. 

Animal studies show that rapamycin is effective at increasing healthy lifespan when initiated in early adulthood or middle age, with the longest lifespans achieved when started earlier. For instance, in the National Institute on Aging’s ITP studies, starting rapamycin in young adult mice led to a 23% to 26% median lifespan improvement, whereas starting in middle age resulted in only an 11% to 15% improvement. Some researchers suggest that optimized dosing schedules may potentially extend human lifespan by up to 30 years. 

Recent 2022 results from the Interventions Testing Program showed a 29% lifespan increase for male mice fed rapamycin starting in early adulthood. Given that age-related changes begin as early as age 26, starting rapamycin earlier may better preserve functionality during aging and increase healthspan. Starting with a low dose in young adulthood, particularly in females, may offer the greatest benefits due to the faster decline in female fertility.

Based on these studies, sirolimus cream should, ideally, be initiated early as part of your skincare antiaging program. It can be argued that topical application should be initiated in the late 20s, early 30s to slow down the aging process. 

Potentially, yes as this has less skin irritation as compared to tretinoin or prescription retinoids, hence maybe a better option for patients who have rosacea or eczema. 

*It is more complex than just the ingredient as sirolimus concentrations vary from 0.01 to 2%, depending on the indication. Additionally the base & formulations play a significant role in product constituency. 

Potentially to any area, limited by surface area*. The biggest study is on the hands, however current studies apply sirolimus to facial areas. I personally use it on facial areas to help reverse skin aging & sun damage. 

*Total surface area absorption has not been studied as of 2024. SA of less than 5% is sensible. 

The choice between sirolimus cream & tablets depends on individual factors such as the condition being treated, treatment goals, and potential side effects. Sirolimus cream is applied topically and is used for reversal & prevention of skin aging. 

Sirolimus tablets are taken orally and provide systemic effects, making them suitable for overall anti-aging affecting the entire body including extension of lift. Both are off-label, & the decision as to which is best suited is a conversation between you & your anti aging physician. 

*For dermatological use, we prescribe sirolimus cream (topically) as it has potentially less side effects as compared to tablets. 

The optimal concentration has not been determined, however it is thought to be in the range of 0.1 to 2% sirolimus-rapamycin cream. 

My personal formulation as of 2024 is 0.2% cream formulation. I think it is the sweet spot. 

Inhibition of mTOR Pathway: Sirolimus works primarily by inhibiting the mammalian target of rapamycin (mTOR) pathway. mTOR is a key regulator of cellular growth, metabolism, and aging. By inhibiting mTOR, sirolimus modulates cellular processes involved in aging, such as protein synthesis, cell proliferation, and autophagy (the process by which cells degrade and recycle damaged components).

Promotion of Autophagy: Sirolimus-rapamycin promotes autophagy, a cellular process that removes damaged or dysfunctional components and helps maintain cellular homeostasis. As cells age, their ability to carry out efficient autophagy declines, leading to the accumulation of cellular waste and damage. By enhancing autophagy, sirolimus may help rejuvenate cells and tissues and mitigate age-related decline.

Reduction of Inflammation: Sirolimus has been shown to reduce inflammation, which is a hallmark of aging and age-related diseases. Chronic inflammation contributes to tissue damage, impaired organ function, and the development of age-related conditions such as cardiovascular disease, neurodegenerative diseases, and cancer. By dampening inflammatory responses, sirolimus may help mitigate age-related inflammation and its detrimental effects on health.

Improvement of Metabolic Health;  Sirolimus has been found to improve metabolic health by enhancing insulin sensitivity and glucose metabolism. Age-related changes in metabolism, including insulin resistance and dysregulated glucose metabolism, contribute to the development of metabolic disorders such as type 2 diabetes and obesity. By modulating metabolic pathways, sirolimus may help improve metabolic health and extend lifespan.

Overall, sirolimus appears to exert its anti-aging effects through multiple mechanisms, including inhibition of the mTOR pathway, promotion of autophagy, reduction of inflammation, and improvement of metabolic health. Sirolimus holds promise as a potential anti-aging intervention.

The evidence supporting the potential life-extending effects of sirolimus (rapamycin) primarily comes from preclinical studies conducted in various model organisms, including mice, rats, and yeast. While sirolimus has shown promising results in these studies, it’s important to note that the translation of findings from animal models to humans is complex and requires further investigation. Here are some key findings from preclinical studies:

Animal Studies: Studies have demonstrated that sirolimus extends lifespan and improves healthspan (the period of life free from age-related diseases and disabilities) in various animal models. For example, research in mice has shown that treatment with sirolimus leads to an increase in median and maximum lifespan, as well as improvements in age-related biomarkers and physiological functions, even when sirolimus was given to older mice. 

Delayed Aging Phenotypes: Sirolimus has been found to delay the onset and progression of aging phenotypes in animals, including age-related declines in cognitive function, motor performance, immune function, and metabolic health. These effects are thought to be mediated by sirolimus’s ability to target key pathways involved in aging, such as the mTOR pathway and cellular senescence.

Protection Against Age-Related Diseases: Sirolimus has been shown to protect against a wide range of age-related diseases and conditions in animal models, including cancer, cardiovascular disease, neurodegenerative diseases, metabolic disorders, and immune dysfunction. By targeting underlying mechanisms of aging and age-related diseases, sirolimus improves overall health and extends lifespan in animals.

Consistency Across Species: The life-extending effects of sirolimus have been observed across different species, including mammals (mice, rats), invertebrates (yeast, worms), and even some primates. This suggests that sirolimus’s effects on longevity may be evolutionarily conserved and not limited to specific organisms.

Further research, including well-designed clinical trials, is needed to determine the safety, efficacy, and potential benefits of sirolimus as an anti-aging intervention in humans.

The evidence supporting the potential life-extending effects of sirolimus (rapamycin) primarily comes from preclinical studies of sirolimus taken orally in various model organisms, including mice, rats, and yeast. While sirolimus tablets are more powerful, one has to be mindful of the unknown. On this basis a cream formulation is most sensible. 

Comparing sirolimus-rapamycin and tretinoin for anti-aging purposes requires consideration of their mechanisms of action, clinical evidence, and potential side effects. Here’s a comparison of both:

Mechanism of Action:

Sirolimus (Rapamycin): Sirolimus inhibits the mTOR (mechanistic target of rapamycin) pathway, which regulates cellular senescence, metabolism, growth, and aging. By inhibiting mTOR, sirolimus slows down cellular processes associated with aging and promotes longevity.

Tretinoin: Tretinoin is a retinoid that works by increasing cell turnover, stimulating collagen production, and promoting skin renewal. It improves skin texture, reduces fine lines and wrinkles, and enhances overall skin appearance. Tretinoin only stimulates the cell line to produce collagen, it does not change cellular age. 

Clinical Evidence:

Sirolimus:  Most of the evidence supporting the anti-aging effects of sirolimus comes from preclinical studies in animal models, where it has been shown to extend lifespan and improve healthspan. Clinical trials evaluating sirolimus for anti-aging purposes in humans are limited, apart from the study on human hands. 

 Tretinoin: Tretinoin has been extensively studied and clinically proven to be effective for reducing signs of aging, such as fine lines, wrinkles, and hyperpigmentation. Numerous clinical trials have demonstrated its efficacy and safety in improving skin texture and appearance.

Side Effects: 

Sirolimus: Common side effects of sirolimus include immunosuppression, increased risk of infections, & skin irritation.

Tretinoin: Common side effects of tretinoin include skin irritation, redness, dryness, and peeling, especially during the initial stages of treatment. Tretinoin can also increase sensitivity to sunlight, so proper sun protection is essential when using this medication.

Usage and Availability:

Sirolimus is primarily used as an immunosuppressant in transplant recipients to prevent organ rejection. Its use for anti-aging purposes is investigational, and clinical guidance on its use for this indication is limited.

Tretinoin: Tretinoin is widely available as a topical medication and is commonly used in dermatology for various skin conditions, including acne and photoaging. It is available in different strengths and formulations, including creams, gels, and lotions.

In conclusion, while both sirolimus and tretinoin have shown promise for anti-aging purposes, tretinoin currently has more substantial clinical evidence supporting its efficacy and safety in improving skin texture and reducing signs of aging. Ultimately, the choice between sirolimus and tretinoin for anti-aging should be based on individual preferences, skin type, and medical history. 

The SiroSkin trial aims to assess the effectiveness of topical Sirolimus in reducing the incidence of skin cancers in solid organ transplant recipients. Participants will apply either Sirolimus or a placebo cream to their face and ears once nightly for six months and will be followed up at six, 12, and 24 months post-intervention. Photos of the face will be taken to monitor skin cancer occurrences, and participants will complete quality of life questionnaires related to skin cancer and health economics.

Joining the trial could potentially contribute to the development of a new therapy with minimal side effects, offering a significant reduction in facial skin cancers for transplant recipients. With approximately 12,000 solid organ transplant recipients in Australia alone, the trial has the potential to improve long-term outcomes and life expectancy for these patients while also potentially reducing healthcare costs globally.

5-10mg per week is the sweet spot for oral rapamycin. 

Individuals taking rapamycin for anti-aging purposes opt for a weekly dosing schedule, following the frequency used in the Mannick 2014 Study of the rapalog everolimus. This regimen showed minor side effects over the study period. However, some individuals consider the half-life of rapamycin, which varies but is typically between 62 and 80+ hours, adjusting their dose based on weight and evaluating when their blood sirolimus levels reach a trough level they consider safe for the next dose. This may result in dosing every 10 or 12 days for some individuals. Blood sirolimus levels peak about 1 hour after ingestion, then decrease by about 50% every 65 to 85 hours.

Disclaimer: I do not prescribe dermatological drugs as my work is procedural, namely I inject, laser, cut & peel. 

Patients typically start sirolimus- rapamycin at a low dose, such as 1mg per week, gradually increasing by 1mg each week until reaching a target dose of 5mg to 10mg per week. Some individuals may ramp up more quickly, but faster increases in dosage may lead to more side effects. It’s common for patients to take rapamycin in the morning as it can be stimulative. 

Before starting rapamycin, it’s recommended to undergo several blood tests to establish baseline information, including insulin, CBC, CMP, ferritin, lipid panel, hemoglobin A1C, and hsCRP. 

Disclaimer: I do not prescribe dermatological drugs as my work is procedural, namely I inject, laser, cut & peel. 

Probably tablets over creams, however there is a lack of information as of 2024. Oral sirolimus exerts an overall anti-aging effect, including the potential to extend life & reverse cellular aging. Undoubtedly it is more powerful than cream formulations in this context. 

Rapamycin or sirolimus can potentially stimulate hair growth & reduce gray hairs, however there is a lack of studies. Anecdotal reports suggest it can work, especially when combined with minoxidil. I suspect combinations of exosomes, PRP & sirolimus will have the best effects on hair growth. 

I do not prescribe this to patients (outside of medical trials) as my work is entirely procedural. To obtain rapamycin for anti-aging purposes, it’s highly recommended to work with a physician, as it’s a new application of the drug. You’ll need a prescription, which can be obtained by contacting doctors who prescribe rapamycin for aging (Google search). 

For topical sirolimus cream, you can source this via your anti-aging doctor. 

In Europe, rapamycin can be purchased in Turkey without a prescription, however you will require a prescription if you reside in Australia. Once you have a prescription, you can choose between brand name (Pfizer Rapamune) and generic sirolimus, with generic options being more affordable. In the USA, services like GoodRx can help you find competitive pricing. Online pharmacies, particularly from India, offer lower prices but may carry some risks. Prices vary, but typically range from $1.00 to $6.00 per milligram tablet.

Disclaimer: I do not prescribe dermatological drugs as my work is procedural, namely I inject, laser, cut & peel. 

I am a procedural dermatologist, I do not typically prescribe sirolimus to patients outside a clinical trial because-

1. You will require clinical follow ups & repeat prescriptions. My appointment slots are taken up with procedural dermatology, not prescriptive dermatology. An anti-aging physician can follow your progress & issue repeat prescriptions as required. 
2. The TGA in Australia is probably one of the most backward governing bodies in the world. Off label prescriptions are frowned upon by red tape enforcers that do not have the capacity to read scientific papers & think outside the box. 

*You can source sirolimus online via numerous pharmacies globally. 

**DIY mixing of creams is not recommended based upon formulation & absorption variables. 

***Clinical trials in Australia are limited to high risk skin cancer patients. 

Sirolimus or rapamycin cream, has immunosuppressive properties. While sirolimus cream is generally considered safe and well-tolerated when used as prescribed, it can still cause side effects in some individuals. Here are some potential side effects –

1. Local Skin Reactions: The most common side effects of sirolimus cream are local skin reactions at the site of application. These may include redness, irritation, itching, burning sensation, dryness, folliculitis, and peeling of the skin. These side effects are usually mild to moderate in severity and tend to improve with continued use or with adjustments in the frequency or concentration of the cream.
2. Photosensitivity: Sirolimus cream may increase the skin’s sensitivity to sunlight, leading to an increased risk of sunburn and sun damage. It is important for individuals using sirolimus cream to apply sunscreen regularly and avoid prolonged sun exposure, especially during peak hours.
3. Skin Discoloration:Some individuals may experience changes in skin pigmentation, such as hyperpigmentation or hypopigmentation, with long-term use of sirolimus cream. These changes are usually reversible upon discontinuation of the medication.
4. Allergic Reactions: Although rare, allergic reactions to sirolimus cream can occur. Signs of an allergic reaction may include rash, hives, swelling of the face, lips, or tongue, difficulty breathing, or severe itching. If any of these symptoms occur, medical attention should be sought immediately.
5. Infection: Sirolimus cream suppresses the immune system locally, which may increase the risk of developing skin infections, such as bacterial, fungal, or viral infections. 
6. Systemic Absorption: Although systemic absorption of sirolimus through the skin is minimal with topical use, it is still possible, especially if large areas of the body are treated or if the skin barrier is compromised. Systemic absorption may increase the risk of systemic side effects, such as immunosuppression and metabolic abnormalities.