Topical rapamycin is an excellent new product for aging human skin.
It is expected that topical rapamycin will both help ameliorate the ubiquitous skin aging seen in adults and also decrease skin diseases associated with aging such as skin cancer.
This paper is featured here for two reasons:
- Topical rapamycin is a new product now offered to my patients.
- This paper provides an excellent discussion of the mechanism of how rapamycin slows aging; which applies not just to the skin; but has a general application.
Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial.
~Chung, Dec 2019.
Abstract: Aging is a major risk factor for the majority of human diseases, and the development of interventions to reduce the intrinsic rate of aging is expected to reduce the risk for age-related diseases, including cardiovascular disease, cancer, and dementia. In the skin, aging manifests itself in photodamage and dermal atrophy, with underlying tissue reduction and impaired barrier function. To determine whether rapamycin, an FDA-approved drug targeting the mechanistic target of rapamycin (mTOR) complex, can reduce senescence and markers of aging human skin, an exploratory, placebo-controlled, interventional trial was conducted in a clinical dermatology setting. Participants were greater than 40 years of age with evidence of age-related photoaging and dermal volume loss...
A significant reduction in p16INK4A protein levels (a marker of senescent cells) and an increase in collagen VII protein levels were observed among participants at the end of the study. Clinical improvement in skin appearance was noted in multiple participants, and immunohistochemical analysis revealed improvement in histological appearance of skin. Topical rapamycin reduced the expression of p16INK4A protein consistent with a reduction in cellular senescence. This change was accompanied by relative improvement in clinical appearance of the skin and histological markers of aging and by an increase in collagen VII, which is critical to the integrity of the basement membrane. These results indicate that rapamycin treatment is a potential anti-aging therapy with efficacy in humans.
Introduction: "Inhibition of the mTOR pathway using rapamycin...is one of the most promising anti-aging pathways...Our laboratory was the first to describe mTOR activation as a feature of senescent human cells, and mTOR activation has recently been described as a feature of aging tissues and cells, suggesting that activation of the pathway is a component of age-related dysfunction in multiple setting and may underlie age-related functional decline. In addition, the mTOR pathway is a direct target of the IGF-1 signaling pathway, which is a major driver of aging....
Senescent cells contribute to age-related decline by influencing the microenvironment and through the production of inflammatory cytokines. We and other have demonstrated that rapamycin can delay or prevent senescence in human cells."
[AG note: This is excellent discussion of how aging is driven by interaction of senescent cells and mTOR pathway and how blocked by rapamycin]
"In the skin, senescent cells measured by increased expression of the p16INK4A protein have been found to correlate with markers of aging such as elastic fiber morphology and wrinkling of the skin Dermal atrophy, a significant problem in the elderly, can lead to skin fragility, impaired wound healing, and an increased rate of infections and complications following injury. Photoaging, manifested by fine wrinkles, dyspigmentation, and dull appearing skin, is nearly ubiquitous in adults older than 50 years."
"In order to address the hypothesis that rapamycin treatment can ameliorate age-related disorder and dysfunction in human tissue through a reduction in senescence, we examined the impact of a topical formulation of rapamycin on markers of senescence and aging in human skin, using a placebo controlled, exploratory trial design"
Methods: A topical rapamycin cream (0.001%) was applied to back of one hand every 24 to 48 hours in evening for 8 months. Results were evaluated by clinical assessment and by immunohistochemistry following skin biopsy.
- Topical rapamycin treatment reduced expression of senescence regulator p16INK4A.
- Rapamycin improves cytokeratin 5/6 distribution with more tightly associated with basal layer.
- Topical rapamycin increases collagen VII in the basement membrane.
- Clinical improvement: Of the 13 subjects, (completing study) all except 2 showed improvement in clinical signs of cutaneous aging. The most notable improvement was a decrease in the prominence of veins and tendons, a hallmark of age-related volume loss of the hands. Fine wrinkling was also improved, consistent with the increase in collagen VII. The dyspigmentation and dull appearance associated with photoaging was also consistently improved. These changes were evident approximately 4 months following the initiation of treatment, and continued improvement was noted upon subsequent visits.
Discussion: "This study demonstrates a clear impact of rapamycin treatment on both the molecular signature associated with senescence and the clinical signs of aging in the skin. The data support the idea that a reduction in the burden of senescent cells underlies these improvements...We favor the concept that rapamycin reduces entry into senescence."
There was a reduction of p16INK4A, a marker of senescent cells. "We anticipate that rapamycin treatment reduces inflammatory cytokines in the skin."
"One quantifiable aspect of skin biology that is improved by the rapamycin treatment is the incorporation of collagen VII into the basement membrane, which represents a functional measure of skin quality that is improved upon treatment with rapamycin. Collagen VII is essential for a functional skin barrier , and the levels of collagen VII decrease with age and specifically beneath wrinkles."
"In summary, we present the first evidence that rapamycin treatment improves function and reduces marker of aging in human tissues"
AG note: This study can be seen on two levels:
First: Clinical evidence that topical rapamycin is a very good anti-skin aging preparation.
Second: An excellent explanation and demonstration of how rapamycin slows down aging with the skin being a good aging model because easy to study.
Topical rapamycin in this study was 0.001%. This is very small concentration and quite remarkable that this very small concentration had a significant anti-aging effect. Concentrations up to 100 times greater are also available by prescription from various compounding pharmacies. These stronger preparations are used for various lesions such as angiofibromas, etc. [One very enterprising patient made his own topical rapamycin preparation and used on flat warts (Verruca plan) with excellent results. The .001 % preparation in this study had no systemic absorption and no side effects were reported.
Topical rapamycin should be available as an OTC product at drug stores. Unfortunately, topicl rapamycin is only available by prescription.
The direction are add 1 capsule, 3 mg sirolimus, to 3.5 0z of Aquaphor Ointment. 3.5 Oz is 99 gm or 99,000 mg. When add 3 mg to jar of 99,000 mg preparation is .003%. I use a much stronger preparation (15 capsules in 3.5 Oz to make a 0.045% ointment for age related and solar related lesions on my scalp with good effect. Since the powder is red, can see that it is well dispersed in the white ointment
Topical Rapamycin is a very good product to improve the appearance and function of aging skin.
Rapamycin has an anti-aging effect on the skin, because rapamycin has an anti-aging effect on every organ of the human body. The skin was just a very accessible human organ to study. Rapamycin has an anti-aging effect on the brain, heart, muscle, joints, bone, kidney, immune system, and eyes demonstrated in human or animal studies. The mechanism shown is this study is the basic anti-aging mechanism. mTOR and senescent cells are driving aging and rapamycin slows down this process and slows aging.
Another paper of great interest is:
"Rapamycin for the aging skin" by Mikhail Blagosklonny 2019.
The paper starts:
"In 2007, I filed a patent application claiming that topical rapamycin (e.g. in the form of a cream or ointment) could be used to prevent and treat skin aging"..."The patent was not granted."
Topical rapamycin might be the best topical preparation; but without a patent, there is no commercial interest.
A paper that provides a glimpse into the real potential of topical rapamycin is:
"mTOR in inflammatory skin disease: review of the literature". Cacciapuoti
"Cold Sores" (HERPES LABIALIS)
Update: 2/4/2021: Topical Rapamycin and oral Herpes virus (cold sore)
Herpesvirus uses mTOR to attack human cells. See paper: "Constitutive mTORC1 activation by a herpesvirus Akt surrogate stimulates mRNA translation and viral replication", Chuluunbaatar, 2010, NYU.
"Classic Kaposi's sarcoma treated with topical rapamycin"; Diaz-Ley, 2014, Spain.
Kaposi's sarcoma is an angioproliferative disorder caused by human herpesvirus 8 (HHV-8). They healed KS lesion with 16 weeks topical Rapamycin. They used 0.5% in petrolatum base. I would suggest 0.05% in petrolatum base for Herpes Simplex-1 (HSV-1) "cold sores". [Apply once a day at very earliest start)
Note: Anybody using topical rapamycin for Herpes cold sores has bragging rights for being PATIENT NUMBER 1