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Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial
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 in 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 and no major morbidities. Thirty-six participants were enrolled in the study, and nineteen discontinued or were lost to follow-up. A significant ( P = 0.008) reduction in p16 INK4A protein levels and an increase in collagen VII protein levels ( P = 0.0077) 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 tissue. Topical rapamycin reduced the expression of the p16 INK4A 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. Trial registration ClinicalTrials.gov Identifier: NCT03103893.
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“Inhibition of mTORC2 signaling extends the lifespan of C. elegans under certain temperatures and dietary conditions111,112, has anti-tumor effects 128–131, is beneficial in mouse models of mitochondrial disease132,133, and has been shown to inhibit or reverse senescence in human cells 134,135.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [135]
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“Rapamycin-treated as compared to placebo-treated subjects were observed to have a significant decrease in senescent cells as assessed by p16 expression, increased collagen VII protein expression, and clinical and histologically assessed improvements in skin appearance.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [135]
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“Rapamycin-treated as compared to placebo-treated subjects were observed to have a significant decrease in senescent cells as assessed by p16 expression, increased collagen VII protein expression, and clinical and histologically assessed improvements in skin appearance.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [135]
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“Treated subjects did not have detectable levels of rapamycin in their blood and there were no treatment-related adverse events.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [135]
In the citing paper
“Rapamycin-treated as compared to placebo-treated subjects were observed to have a significant decrease in senescent cells as assessed by p16 expression, increased collagen VII protein expression, and clinical and histologically assessed improvements in skin appearance.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [135]
In the citing paper
“Treated subjects did not have detectable levels of rapamycin in their blood and there were no treatment-related adverse events.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [135]
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Cites
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Aging, Cell Senescence, and Chronic Disease: Emerging Therapeutic Strategies
Tchkonia, T., & Kirkland, J. L. (2018) · JAMA · doi:10.1001/jama.2018.12440 · Cited by 302
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A Senescence-Centric View of Aging: Implications for Longevity and Disease
Borghesan, M., Hoogaars, W. M. H., Varela-Eirin, M., Talma, N., & Demaria, M. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.07.002 · Cited by 267
Connective tissue and fibroblast senescence in skin aging
Wlaschek, M., Maity, P., Makrantonaki, E., & Scharffetter-Kochanek, K. (2021) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2020.11.010 · Cited by 245
Metadata
- Authors
- Chung, C. L., Lawrence, I., Hoffman, M., Elgindi, D., Nadhan, K., Potnis, M., Jin, A., Sershon, C., Binnebose, R., Lorenzini, A., & Sell, C.
- ORCID
- Sell, Christian
- Venue
- GeroScience
- Published
- 2019-11-25
- Volume
- 41
- Issue
- 6
- Pages
- 861-869
- ISSN
- 2509-2715
- 2509-2723
- PMC
- PMC6925069
- Cited by
- 219
- References
- 3
- Language
- en
- Funders
- Drexel Coulter Foundation
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