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 p16INK4A 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 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.Trial registration ClinicalTrials.gov Identifier: NCT03103893.Electronic supplementary materialThe online version of this article (10.1007/s11357-019-00113-y) contains supplementary material, which is available to authorized users.

Highly accurate skin-specific methylome analysis algorithm as a platform to screen and validate therapeutics for healthy aging

“…6 b), but it resulted in a statistically significant increase in insulin growth factor binding protein 3 ( IGFBP3 ) mRNA expression and a significant decrease in interleukin-8 ( CXCL8 or IL8) mRNA expression (Fig. 6 c), similar to what has been published previously [ 29 ]. CDKN2A (P16), β2 microglobulin ( B2M ), and marker of proliferation Ki-67 ( MKi67 ) presented non-statistically significant mRNA expression alterations.…”

Advancements in therapeutic drugs targeting of senescence

“…Besides, we also collected data on some drugs that have been applied in clinical trials ( Table 2 ). 6 , 31 , 43 , 195 – 198 In addition to promote healthy aging, these drugs could also serve as the therapeutic drugs for various age-related diseases. To improve healthy aging and longevity is a big strategy for social and economic development in the world.…”

Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases

“…A phase 2a clinical study with a low-dose combination of a catalytic (BEZ235) plus an allosteric (RAD001) mTOR inhibitor that selectively inhibits mTOR downstream target of rapamycin complex 1 (TORC1) for 6 weeks demonstrates that mTOR inhibitor therapy is safe, enhances immune function, decreases the incidence of upper respiratory infections and improves the response to influenza vaccination in seniors [101]. The clinical trial NCT03103893 indicates that topical rapamycin treatment for 6~8 months decreases p16 expression associated with reduced cellular senescence of human skin and improves the clinical signs of ageing with increased collagen VII expression in the skin [102].…”