Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial

AbstractAging 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.

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Outcomes of Eyes Lost to Follow-up with Neovascular Age-Related Macular Degeneration Receiving Intravitreal Anti-Vascular Endothelial Growth Factor

Ophthalmology Retina ◽

10.1016/j.oret.2019.07.010 ◽

2020 ◽

Vol 4 (2) ◽

pp. 134-140 ◽

Cited By ~ 3

Author(s):

Rebecca Russ Soares ◽

Phoebe Mellen ◽

Hannah Garrigan ◽

Anthony Obeid ◽

Turner D. Wibbelsman ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Macular Degeneration ◽

Age Related Macular Degeneration ◽

Vascular Endothelial ◽

Age Related ◽

Lost To Follow Up ◽

Endothelial Growth Factor

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A Peripheral Ameloblastic Fibro-Odontoma in a 3-Year-Old Girl: Case Report, Immunohistochemical Analysis, and Literature Review

Case Reports in Dentistry ◽

10.1155/2014/321671 ◽

2014 ◽

Vol 2014 ◽

pp. 1-6 ◽

Cited By ~ 1

Author(s):

Yi-Chun Lin ◽

Hsiu-Ming Hsu ◽

Chiang-Shin Liu ◽

Kuo Yuan

Keyword(s):

Histopathological Examination ◽

Correct Diagnosis ◽

Immunohistochemical Analysis ◽

Clinical Appearance ◽

Jaw Bones ◽

Tissue Sections ◽

Odontogenic Epithelium ◽

Histological Characteristics ◽

Children And Young Adults

Ameloblastic fibro-odontoma (AFO) predominantly occurs in the jaw bones of children and young adults. Extraosseous AFO is extremely rare. We describe a peripheral ameloblastic fibro-odontoma in the maxillary gingiva of a 3-year-old girl. The clinical appearance resembled fiery red reactive gingival lesions. The histopathological examination of the excised lesion showed small islands and cords of odontogenic epithelium with cellular myxoid stroma in the subepithelial tissue. The mass contained calcified material and an enamel-like deposit. Many small blood vessels appeared in the connective tissue surrounding the odontogenic epithelium. The immunohistochemical assays showed strong reactivity for amelogenin,β-catenin, CD44, and CD31 in the tissue sections. There was no recurrence after the 1-year follow-up. Because this lesion clinically resembles other nonneoplastic lesions and is very rare in gingiva, establishing a correct diagnosis is achieved only based on specific histological characteristics. Conservative excision of the tumor is the treatment of choice.

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Natural course of acquired vitelliform lesions associated with pigment epithelial detachments in dry age related macular degeneration

European Journal of Ophthalmology ◽

10.1177/1120672121990566 ◽

2021 ◽

pp. 112067212199056

Author(s):

Özge Yanık ◽

Sibel Demirel ◽

Figen Batıoğlu ◽

Emin Özmert

Keyword(s):

Macular Degeneration ◽

Age Related Macular Degeneration ◽

Final Visit ◽

Imaging Data ◽

Pigment Epithelial ◽

Age Related ◽

History Of ◽

The Mean ◽

Lost To Follow Up

Purpose: To describe the natural history of acquired vitelliform lesions (AVLs) associated with different types of pigment epithelial detachments (PEDs) in dry age-related macular degeneration. Methods: A retrospective review of clinical examination and multimodal imaging data of patients with AVLs associated with PED(s) was performed. Results: This study included 25 eyes of 17 patients. The mean age of patients was 67.2 ± 9.7 (47–83) years. The mean follow-up time was 32.6 ± 16.2 (12–66) months, excluding four patients (five eyes) that were lost to follow-up. The mean logMAR BCVA was 0.21 ± 0.16 at baseline and 0.38 ± 0.28 at final visit ( p = 0.016). At the end of the follow-up period, PEDs enlarged in eight eyes (40%) and were unchanged in two eyes (10%). Spontaneous resolution of the central PED(s) with AVLs was seen in four (20%) eyes. Rupture of the PED(s) occurred in four eyes (20%), with two developing central foveolar atrophy afterwards. Overall, central foveolar atrophy was seen ultimately in four eyes (20%). Conclusion: It seems that high PED size may be a risk factor for PED rupture during follow-up. 1/3 of the eyes ended up with unfavorable anatomical outcome.

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A new survivorship model for adolescents and young adults (AYA).

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.3_suppl.43 ◽

2016 ◽

Vol 34 (3_suppl) ◽

pp. 43-43

Author(s):

Erin Marie Barthel ◽

Sabrina Karim ◽

Elizabeth Kiernan ◽

Katherine Spencer ◽

Rachel Murphy-Banks ◽

...

Keyword(s):

Mental Health ◽

Active Treatment ◽

Hematologic Malignancy ◽

Life Assessment ◽

Survivorship Care ◽

Active Therapy ◽

Care Plans ◽

Age Related ◽

Lost To Follow Up

43 Background: The AYA population is a growing group of cancer survivors, currently exceeding 600,000 in the US, with 70,000 new diagnoses each year. These survivors experience deficits in general health, mental health, and functional status. Unfortunately, many are lost to follow-up after the completion of active therapy. They lack clarity about where to go for care and why such care is needed. To further complicate this, many have not established a primary care provider (PCP). Methods: We present a model of survivorship care tailored to the AYA population. Our clinic has dedicated physical space and is staffed by pediatric- and adult-trained oncologists. Survivors are paired with age-matched peer navigators to guide them through the logistics of follow-up care and assist with age- related transitions in education, housing, and insurance. Additionally, we have established a new model of survivorship care, introduced immediately at the end of active therapy, utilizing a staged curriculum, survivorship care plans, and point-of-care health-related quality of life assessment. Results: Fifty-five unique patients seen in 182 visits provided data for this report. The median age was 26 years (range 18-40). Twenty-nine (53%) of the patients were female. The majority of patients (58%) had been treated for a hematologic malignancy. One third of patients had completed college (31%). Most were employed (71%), but a majority still lived with their parents (64%). The majority of patients had more than one late effect (62%). Twenty-three (43%) reported mental health symptoms, including anxiety, mood swings, or sleep problems. Conclusions: A survivorship clinic with tailored programs for AYAs is feasible and necessary. In our sample, many AYA survivors have late effects and almost half reported psychosocial distress. Clinicians need to monitor this age group closely to ensure that patients are not lost to follow-up as they transition from active treatment to survivorship care and from pediatric to adult-based care. Our clinic provides an integrated medical home for the AYA survivor that continues to care for them when active treatment comes to completion and provides ongoing care coordination with PCPs and subspecialists to co-manage their complex health issues.

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Human skin aging is associated with increased expression of the histone variant H2A.J in the epidermis

npj Aging and Mechanisms of Disease ◽

10.1038/s41514-021-00060-z ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Claudia E. Rübe ◽

Caroline Bäumert ◽

Nadine Schuler ◽

Anna Isermann ◽

Zoé Schmal ◽

...

Keyword(s):

Dna Damage ◽

Human Skin ◽

Cellular Senescence ◽

Skin Aging ◽

Histone Variant ◽

Epidermal Keratinocytes ◽

Basal Cells ◽

Telomere Attrition ◽

Age Related ◽

And Function

AbstractCellular senescence is an irreversible growth arrest that occurs as a result of damaging stimuli, including DNA damage and/or telomere shortening. Here, we investigate histone variant H2A.J as a new biomarker to detect senescent cells during human skin aging. Skin biopsies from healthy volunteers of different ages (18–90 years) were analyzed for H2A.J expression and other parameters involved in triggering and/or maintaining cellular senescence. In the epidermis, the proportions of H2A.J-expressing keratinocytes increased from ≈20% in young to ≈60% in aged skin. Inverse correlations between Ki67- and H2A.J staining in germinative layers may reflect that H2A.J-expressing cells having lost their capacity to divide. As cellular senescence is triggered by DNA-damage signals, persistent 53BP1-foci, telomere lengths, and telomere-associated damage foci were analyzed in epidermal keratinocytes. Only slight age-related telomere attrition and few persistent nuclear 53BP1-foci, occasionally colocalizing with telomeres, suggest that unprotected telomeres are not a significant cause of senescence during skin aging. Quantification of integrin-α6+ basal cells suggests that the number and function of stem/progenitor cells decreased during aging and their altered proliferation capacities resulted in diminished tissue renewal with epidermal thinning. Collectively, our findings suggest that H2A.J is a sensitive marker of epidermal aging in human skin.

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Anti-VEGF therapy of wet age-related macular degeneration: analysis of patients lost to follow-up

Vestnik oftal mologii ◽

10.17116/oftalma202113702166 ◽

2021 ◽

Vol 137 (2) ◽

pp. 66

Author(s):

E.V. Bobykin ◽

S.A. Korotkih ◽

V.Ya. Krokhalev ◽

R.V. Buslaev ◽

N.S. Beresneva ◽

...

Keyword(s):

Macular Degeneration ◽

Age Related Macular Degeneration ◽

Anti Vegf ◽

Age Related ◽

Lost To Follow Up

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Epigenetic scores for the circulating proteome as tools for disease prediction

eLife ◽

10.7554/elife.71802 ◽

2022 ◽

Vol 11 ◽

Author(s):

Danni A Gadd ◽

Robert F Hillary ◽

Daniel L McCartney ◽

Shaza B Zaghlool ◽

Anna J Stevenson ◽

...

Keyword(s):

Immune Cell ◽

Biological Aging ◽

Disease Prediction ◽

Protein Biomarkers ◽

Protein Levels ◽

Age Related ◽

Generation Scotland ◽

Disease Associations ◽

Using Data

Protein biomarkers have been identified across many age-related morbidities. However, characterising epigenetic influences could further inform disease predictions. Here, we leverage epigenome-wide data to study links between the DNAm signatures of the circulating proteome and incident diseases. Using data from four cohorts, we trained and tested epigenetic scores (EpiScores) for 953 plasma proteins, identifying 109 scores that explained between 1% and 58% of the variance in protein levels after adjusting for known protein quantitative trait loci (pQTL) genetic effects. By projecting these EpiScores into an independent sample, (Generation Scotland; n=9,537) and relating them to incident morbidities over a follow-up of 14 years, we uncovered 137 EpiScore – disease associations. These associations were largely independent of immune cell proportions, common lifestyle and health factors and biological aging. Notably, we found that our diabetes-associated EpiScores highlighted previous top biomarker associations from proteome-wide assessments of diabetes. These EpiScores for protein levels can therefore be a valuable resource for disease prediction and risk stratification.

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Single-cell transcriptomes of the aging human skin reveal loss of fibroblast priming

10.1101/633131 ◽

2019 ◽

Cited By ~ 5

Author(s):

Llorenç Solé-Boldo ◽

Günter Raddatz ◽

Sabrina Schütz ◽

Jan-Philipp Mallm ◽

Karsten Rippe ◽

...

Keyword(s):

Single Cell ◽

Human Skin ◽

Expression Patterns ◽

Cell Types ◽

Skin Aging ◽

Dermal Fibroblasts ◽

Skin Cell ◽

Age Related ◽

Dermal Cell ◽

And Function

SummaryFibroblasts are the main dermal cell type and are essential for the architecture and function of human skin. Important differences have been described between fibroblasts localized in distinct dermal layers, and these cells are also known to perform varied functions. However, this phenomenon has not been analyzed comprehensively yet. Here we have used single-cell RNA sequencing to analyze >15,000 cells from a sun-protected area in young and old donors. Our results define four main fibroblast subpopulations that can be spatially localized and functionally distinguished. Importantly, intrinsic aging reduces this fibroblast ‘priming’, generates distinct expression patterns of skin aging-associated genes, and substantially reduces the interactions of dermal fibroblasts with other skin cell types. Our work thus provides comprehensive evidence for a functional specialization of human dermal fibroblasts and suggests that the age-related loss of fibroblast priming contributes to human skin aging.

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