HORMESIS-BASED ANTI-AGING PRODUCTS: A CASE STUDY OF A NOVEL COSMETIC

Application of hormesis in aging research and interventions is becoming increasingly attractive and successful. The reason for this is the realization that mild stress-induced activation of one or more stress response (SR) pathways, and its consequent stimulation of repair mechanisms, is effective in reducing the age-related accumulation of molecular damage. For example, repeated heat stress-induced synthesis of heat shock proteins has been shown to have a variety of anti-aging effects on growth and other cellular and biochemical characteristics of normal human skin fibroblasts, keratinocytes and endothelial cells undergoing aging in vitro. Therefore, searching for potential hormetins – conditions and compounds eliciting SR-mediated hormesis – is drawing attention of not only the researchers but also the industry involved in developing healthcare products, including nutriceuticals, functional foods and cosmeceuticals. Here we present the example of a skin care cosmetic as one of the first successful product developments incorporating the ideas of hormesis. This was based on the studies to analyse the molecular effects of active ingredients extracted from the roots of the Chinese herb Sanchi (Panax notoginseng) on gene expression at the level of mRNAs and proteins in human skin cells. The results showed that the ginsenosides extracted from Sanchi induced the transcription of stress genes and increased the synthesis of stress proteins, especially the heat shock protein HSP1A1 or Hsp70, in normal human keratinocytes and dermal fibroblasts. Furthermore, this extract also has significant positive effects against facial wrinkles and other symptoms of facial skin aging as tested clinically, which may be due to its hormetic mode of action by stressinduced synthesis of chaperones involved in protein repair and removal of abnormal proteins. Acceptance of such a hormesis-based product by the wider public could be instrumental in the social recognition of the concept of hormesis as the beneficial effects of mild stress of choice, and will encourage the development of novel health care products with physical, nutritional and mental hormetins

Isolation of an "early" transit amplifying keratinocyte population in human epidermis: a role for the low affinity neurotrophin receptor CD271

In the interfollicular epidermis (IFE), stem cells (KSC) generate transit amplifying (TA) cells that, after symmetric divisions, produce differentiating daughters. Here, we isolated and characterized the highly proliferative interfollicular epidermal basal cell population "early" TA (ETA) cells, based on their capacity to adhere to type IV collagen. Proliferation and colony-forming efficiency in ETA cells are lower than in KSC but higher than in "late" TA (LTA). Stemness, proliferation, and differentiation markers confirmed that ETA cells display a unique phenotype. Skin reconstructs derived from ETA cells present different features (epidermal thickness, Ki67, and Survivin expression), as compared to skin equivalents generated from either KSC or LTA cells. The low-affinity neurotrophin receptor CD271, which regulates the KSC to TA cell transition in the human epidermis through an on/off switch control mechanism, is predominantly expressed in ETA cells. Skin equivalents generated from siRNA CD271 ETA cells display a more proliferative and less differentiated phenotype, as compared to mock-derived reconstructs. Consistently, CD271 overexpression in LTA cells generates a more proliferative skin equivalent than mock LTA cells. Finally, the CD271 level declines with cellular senescence, while it induces a delay in p16INK4 expression. We conclude that ETA cells represent the first KSC progenitor with exclusive features. CD271 identifies and modulates ETA cells, thus participating in the early differentiation and regenerative capacity of the human epidermis

Breast carcinoma detection in ex vivo fresh human breast surgical specimens using a fast slide-free confocal microscopy scanner: HIBISCUSS project

Background: New generation ultra-fast fluorescence confocal microscopy allows the ex vivo intraoperative analysis of fresh tissue. The High resolution Imaging for Breast carcInoma detection in ex vivo Specimens after breast Conserving sUrgery by hiStolog Scanner (HIBISCUSS) project aimed to develop an online learning program to recognize the main breast tissue features on ultra-fast fluorescence confocal microscopy images and to evaluate the performance of surgeons and pathologists in diagnosing cancerous and non-cancerous breast tissue in ultra-fast fluorescence confocal microscopy images. Methods: Patients who underwent conservative surgery or mastectomy for breast carcinoma (invasive or in situ lesions) were included. The fresh specimens were stained with a fluorescent dye and imaged using a large field-of-view (20 cm2) ultra-fast fluorescence confocal microscope. Results: One hundred and eighty-one patients were included. The images from 55 patients were annotated to generate learning sheets and images from 126 patients were blindly interpreted by seven surgeons and two pathologists. The time for tissue processing and ultra-fast fluorescence confocal microscopy imaging was between 8 and 10 min. The training program was composed of 110 images divided into nine learning sessions. The final database for blind performance assessment comprised 300 images. The mean duration for one training session and one performance round was 17 and 27 min respectively. The performance of pathologists was almost perfect with 99.6 per cent (standard deviation (s.d.) 5.4 per cent) accuracy. Surgeons' accuracy significantly increased (P = 0.001) from 83 per cent (s.d. 8.4 per cent) in round 1 to 98 per cent (s.d. 4.1 per cent) in round 7 as well as the sensitivity (P = 0.004). Specificity increased without significance from 84 per cent (s.d. 16.7 per cent) in round 1 to 87 per cent (s.d. 16.4 per cent) in round 7 (P = 0.060). Conclusion: Pathologists and surgeons showed a short learning curve in differentiating breast cancer from non-cancerous tissue in ultra-fast fluorescence confocal microscopy images. Performance assessment for both specialties supports ultra-fast fluorescence confocal microscopy evaluation for intraoperative management. Registration number: NCT04976556 (http://www.clinicaltrials.gov)

Knee Arthroplasty: Disabilities in Comparison to the General Population and to Hip Arthroplasty Using a French National Longitudinal Survey

International audienceBACKGROUND: Knee arthroplasty is increasing exponentially due to the aging of the population and to the broadening of indications. We aimed to compare physical disability and its evolution over two years in people with knee arthroplasty to that in the general population. A secondary objective was to compare the level of disabilities of people with knee to people with hip arthroplasty. METHODOLOGY/PRINCIPAL FINDINGS: 16,945 people representative of the French population were selected in 1999 from the French census and interviewed about their level of disability. This sample included 815 people with lower limb arthroplasty. In 2001, 608 of them were re-interviewed, among whom 134 had knee arthroplasty. Among the other participants re-interviewed, we identified 68 who had undergone knee arthroplasty and 145 hip arthroplasty within the last two years (recent arthroplasty). People with knee arthroplasty reported significantly greater difficulties than the general population with bending forward (odds ratio [OR] = 4.7; 95% confidence interval [CI]: 1.7, 12.6), walking more than 500 meters (OR = 6.0; 95% CI: 1.5, 24.7) and carrying 5 kg kilograms for 10 meters (OR = 4.6; 95% CI: 1.3, 16.4). However, the two years evolution in disability was similar to that in the general population for most activities. The level of mobility was similar between people with recent knee arthroplasty and those with recent hip arthroplasty. Nevertheless, people with recent knee arthroplasty reported a lower level of disability than the other group for washing and bending forward (OR = 0.3; 95% CI: 0.1, 0.6 and OR = 0.4; 95% CI: 0.1, 0.9, respectively). CONCLUSIONS/SIGNIFICANCE: People with knee arthroplasty reported a higher risk of disability than the general population for common activities of daily living but a similar evolution. There was no relevant difference between recent knee and hip arthroplasties for mobility

Evaluation du potentiel genotoxique et epigenetique de deux amines aromatiques: le 2-acetylaminofluorene (2-AAF) et le 4-acetylaminofluorene (4-AAF). Etude des cassures de DNA et des modifications du cytosquelette dans des cellules hepatiques

SIGLEINIST T 77529 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Role of glyoxalases system in skin aging and in response to dicarbonyl mediated stress

International audienceno abstrac

Basal level of autophagy is increased in aging human skin fibroblasts in vitro, but not in old skin.

Intracellular autophagy (AP) is a stress response that is enhanced under conditions of limitation of amino acids, growth factors and other nutrients, and also when macromolecules become damaged, aggregated and fibrillated. Aging is generally accompanied by an increase in intracellular stress due to all the above factors. Therefore, we have compared the basal levels of AP in serially passaged human facial skin fibroblasts undergoing aging and replicative senescence in vitro, and ex vivo in the skin biopsies from the photo-protected and photo-exposed area of the arms of 20 healthy persons of young and old ages. Immunofluorescence microscopy, employing antibodies against a specific intracellular microtubule-associated protein-1 light chain-3 (LC3) as a well established marker of AP, showed a 5-fold increase in the basal level of LC3 in near senescent human skin fibroblasts. However, no such age-related increase in LC3 fluorescence and AP could be detected in full thickness skin sections from the biopsies obtained from 10 healthy young (age 25 to 30 yr) and 10 old (age 60 to 65 yr) donors. Furthermore, there was no difference in the basal level of LC3 in the skin sections from photo-protected and photo-exposed areas of the arm. Thus, in normal conditions, the aging phenotype of the skin cells in culture and in the body appears to be different in the case of AP

Differential translocation of heat shock factor-1 after mild and severe stress to human skin fibroblasts undergoing aging in vitro

Repeated exposure to mild heat shock (HS) has been shown to induce a wide range of health promoting hormetic effects in various biological systems, including human cells undergoing aging in vitro. In order to understand how cells distinguish between mild and severe stress, we have investigated the extent of early and immediate HS response by analyzing the nuclear translocation of the transcription factor heat shock factor-1 (HSF1), in serially passaged normal adult human facial skin fibroblasts exposed to mild (41 °C) or severe (43 °C) HS. Cells respond differently when exposed to mild and severe HS at different passage levels in terms of the extent of HSF1 translocation. In early passage young cells there was a 5-fold difference between mild and severe HS in the extent of HSF1 translocation. However, in near senescent late passage cells, the difference between mild and severe stress in terms of the extent of HSF1 translocation was reduced to less than 2-fold. One of the reasons for this age-related attenuation of heat shock response is due to the fact there was a higher basal level of HSF1 in the nuclei of late passage cells, which is indicative of increased intrinsic stress during cellular aging. These observations are consistent with previously reported data that whereas repeated mild stress given at younger ages can slow down aging and increase the lifespan, the same level of stress given at older ages may not provide the same benefits. Therefore, elucidating the early and immediate steps in the induction of stress response can be useful in deciding whether a particular level of stress is potentially hormetically beneficial or not.LVMH, FranceDepto. de Genética, Fisiología y MicrobiologíaFac. de Ciencias BiológicasTRUEpu

Immunoblotting-based comparison of levels of LC3-I and LC3-II in serially passaged human skin fibroblasts during aging <i>in vitro</i>.

<p>Cell samples were analyzed at six age points (P4, 16, 24, 36, 44 and 56) covering the whole replicative lifespan. (A) Immunoblot bands for LC3-I and LC3-II, and ß-actin as internal loading control. (B) Quantitative analysis of band intensity using ImageJ gel analysis software; data are presented as LC3-II/LC3-I ratio/ ß-actin.</p

Evolution of disability in adults with hip arthroplasty: a national longitudinal study.

OBJECTIVE: To describe disability in individuals with hip arthroplasty and its evolution over 2 years compared with that in the general population, and to compare the degree of disability between subjects with recent and older hip arthroplasty. METHODS: We selected a national representative sample of 16,945 subjects from the 1999 French population census. This sample, interviewed in 1999 and 2001 about their level of disability, included 527 subjects with hip arthroplasty (i.e., representing 424,000 individuals in the French noninstitutionalized population): 145 who underwent the procedure between 1999 and 2001 (recent hip arthroplasty) and 382 with an older hip arthroplasty. RESULTS: Subjects with hip arthroplasty reported more difficulty in bending forward (odds ratio [OR] 4.5, 95% confidence interval [95% CI] 3.1-6.6), climbing stairs (OR 2.2, 95% CI 1.5-3.1), walking >300 meters (OR 1.6, 95% CI 1.03-2.6), dressing (OR 2.9, 95% CI 2.1-4.2), and getting in and out of a chair (OR 2.5, 95% CI 1.7-3.6) than the general population. However, the evolution in disability was similar to that of the general population. Compared with subjects with older hip arthroplasty, those with recent hip arthroplasty reported more difficulty walking >300 meters (OR 2.7, 95% CI 1.3-5.6), washing (OR 2.9, 95% CI 1.6-5.4), dressing (OR 2.2, 95% CI 1.2-4.2), and getting in and out of a chair (OR 2.1, 95% CI 1.1-3.9). CONCLUSION: This study describes the potential future disability in the more elderly population, with implications for health-related planning