Alexander Payares - Academia.edu (original) (raw)

Papers by Alexander Payares

Research paper thumbnail of ДЕТОКСИКАЦИЯ ЦИАНИДОВ МИКРОБНЫМИ КОНСОРЦИУМАМИ ИЗ ПРИРОДНО-ТЕХНОГЕННЫХ КОМПЛЕКСОВ КУЧНОГО ВЫЩЕЛАЧИВАНИЯ ЗОЛОТА, "Прикладная биохимия и микробиология

Прикладная биохимия и микробиология, 2017

Research paper thumbnail of The "what's next economy

Journal of Computing Sciences in Colleges, 2020

The COVID-19 pandemic has changed our society and economy already, with many more challenges and ... more The COVID-19 pandemic has changed our society and economy already, with many more challenges and changes to come. Jonathan Aberman, Dean of Marymount University School of Business and Technology is...

Research paper thumbnail of Внутренний аудит в системе управления предприятием

Research paper thumbnail of Gestión del conocimiento. Perspectiva multidisciplinaria. Volumen 17

Research paper thumbnail of Vaccination of older adults: Influenza, pneumococcal disease, herpes zoster, COVID-19 and beyond

Immunity & Ageing, 2021

Preserving good health in old age is of utmost importance to alleviate societal, economic and hea... more Preserving good health in old age is of utmost importance to alleviate societal, economic and health care-related challenges caused by an aging society. The prevalence and severity of many infectious diseases is higher in older adults, and in addition to the acute disease, long-term sequelae, such as exacerbation of underlying chronic disease, onset of frailty or increased long-term care dependency, are frequent. Prevention of infections e.g. by vaccination is therefore an important measure to ensure healthy aging and preserve quality of life. Several vaccines are specifically recommended for older adults in many countries, and in the current SARS-CoV-2 pandemic older adults were among the first target groups for vaccination due to their high risk for severe disease. This review highlights clinical data on the influenza, Streptococcus pneumoniae and herpes zoster vaccines, summarizes recent developments to improve vaccine efficacy, such as the use of adjuvants or higher antigen dose...

Research paper thumbnail of Ratios and the Celestial Spheres: De proportionibus proportionum; Ad pauca respicientes .Nicole Oresme. English translation, commentary, and notes by Edward Grant. University of Wisconsin Press, Madison, 1966. 488 pp., illus. $10.75

Research paper thumbnail of Therapeutic potential of lipids obtained from γ-irradiated PBMCs in dendritic cell-mediated skin inflammation

EBioMedicine, 2020

Background: Since numerous pathological conditions are evoked by unwanted dendritic cell (DC) act... more Background: Since numerous pathological conditions are evoked by unwanted dendritic cell (DC) activity, therapeutic agents modulating DC functions are of great medical interest. In regenerative medicine, cellular secretomes have gained increasing attention and valuable immunomodulatory properties have been attributed to the secretome of g-irradiated peripheral blood mononuclear cells (PBMCs). Potential effects of the PBMC secretome (PBMCsec) on key DC functions have not been elucidated so far. Methods: We used a hapten-mediated murine model of contact hypersensitivity (CH) to study the effects of PBMCsec on DCs in vivo. Effects of PBMCsec on human DCs were investigated in monocyte-derived DCs (MoDC) and ex vivo skin cultures. DCs were phenotypically characterised by transcriptomics analyses and flow cytometry. DC function was evaluated by cytokine secretion, antigen uptake, PBMC proliferation and Tcell priming. Findings: PBMCsec significantly alleviated tissue inflammation and cellular infiltration in hapten-sensitized mice. We found that PBMCsec abrogated differentiation of MoDCs, indicated by lower expression of classical DC markers CD1a, CD11c and MHC class II molecules. Furthermore, PBMCsec reduced DC maturation, antigen uptake, lipopolysaccharides-induced cytokine secretion, and DC-mediated immune cell proliferation. Moreover, MoDCs differentiated with PBMCsec displayed diminished ability to prime naïve CD4 + T-cells into T H 1 and T H 2 cells. Furthermore, PBMCsec modulated the phenotype of DCs present in the skin in situ. Mechanistically, we identified lipids as the main biomolecule accountable for the observed immunomodulatory effects. Interpretation: Together, our data describe DC-modulatory actions of lipids secreted by stressed PBMCs and suggest PBMCsec as a therapeutic option for treatment of DC-mediated inflammatory skin conditions.

Research paper thumbnail of Imaging of metabolic activity adaptations to UV stress, drugs and differentiation at cellular resolution in skin and skin equivalents – Implications for oxidative UV damage

Research paper thumbnail of Different pro-angiogenic potential of γ-irradiated PBMC-derived secretome and its subfractions

Research paper thumbnail of The impact of recent advances in lipidomics and redox lipidomics on dermatological research

Free Radical Biology and Medicine, 2019

Research paper thumbnail of 629 Suppression of autophagy by Tyrosinase-Cre –mediated deletion of Atg7 leads to accumulation of p62/sequestosome 1 in pigment cells and neurons

Journal of Investigative Dermatology, 2017

Research paper thumbnail of 693 Blocking negative effects of senescence in human skin fibroblasts with a plant extract

Journal of Investigative Dermatology, 2017

There is increasing evidence that senescent cells are a driving force behind many age-related pat... more There is increasing evidence that senescent cells are a driving force behind many age-related pathologies and that their selective elimination increases the life-and healthspan of mice. Senescent cells negatively affect their surrounding tissue by losing their cell specific functionality and by secreting a pro-tumorigenic and pro-inflammatory mixture of growth hormones, chemokines, cytokines and proteases, termed the senescence-associated secretory phenotype (SASP). Here we identified an extract from the plant Solidago virgaurea subsp. alpestris, which exhibited weak senolytic activity, delayed the acquisition of a senescent phenotype and induced a papillary phenotype with improved functionality in human dermal fibroblasts. When administered to stress-induced premature senescent fibroblasts, this extract changed their global mRNA expression profile and particularly reduced the expression of various SASP components, thereby ameliorating the negative influence on nearby cells. Thus, the investigated plant extract represents a promising possibility to block age-related loss of tissue functionality.

Research paper thumbnail of 630 Multi-omics identify nuclear protein 1 (Nupr1/p8) as central regulator of redox stress mediated by ultraviolet A light

Journal of Investigative Dermatology, 2017

Research paper thumbnail of HO-1 inhibits preadipocyte proliferation and differentiation at the onset of obesity via ROS dependent activation of Akt2

Scientific Reports, 2017

Excessive accumulation of white adipose tissue (WAT) is a hallmark of obesity. The expansion of W... more Excessive accumulation of white adipose tissue (WAT) is a hallmark of obesity. The expansion of WAT in obesity involves proliferation and differentiation of adipose precursors, however, the underlying molecular mechanisms remain unclear. Here, we used an unbiased transcriptomics approach to identify the earliest molecular underpinnings occuring in adipose precursors following a brief HFD in mice. Our analysis identifies Heme Oxygenase-1 (HO-1) as strongly and selectively being upregulated in the adipose precursor fraction of WAT, upon high-fat diet (HFD) feeding. Specific deletion of HO-1 in adipose precursors of Hmox1 fl/fl Pdgfra Cre mice enhanced HFD-dependent visceral adipose precursor proliferation and differentiation. Mechanistically, HO-1 reduces HFD-induced AKT2 phosphorylation via ROS thresholding in mitochondria to reduce visceral adipose precursor proliferation. HO-1 influences adipogenesis in a cell-autonomous way by regulating events early in adipogenesis, during the process of mitotic clonal expansion, upstream of Cebpα and PPARγ. Similar effects on human preadipocyte proliferation and differentiation in vitro were observed upon modulation of HO-1 expression. This collectively renders HO-1 as an essential factor linking extrinsic factors (HFD) with inhibition of specific downstream molecular mediators (ROS & AKT2), resulting in diminished adipogenesis that may contribute to hyperplastic adipose tissue expansion. White adipose tissue (WAT) has a remarkable capacity to expand or remodel in order to meet the energy demands of the organism. In the face of caloric excess, WAT expands through the enlargement of existing white adipocytes (hypertrophy) as well as by recruitment of new fat cells (hyperplasia) 1-3. Visceral adipocyte hypertrophy is detrimental for metabolic health in humans/mice 4-7. However, increased fat tissue expansion resulting from adipocyte hyperplasia produces less pronounced impairments in glucose tolerance than a similar magnitude of obesity resulting from adipocyte hypertrophy 8. Accordingly, adequate adipogenesis throughout the process of adipose expansion is a necessity to maintain metabolic homeostasis in "metabolically healthy obese humans/ mice", whereas excessive hypertrophy in the absence of the generation of new, metabolically healthy adipocytes is

Research paper thumbnail of Autophagy deficient keratinocytes display increased DNA damage, senescence and aberrant lipid composition after oxidative stress in vitro and in vivo

Research paper thumbnail of 528 Autophagy deficient keratinocytes display increased DNA damage and senescence markers after oxidative stress in vitro and in vivo

Journal of Investigative Dermatology, 2016

Research paper thumbnail of 139 Studying the effects of senescent cells on skin formation in a newly developed three-dimensional tissue model for skin aging

Journal of Investigative Dermatology, 2016

Research paper thumbnail of A "multi-omic" investigation of the effects of long wavelength ultraviolet light on primary human keratinocytes

Free Radical Biology and Medicine, 2016

secretory dysfunction and a decreased β-cell mass coincided with advanced age, this leads to wors... more secretory dysfunction and a decreased β-cell mass coincided with advanced age, this leads to worsening of glucose tolerance and finally to hyperglycemia and the onset of type-2-diabetes. Investigations regarding the molecular basis of the limited proliferation capacity of aged endocrine pancreas revealed that cellular senescence seems to be involved. Senescence is characterized by an upregulation of tumor suppressor proteins such as p16Ink4a and p53, severe morphological diversifications or widespread changes in protein expression and secretion. But the impact of senescence-related changes on β-cell impairment has not yet been described. Therefore, by comparing lean C57Bl/6 J mice and adipose, diabetes-prone New Zealand Obese mice with diabetes-resistant B6.V-Lepob/J mice in different stages of age, we aim to characterize senescent β-cells and investigate the role of cellular senescence on β-cell functionality and proliferation.

Research paper thumbnail of Analysis of the Secretome of Apoptotic Peripheral Blood Mononuclear Cells: Impact of Released Proteins and Exosomes for Tissue Regeneration

Scientific reports, Jan 16, 2015

We previously showed that, when peripheral blood mononuclear cells (PBMCs) were stressed with ion... more We previously showed that, when peripheral blood mononuclear cells (PBMCs) were stressed with ionizing radiation, they released paracrine factors that showed regenerative capacity in vitro and in vivo. This study aimed to characterize the secretome of PBMCs and to investigate its biologically active components in vitro and vivo. Bioinformatics analysis revealed that irradiated PBMCs differentially expressed genes that encoded secreted proteins. These genes were primarily involved in (a) pro-angiogenic and regenerative pathways and (b) the generation of oxidized phospholipids with known pro-angiogenic and inflammation-modulating properties. Subsequently, in vitro assays showed that the exosome and protein fractions of irradiated and non-irradiated PBMC secretome were the major biological components that enhanced cell mobility; conversely, secreted lipids and microparticles had no effects. We tested a viral-cleared PBMC secretome, prepared according to good manufacturing practice (GMP...

Research paper thumbnail of Functional MC1R-Gene Variants Are Associated with Increased Risk for Severe Photoaging of Facial Skin

Journal of Investigative Dermatology, 2010

The objective of this study was to assess the association between melanocortin-1 receptor (MC1R) ... more The objective of this study was to assess the association between melanocortin-1 receptor (MC1R) variants and the severity of facial skin photoaging. The study population comprised 530 middle-aged French women. A trained dermatologist graded the severity of facial skin photoaging from photographs using a global scale. Logistic regressions were performed to assess the influence of MC1R polymorphisms on severe photoaging with adjustment for possible confounders (demographic and phenotypic data and sun exposure intensity). Among the fifteen MC1R variants identified, the nine most common were V60L, V92M, R151C, R160W, R163Q, R142H, D294H, D84E, and I155T. One hundred and eighty-five individuals (35%) were WT homozygotes, 261 (49%) had one common variant, 78 (15%) had two common variants, and six (1%) had at least one rare variant. After adjustment for possible confounders, the presence of two common variants was already a risk factor for severe photoaging (AOR (95% confidence interval): 2.33 (1.17-4.63)). This risk reached 5.61 (1.43-21.96) when two major diminished-function variants were present. Surprisingly, the minor variant, V92M, was associated with increased risk of photoaging (2.57 (1.23-5.35)). Our results suggest that genetic variations of MC1R are important determinants for severe photoaging.

Research paper thumbnail of ДЕТОКСИКАЦИЯ ЦИАНИДОВ МИКРОБНЫМИ КОНСОРЦИУМАМИ ИЗ ПРИРОДНО-ТЕХНОГЕННЫХ КОМПЛЕКСОВ КУЧНОГО ВЫЩЕЛАЧИВАНИЯ ЗОЛОТА, "Прикладная биохимия и микробиология

Прикладная биохимия и микробиология, 2017

Research paper thumbnail of The "what's next economy

Journal of Computing Sciences in Colleges, 2020

The COVID-19 pandemic has changed our society and economy already, with many more challenges and ... more The COVID-19 pandemic has changed our society and economy already, with many more challenges and changes to come. Jonathan Aberman, Dean of Marymount University School of Business and Technology is...

Research paper thumbnail of Внутренний аудит в системе управления предприятием

Research paper thumbnail of Gestión del conocimiento. Perspectiva multidisciplinaria. Volumen 17

Research paper thumbnail of Vaccination of older adults: Influenza, pneumococcal disease, herpes zoster, COVID-19 and beyond

Immunity & Ageing, 2021

Preserving good health in old age is of utmost importance to alleviate societal, economic and hea... more Preserving good health in old age is of utmost importance to alleviate societal, economic and health care-related challenges caused by an aging society. The prevalence and severity of many infectious diseases is higher in older adults, and in addition to the acute disease, long-term sequelae, such as exacerbation of underlying chronic disease, onset of frailty or increased long-term care dependency, are frequent. Prevention of infections e.g. by vaccination is therefore an important measure to ensure healthy aging and preserve quality of life. Several vaccines are specifically recommended for older adults in many countries, and in the current SARS-CoV-2 pandemic older adults were among the first target groups for vaccination due to their high risk for severe disease. This review highlights clinical data on the influenza, Streptococcus pneumoniae and herpes zoster vaccines, summarizes recent developments to improve vaccine efficacy, such as the use of adjuvants or higher antigen dose...

Research paper thumbnail of Ratios and the Celestial Spheres: De proportionibus proportionum; Ad pauca respicientes .Nicole Oresme. English translation, commentary, and notes by Edward Grant. University of Wisconsin Press, Madison, 1966. 488 pp., illus. $10.75

Research paper thumbnail of Therapeutic potential of lipids obtained from γ-irradiated PBMCs in dendritic cell-mediated skin inflammation

EBioMedicine, 2020

Background: Since numerous pathological conditions are evoked by unwanted dendritic cell (DC) act... more Background: Since numerous pathological conditions are evoked by unwanted dendritic cell (DC) activity, therapeutic agents modulating DC functions are of great medical interest. In regenerative medicine, cellular secretomes have gained increasing attention and valuable immunomodulatory properties have been attributed to the secretome of g-irradiated peripheral blood mononuclear cells (PBMCs). Potential effects of the PBMC secretome (PBMCsec) on key DC functions have not been elucidated so far. Methods: We used a hapten-mediated murine model of contact hypersensitivity (CH) to study the effects of PBMCsec on DCs in vivo. Effects of PBMCsec on human DCs were investigated in monocyte-derived DCs (MoDC) and ex vivo skin cultures. DCs were phenotypically characterised by transcriptomics analyses and flow cytometry. DC function was evaluated by cytokine secretion, antigen uptake, PBMC proliferation and Tcell priming. Findings: PBMCsec significantly alleviated tissue inflammation and cellular infiltration in hapten-sensitized mice. We found that PBMCsec abrogated differentiation of MoDCs, indicated by lower expression of classical DC markers CD1a, CD11c and MHC class II molecules. Furthermore, PBMCsec reduced DC maturation, antigen uptake, lipopolysaccharides-induced cytokine secretion, and DC-mediated immune cell proliferation. Moreover, MoDCs differentiated with PBMCsec displayed diminished ability to prime naïve CD4 + T-cells into T H 1 and T H 2 cells. Furthermore, PBMCsec modulated the phenotype of DCs present in the skin in situ. Mechanistically, we identified lipids as the main biomolecule accountable for the observed immunomodulatory effects. Interpretation: Together, our data describe DC-modulatory actions of lipids secreted by stressed PBMCs and suggest PBMCsec as a therapeutic option for treatment of DC-mediated inflammatory skin conditions.

Research paper thumbnail of Imaging of metabolic activity adaptations to UV stress, drugs and differentiation at cellular resolution in skin and skin equivalents – Implications for oxidative UV damage

Research paper thumbnail of Different pro-angiogenic potential of γ-irradiated PBMC-derived secretome and its subfractions

Research paper thumbnail of The impact of recent advances in lipidomics and redox lipidomics on dermatological research

Free Radical Biology and Medicine, 2019

Research paper thumbnail of 629 Suppression of autophagy by Tyrosinase-Cre –mediated deletion of Atg7 leads to accumulation of p62/sequestosome 1 in pigment cells and neurons

Journal of Investigative Dermatology, 2017

Research paper thumbnail of 693 Blocking negative effects of senescence in human skin fibroblasts with a plant extract

Journal of Investigative Dermatology, 2017

There is increasing evidence that senescent cells are a driving force behind many age-related pat... more There is increasing evidence that senescent cells are a driving force behind many age-related pathologies and that their selective elimination increases the life-and healthspan of mice. Senescent cells negatively affect their surrounding tissue by losing their cell specific functionality and by secreting a pro-tumorigenic and pro-inflammatory mixture of growth hormones, chemokines, cytokines and proteases, termed the senescence-associated secretory phenotype (SASP). Here we identified an extract from the plant Solidago virgaurea subsp. alpestris, which exhibited weak senolytic activity, delayed the acquisition of a senescent phenotype and induced a papillary phenotype with improved functionality in human dermal fibroblasts. When administered to stress-induced premature senescent fibroblasts, this extract changed their global mRNA expression profile and particularly reduced the expression of various SASP components, thereby ameliorating the negative influence on nearby cells. Thus, the investigated plant extract represents a promising possibility to block age-related loss of tissue functionality.

Research paper thumbnail of 630 Multi-omics identify nuclear protein 1 (Nupr1/p8) as central regulator of redox stress mediated by ultraviolet A light

Journal of Investigative Dermatology, 2017

Research paper thumbnail of HO-1 inhibits preadipocyte proliferation and differentiation at the onset of obesity via ROS dependent activation of Akt2

Scientific Reports, 2017

Excessive accumulation of white adipose tissue (WAT) is a hallmark of obesity. The expansion of W... more Excessive accumulation of white adipose tissue (WAT) is a hallmark of obesity. The expansion of WAT in obesity involves proliferation and differentiation of adipose precursors, however, the underlying molecular mechanisms remain unclear. Here, we used an unbiased transcriptomics approach to identify the earliest molecular underpinnings occuring in adipose precursors following a brief HFD in mice. Our analysis identifies Heme Oxygenase-1 (HO-1) as strongly and selectively being upregulated in the adipose precursor fraction of WAT, upon high-fat diet (HFD) feeding. Specific deletion of HO-1 in adipose precursors of Hmox1 fl/fl Pdgfra Cre mice enhanced HFD-dependent visceral adipose precursor proliferation and differentiation. Mechanistically, HO-1 reduces HFD-induced AKT2 phosphorylation via ROS thresholding in mitochondria to reduce visceral adipose precursor proliferation. HO-1 influences adipogenesis in a cell-autonomous way by regulating events early in adipogenesis, during the process of mitotic clonal expansion, upstream of Cebpα and PPARγ. Similar effects on human preadipocyte proliferation and differentiation in vitro were observed upon modulation of HO-1 expression. This collectively renders HO-1 as an essential factor linking extrinsic factors (HFD) with inhibition of specific downstream molecular mediators (ROS & AKT2), resulting in diminished adipogenesis that may contribute to hyperplastic adipose tissue expansion. White adipose tissue (WAT) has a remarkable capacity to expand or remodel in order to meet the energy demands of the organism. In the face of caloric excess, WAT expands through the enlargement of existing white adipocytes (hypertrophy) as well as by recruitment of new fat cells (hyperplasia) 1-3. Visceral adipocyte hypertrophy is detrimental for metabolic health in humans/mice 4-7. However, increased fat tissue expansion resulting from adipocyte hyperplasia produces less pronounced impairments in glucose tolerance than a similar magnitude of obesity resulting from adipocyte hypertrophy 8. Accordingly, adequate adipogenesis throughout the process of adipose expansion is a necessity to maintain metabolic homeostasis in "metabolically healthy obese humans/ mice", whereas excessive hypertrophy in the absence of the generation of new, metabolically healthy adipocytes is

Research paper thumbnail of Autophagy deficient keratinocytes display increased DNA damage, senescence and aberrant lipid composition after oxidative stress in vitro and in vivo

Research paper thumbnail of 528 Autophagy deficient keratinocytes display increased DNA damage and senescence markers after oxidative stress in vitro and in vivo

Journal of Investigative Dermatology, 2016

Research paper thumbnail of 139 Studying the effects of senescent cells on skin formation in a newly developed three-dimensional tissue model for skin aging

Journal of Investigative Dermatology, 2016

Research paper thumbnail of A "multi-omic" investigation of the effects of long wavelength ultraviolet light on primary human keratinocytes

Free Radical Biology and Medicine, 2016

secretory dysfunction and a decreased β-cell mass coincided with advanced age, this leads to wors... more secretory dysfunction and a decreased β-cell mass coincided with advanced age, this leads to worsening of glucose tolerance and finally to hyperglycemia and the onset of type-2-diabetes. Investigations regarding the molecular basis of the limited proliferation capacity of aged endocrine pancreas revealed that cellular senescence seems to be involved. Senescence is characterized by an upregulation of tumor suppressor proteins such as p16Ink4a and p53, severe morphological diversifications or widespread changes in protein expression and secretion. But the impact of senescence-related changes on β-cell impairment has not yet been described. Therefore, by comparing lean C57Bl/6 J mice and adipose, diabetes-prone New Zealand Obese mice with diabetes-resistant B6.V-Lepob/J mice in different stages of age, we aim to characterize senescent β-cells and investigate the role of cellular senescence on β-cell functionality and proliferation.

Research paper thumbnail of Analysis of the Secretome of Apoptotic Peripheral Blood Mononuclear Cells: Impact of Released Proteins and Exosomes for Tissue Regeneration

Scientific reports, Jan 16, 2015

We previously showed that, when peripheral blood mononuclear cells (PBMCs) were stressed with ion... more We previously showed that, when peripheral blood mononuclear cells (PBMCs) were stressed with ionizing radiation, they released paracrine factors that showed regenerative capacity in vitro and in vivo. This study aimed to characterize the secretome of PBMCs and to investigate its biologically active components in vitro and vivo. Bioinformatics analysis revealed that irradiated PBMCs differentially expressed genes that encoded secreted proteins. These genes were primarily involved in (a) pro-angiogenic and regenerative pathways and (b) the generation of oxidized phospholipids with known pro-angiogenic and inflammation-modulating properties. Subsequently, in vitro assays showed that the exosome and protein fractions of irradiated and non-irradiated PBMC secretome were the major biological components that enhanced cell mobility; conversely, secreted lipids and microparticles had no effects. We tested a viral-cleared PBMC secretome, prepared according to good manufacturing practice (GMP...

Research paper thumbnail of Functional MC1R-Gene Variants Are Associated with Increased Risk for Severe Photoaging of Facial Skin

Journal of Investigative Dermatology, 2010

The objective of this study was to assess the association between melanocortin-1 receptor (MC1R) ... more The objective of this study was to assess the association between melanocortin-1 receptor (MC1R) variants and the severity of facial skin photoaging. The study population comprised 530 middle-aged French women. A trained dermatologist graded the severity of facial skin photoaging from photographs using a global scale. Logistic regressions were performed to assess the influence of MC1R polymorphisms on severe photoaging with adjustment for possible confounders (demographic and phenotypic data and sun exposure intensity). Among the fifteen MC1R variants identified, the nine most common were V60L, V92M, R151C, R160W, R163Q, R142H, D294H, D84E, and I155T. One hundred and eighty-five individuals (35%) were WT homozygotes, 261 (49%) had one common variant, 78 (15%) had two common variants, and six (1%) had at least one rare variant. After adjustment for possible confounders, the presence of two common variants was already a risk factor for severe photoaging (AOR (95% confidence interval): 2.33 (1.17-4.63)). This risk reached 5.61 (1.43-21.96) when two major diminished-function variants were present. Surprisingly, the minor variant, V92M, was associated with increased risk of photoaging (2.57 (1.23-5.35)). Our results suggest that genetic variations of MC1R are important determinants for severe photoaging.