Photo-downregulation of SIRT4 mitigates aging in mice by enhancing H3K9ac via fatty acid metabolism
- School of Life Science and Technology, Northwestern Polytechnical University, China
- The First Affiliated Hospital of Xi'an Medical University, China
Figures
Figure 1 with 1 supplement
Periodic red light irradiation treatment leads to increased H3K9ac and metabolism in skin tissues of a senescent mouse model.
(a) CCK-8 analysis of keratinocyte activity after red light treatment, n = 3. (b) Fluorescence images of H3K9ac protein in keratinocytes after treatment with different doses of red light; ANOVA was used to analyze the significant differences in (b). (c) Image of β-galactosidase staining in senescent keratinocyte model after red light irradiation treatment. ChIP–qPCR experiments were conducted to assess the enrichment of H3K9ac in the promoter regions of Ppargc1a (d), Sod2 (e), Lamb1 (f), Cdkn1a (g), and Cdkn2a (h). Following ChIP experiments using the H3K9ac antibody or control IgG, qPCR analysis was performed using primers targeting the promoters of these genes; RPL30 is used as an internal standard for the calibration of the target gene, n = 3. (i) Fluorescence images of H3K9ac (red) protein in skin tissues of mice of different ages (DAPI, blue); histogram shows the relative quantification of the red signal within the white dashed line in (i), n = 9. (j) Fluorescence images of H3K9ac (red) proteins in skin tissues of 1- and 2-year-old mice after red light irradiation treatment (DAPI, blue); histogram shows the relative quantification of the red signal within the white dashed line in (j), n = 9. In (i) and (j), only the H3K9ac fluorescence signal within the epidermal region enclosed by the white dotted lines was quantified. (k) The levels of H3K9ac and H3 proteins in the skin of mice in groups 2Y and 2Y+R, n = 3. The levels of P16 (l) and LAMB1 (m) proteins in the skin of mice in groups 4M, 2Y, and 2Y+R. (n) The expression heatmap of SASP inflammatory factors in the skin of mice in groups 2Y and 2Y+R, n = 3. PET/CT images (o) and 18F-FDG radiological signals in skin (p), liver (q), and brain (r) of mice in the 4M, 2Y, and 2Y+R treatment groups, n = 6. (s) Relative content of acetyl-CoA in the skin tissues of mice in groups 4M, 2Y, and 2Y+R, n = 5. p values were calculated applying an unpaired Student’s t-test with unequal variances. ns = not significant (p > 0.05).
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Figure 1—source data 1
Original western blots for Figure 1, indicating the relevant bands and treatments.
- https://cdn.elifesciences.org/articles/111498/elife-111498-fig1-data1-v1.zip
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Figure 1—source data 2
Original files for western blot analysis displayed in Figure 1.
- https://cdn.elifesciences.org/articles/111498/elife-111498-fig1-data2-v1.zip
Figure 1—figure supplement 1
Schematic diagram of the irradiation system and biosafety analysis for this study.
(a) The wavelength range of the red LED lamp used in this study. (b) Protein expression levels of H3K4ac, H3K27ac, H3K9ac, H3-K9/K14/K18/K23/K27ac, and H3 in keratinocytes treated with red light, n = 3. (c) Protein expression levels of P16, P21, Actin, and LAMB1 in aging keratinocytes treated with red light, n = 3. (c) Expression heatmap of SASP inflammatory factors in aging keratinocytes, n = 3. (d) The effect of red light irradiation on the level of H3K9ac enrichment at the RPL30 locus, n = 3. (e) Schematic diagram of animal senescence and red light irradiation treatment protocols. Description of the irradiation device used for aging C57 mice. Female C57 mice up to 8 months of age were used for periodic red light irradiation. Every 2 months, the mice were irradiated for 15 days at a daily dose of 80 J/cm2. As shown in a, 1-year-old mice were irradiated three times for 15 days, whereas 2-year-old mice were irradiated nine times for 15 days. After the red light irradiation program, 1- and 2-year-old mice were used for subsequent analysis. (f) Facial images of mice at different ages after cyclic red light irradiation. n = 6. (g) Light protocol and tissue penetration depth validation of the red light LED device used in this study. As shown in (1), eye-covered mice were immobilized on a stand and irradiated using the red lamp panel shown in (2) and (3). Visible light penetration experiments were performed using muscle tissue with a thickness of 5 cm to simulate mouse skin tissue, as shown in (4) and (5). The results showed that the tissue penetration of the red light could reach up to 4 cm under this condition. (h) Infrared imaging of mice following red light irradiation. (i) H&E staining of the brain, heart, liver, lungs, kidneys, spleen, and skin of mice in the 4M, 2Y, and 2Y+R treatment groups. Number of hippocampal nerve cells (j, n = 9), number of hyperchromatic nuclei (k, n = 9), average cross-sectional hepatocytes (l, n = 18), white pulp area (m, n = 18), alveolar septal thickness (n, n = 18), number of glomeruli (o, n = 9), and relative collagen content of the skin (p, n = 18) in the H&E staining field of view of tissues from the 4M, 2Y, and 2Y+R treatment groups.
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Figure 1—figure supplement 1—source data 1
Original western blots for Figure 1—figure supplement 1, indicating the relevant bands and treatments.
- https://cdn.elifesciences.org/articles/111498/elife-111498-fig1-figsupp1-data1-v1.zip
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Figure 1—figure supplement 1—source data 2
Original files for western blot analysis displayed in Figure 1—figure supplement 1.
- https://cdn.elifesciences.org/articles/111498/elife-111498-fig1-figsupp1-data2-v1.zip
Figure 2 with 1 supplement
Red light irradiation promotes keratinocyte metabolic reprogramming.
(a) Migration of keratinocytes after 24 hr of red light treatment (n = 6). (b) Proliferation of keratinocytes: 0–24 hr after red light treatment (n = 3). Uptake of glucose (c, n = 3) and fatty acid (d, n = 6) in the culture medium by keratinocytes 24 hr after red light treatment. (e) Mitochondrial membrane potential of keratinocytes after red-light treatment. CCCP, carbonyl cyanide m-chlorophenylhydrazone (n = 6). (f) Graded-dose red light treatment affects ATP production in keratinocytes (n = 4). Relative changes in cellular GSH (g) and NADPH (h) contents 12 hr after treatment of keratinocytes with graded doses of red light (n = 3). (g, h) Fluorescence images of total reactive oxygen species (ROS) levels (i, n = 6) and mitochondrial ROS levels (j, n = 6) in keratinocytes under different red light doses. Relative changes in intracellular lactate (k, n = 6), pyruvate (l, n = 6), triglyceride (m, n = 6), fatty acid (n, n = 6), NADH (o, n = 4), and acetyl-CoA (p, n = 4) at 0 and 12 hr after treatment of keratinocytes with graded doses of red light. ANOVA was used to analyze the significant differences in (f–p). p values were calculated applying an unpaired Student’s t-test with unequal variances. ns = not significant (p > 0.05).
Figure 2—figure supplement 1
Analysis of mitochondrial metabolism in keratinocytes under red light irradiation.
(a) Mitochondrial membrane potential images of keratinocytes under different red light doses. (b) Relative changes in nucleus acetyl-CoA of keratinocytes with graded doses of red light, n = 4.
Figure 3 with 1 supplement
Red light activated the PI3K–AKT signaling pathway and PPAR-α in keratinocytes simultaneously with H3k9ac.
(a) Schematic representation of substance metabolism in mitochondria. (b) Scatterplot of significantly enriched functions for transcript data from keratinocytes treated with red light (top 20 KEGG for plotting). (c) Differential gene module expression trend line graph. Colored lines indicate the mean value of the change for this group of genes. (d) Expression of keratinocyte metabolism-related genes after red light treatment. (e) Principal component analysis (PCA) of keratinocyte proteomics in the red light and dark treatment groups, n = 3. Genome-wide signature analysis (GSEA) of gluconeogenesis (f) and PPAR signaling pathway (g) proteins in keratinocytes after red light irradiation. (h) Expression levels of p-mTOR, Glut1, PI3K, and p-AKT proteins in keratinocytes after red light treatment in the presence of AKT and PI3K inhibitors (n = 3). Immunohistochemical staining of PI3K (i) and Glut1(j) proteins in skin tissues after red light irradiation, n = 9. Immunofluorescence staining of PPAR-α (k) and PPAR-γ (l) proteins in skin tissues after red light irradiation (n = 6). (m) Changes in the levels of PI3K, p-AKT1, PPAR-α, Actin, H3K9ac and H3 proteins in keratinocytes at 0, 12, 18, and 24 hr after red light treatment, n = 3. (n) Schematic diagram of increased glycolipid metabolism driving histone acetylation in cells after red light treatment of keratinocytes. Ctrl: control; RL: red light. p values were calculated applying an unpaired Student’s t-test with unequal variances. ns = not significant (p > 0.05).
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Figure 3—source data 1
Original western blots for Figure 3, indicating the relevant bands and treatments.
- https://cdn.elifesciences.org/articles/111498/elife-111498-fig3-data1-v1.zip
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Figure 3—source data 2
Original files for western blot analysis displayed in Figure 3.
- https://cdn.elifesciences.org/articles/111498/elife-111498-fig3-data2-v1.zip
Figure 3—figure supplement 1
Transcriptomic and proteomic analyses of the regulatory effects of red light on keratinocyte metabolism.
(a) Volcano plot of the differences in gene expression after red light treatment. Conducting a significance test using the corrected p value (Q value). Volcano plot showing differentially expressed genes between the red-light irradiation and control groups. Differentially expressed genes were defined as Q value <0.05 and |log2 fold change| > 1. For visualization, Q values smaller than 1 × 10–50 were capped at 1 × 10–50. Red and blue dots indicate significantly upregulated and downregulated genes, respectively; gray dots indicate non-significant genes. (b) Enrichment analysis of metabolic pathways after red light treatment (p value >0.5). Proteomic analysis of red light-irradiated keratinocytes, showing the pathways enriched for significant differences in top 20 up- and downregulation by Inter Pro analysis (c) and chord diagrams of Top 10 processes with significant differences obtained from Inter Pro analysis (d). (e) Changes in the levels of p-mTOR, mTORC1, mTORC2, and PPAR-γ proteins in keratinocytes at 0, 12, 18, and 24 hr after red light treatment, n = 3. (f) Fluorescence images of H3K9ac protein at different time points after red light treatment in keratinocytes.
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Figure 3—figure supplement 1—source data 1
Original western blots for Figure 3—figure supplement 1, indicating the relevant bands and treatments.
- https://cdn.elifesciences.org/articles/111498/elife-111498-fig3-figsupp1-data1-v1.zip
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Figure 3—figure supplement 1—source data 2
Original files for western blot analysis displayed in Figure 3—figure supplement 1.
- https://cdn.elifesciences.org/articles/111498/elife-111498-fig3-figsupp1-data2-v1.zip
Figure 4 with 1 supplement
Red light drives metabolism through mitochondria and mediates histone-acetylation primarily through lipid metabolism.
Fluorescence images of H3K9ac (green, a, n = 12) protein and levels of H3K9ac and H3 proteins (b, n = 3) in keratinocytes under different concentrations of SC-79 treatment conditions (DAPI, blue). Fluorescence images of H3K9ac (green, c, n = 12) protein and levels of H3K9ac and H3 proteins (d, n = 3) in keratinocytes under different concentrations of MK2206 treatment conditions (DAPI, blue). Effects of different concentrations of SC-79 (e) and MK2206 (f) on acetyl-CoA content in keratinocytes, n = 4. Fluorescence images of H3K9ac (green, g, n = 12) protein and levels of H3K9ac and H3 proteins (h, n = 3) in keratinocytes under different concentrations of WY14643 treatment conditions (DAPI, blue). Fluorescence images of H3K9ac (green, i, n = 12) protein and levels of H3K9ac and H3 proteins (j, n = 3) in keratinocytes under different concentrations of GW6471 treatment conditions (DAPI, blue). Effects of different concentrations of WY14643 (k) and GW6471 (l) on acetyl-CoA content in keratinocytes, n = 4. Effect of red light treatment on the levels of H3K9ac and H3 proteins in keratinocytes in the presence of 5 µM Nicur (m) and TSA (n), n = 3. Effect of red light treatment on the levels of H3K9ac and H3 proteins in keratinocytes in the presence of 2 µM Mk2206 (o) and 20 µM GW6471 (p), n = 3. Effect of red light treatment on the levels of H3K9ac and H3 proteins in keratinocytes in the presence of 5 µM Antimycin (q) and Elamipretide (r), n = 3. Relative contents of lactate (s, n = 6), triglycerides (t, n = 6), fatty acids (u, n = 6), and acetyl-CoA (v, n = 4) in keratinocytes after irradiation of 5 µM Elamipretide-treated keratinocytes with graded doses of red light. p values were calculated applying an unpaired Student’s t-test with unequal variances. ns = not significant (p > 0.05).
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Figure 4—source data 1
Original western blots for Figure 4, indicating the relevant bands and treatments.
- https://cdn.elifesciences.org/articles/111498/elife-111498-fig4-data1-v1.zip
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Figure 4—source data 2
Original files for western blot analysis displayed in Figure 4.
- https://cdn.elifesciences.org/articles/111498/elife-111498-fig4-data2-v1.zip
Figure 4—figure supplement 1
Changes in the expression of proteins related to glucose and lipid metabolism in keratinocytes under red light and inhibitor treatment conditions.
Effects of different concentrations of SC-79 (a) and MK2206 (b) levels of PI3K, p-mTOR, p-AKT and Actin proteins in keratinocytes, n = 3 (DAPI, blue). Effects of different concentrations of WY14643 (c) and GW6471 (d) levels of PI3K, p-mTOR, p-AKT, PPAR-α, PPAR-γ, and Actin proteins in keratinocytes, n = 3 (DAPI, blue). Effect of red light treatment on the levels of PI3K, Raptor, Rictor, p-AKT, PPAR-α, PPAR-γ and p-S6 proteins in keratinocytes in the presence of 5 µM Nicur (e) and TSA (f), n = 3. Fluorescence images of intracellular H3K9ac protein in keratinocytes treated with red light irradiation in the presence of 5 µM Nicur (g) and 5 µM TSA (h). Effect of red light treatment on the levels of PI3K, Raptor, Rictor, PPAR-α, PPAR-γ, p-S6, and Actin proteins in keratinocytes in the presence of 2 µM Mk2206 (i) and 20 µM GW6471 (j), n = 3. Effect of red light treatment on the levels of PI3K, p-mTOR, p-AKT, PPAR-α, PPAR-γ, and Actin proteins in keratinocytes in the presence of 5 µM Antimycin (k) and Elamipretide (l), n = 3. Acetylation modification proteomics analysis illustrating differential expression GO analysis (cellular component pathway, m) and chordal analysis (n) of acetylation-modified proteins in cells after red light irradiation of keratinocytes.
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Figure 4—figure supplement 1—source data 1
Original western blots for Figure 4—figure supplement 1, indicating the relevant bands and treatments.
- https://cdn.elifesciences.org/articles/111498/elife-111498-fig4-figsupp1-data1-v1.zip
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Figure 4—figure supplement 1—source data 2
Original files for western blot analysis displayed in Figure 4—figure supplement 1.
- https://cdn.elifesciences.org/articles/111498/elife-111498-fig4-figsupp1-data2-v1.zip
Figure 5 with 1 supplement
Red light-induced downregulation of SIRT4 is primarily responsible for the activation of lipid metabolism, alleviation of inflammation, and resistance to aging in keratinocytes.
(a) Heatmap showing the top 50 significantly differentially expressed proteins in red light-irradiated keratinocytes. (b) Volcano plot of protein content changes in keratinocytes after red light treatment. (c) Schematic representation of the role of SIRT4 in mitochondria and cell. Fluorescence images of SIRT4 (d) and SIRT1 (e) protein and nucleus in keratinocytes after red light treatment, n = 9. (f) Intracellular protein levels of SIRT1 and SIRT4 after dose-gradient red light treatment of keratinocytes, n = 3. (g) Protein levels of p-Nf-κB, PPAR-α and SIRT4 in keratinocytes after red light treatment, n = 3. (h) H&E staining images and fluorescence images of SIRT4 (green) and SIRT1 (red) proteins of mouse skin tissues in 4M, 2Y and 2Y+R treatment groups (DAPI, blue), n = 3. (i) The levels of SIRT4 and SIRT1 proteins in the skin of aged mice after cyclic red light treatment, n = 3. Fluorescence images of p-Nf-κB (red, j) in mice skin tissues after red light treatment of 1Y and 2Y senescent mice (DAPI, blue) and the levels of p-Nf-κB protein (k) in skin tissues of 2Y senescent mice after red light treatment, n = 3. Relative expression of Sirt4 mRNA (l) (n = 3) and fluorescence images of SIRT4 protein (green) (m, n = 6) in keratinocytes after silencing of the Sirt4 gene in keratinocytes using siRNA. Changes in cellular activity (n, n = 3), relative content of intracellular acetyl-CoA (o, n = 6) in keratinocytes after silencing the SIRT4 gene in keratinocytes using siRNA. Fluorescence images of PPAR-α (p) and P16 (q) proteins in keratinocytes after silencing the SIRT4 gene in keratinocytes using siRNA, n = 6. (r) Protein levels of p-Nf-κB, LAMB1, PPAR-α, SIRT4, p21, p16, H3K9ac, and H3 in keratinocytes after silencing the SIRT4 gene in keratinocytes using siRNA, n = 3. (s) Fluorescence images of H3K9ac proteins in keratinocytes after silencing the Sirt4 gene in keratinocytes using siRNA, n = 6. (t) Relative expression of SASP inflammatory factors in keratinocytes following silencing of the Sirt4 gene in keratinocytes using siRNA, n = 3. (u) Images of β-galactosidase staining in keratinocytes after silencing the SIRT4 gene in keratinocytes cells using siRNA, n = 6. N-Con: negative control; RL: red light. p values were calculated applying an unpaired Student’s t-test with unequal variances. ns = not significant (p > 0.05).
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Figure 5—source data 1
Original western blots for Figure 5, indicating the relevant bands and treatments.
- https://cdn.elifesciences.org/articles/111498/elife-111498-fig5-data1-v1.zip
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Figure 5—source data 2
Original files for western blot analysis displayed in Figure 5.
- https://cdn.elifesciences.org/articles/111498/elife-111498-fig5-data2-v1.zip
Figure 5—figure supplement 1
Age-related changes in p-NF-κB and PPAR-α in mouse skin tissue.
(a) Fluorescence images of p-NF-κB protein (p-NF-κB, red; DAPI, blue) in skin tissues from 3D, 3W, 2M, 1Y, and 2Y mice. (b) Intracellular protein levels of PPAR-α and p-NF-κB after RL treatment in the presence of the PPARα inhibitor GW6471 (20 µM). (c) Fluorescent images of PPAR-α, PPAR-γ, and p-NF-κB in the skin of 2M and 2Y old mice (DAPI, blue).
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Figure 5—figure supplement 1—source data 1
Original western blots for Figure 5—figure supplement 1, indicating the relevant bands and treatments.
- https://cdn.elifesciences.org/articles/111498/elife-111498-fig5-figsupp1-data1-v1.zip
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Figure 5—figure supplement 1—source data 2
Original files for western blot analysis displayed in Figure 5—figure supplement 1.
- https://cdn.elifesciences.org/articles/111498/elife-111498-fig5-figsupp1-data2-v1.zip
Figure 6 with 1 supplement
Red light activates lipid metabolism and increases H3K9ac levels in keratinocytes via SIRT4 downregulation-mediated MCD acetylation.
(a) Heatmap showing the top 50 significantly differentially expressed acetylated proteins in red light-irradiated keratinocytes. (b) Volcano plot of changes in the content of acetylation-modified proteins in keratinocytes after red light treatment. (c) Acetylation modification proteomics top 10 protein functional enrichment analysis (Protein functional annotation by InterPro). (d) Proteomic top 10 enriched pathway chordal map of red light irradiated keratinocytes (KEGG analysis). (e) Top 12 molecular processes enriched by combined analysis of keratinocyte proteomics and acetylation modification proteomics after red light treatment (KEGG analysis). (f) Top 10 pathways chordal map enriched by combined analysis of keratinocyte proteomics and acetylation modification proteomics after red light treatment. (g) Schematic representation of the role of SIRT4 in mitochondria FAO and TCA cycle progress. Effects of red light on cell viability (CCK-8, h, n = 12), fatty acid uptake (i, n = 6), ATP production (j, n = 4), NADH levels (k, n = 4), and acetyl-CoA content (l, n = 4) in keratinocytes treated with 5 μM CBM-301940. Representative immunofluorescence staining of H3K9ac (m, n = 9) and Western blot analysis of CPT1A, β-Actin, H3K9ac, and H3 in keratinocytes treated with red light and 5 μM CBM-301940 (n, n = 3). p values were calculated applying an unpaired Student’s t-test with unequal variances. ns = not significant (p > 0.05).
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Figure 6—source data 1
Original western blots for Figure 6, indicating the relevant bands and treatments.
- https://cdn.elifesciences.org/articles/111498/elife-111498-fig6-data1-v1.zip
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Figure 6—source data 2
Original files for western blot analysis displayed in Figure 6.
- https://cdn.elifesciences.org/articles/111498/elife-111498-fig6-data2-v1.zip
Figure 6—figure supplement 1
Proteomics and acetyloproteomics analyses of keratinocytes following red light irradiation.
Acetylation modification proteomics analysis, illustrating differential expression GO analysis molecular function pathway, (a) and chordal analysis (b) of acetylation modification proteins in cells after red light irradiation of keratinocytes. (c) Heatmap of changes in the content of mitochondrial electron-conducting chain complex-related proteins in keratinocytes after red light treatment. (d) Proteomic and chordal plots after red light treatment of keratinocytes, demonstrating the processes involved in the significant difference top 10 in the cellular component pathway. (e) Conjoint GO analysis of proteomics and acetylation modification proteomics after red light treatment of keratinocytes demonstrated significant differences top 10 processes in biological process, cellular component, and molecular function pathways within keratinocytes, respectively.
Figure 7 with 1 supplement
Inflammation and senescence signaling in aging model mice alleviated after cyclic treatment with red light.
Fluorescence images of SIRT4 (red) proteins in the heart (a), liver (b), lung (c), and kidney (d) of mice in groups 4M, 2Y, and 2Y+R (DAPI, blue), n = 6. The levels of H3K9ac proteins in the heart (e), liver (f), lung (g), and kidney (h) of mice in groups 4M, 2Y, and 2Y+R, n = 3. Fluorescence images of H3K9ac (red), p-Nf-κB (green), and p16 (yellow) proteins in the heart (i), liver (j), lung (k), and kidney (l) of mice in groups 4M, 2Y, and 2Y+R (DAPI, blue), n = 6. The levels of p-Nf-κB, LAMB1, p21, and p16 proteins in the heart (m), liver (n), lung (o), and kidney (p) of mice in groups 4M, 2Y, and 2Y+R, n = 3. The expression heatmap of SASP inflammatory factors in the heart (q), liver (r), lung (s), and kidney (t) of mice in groups 4M, 2Y, and 2Y+R, n = 3. p values were calculated applying an unpaired Student’s t-test with unequal variances. ns = not significant (p > 0.05).
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Figure 7—source data 1
Original western blots for Figure 7, indicating the relevant bands and treatments.
- https://cdn.elifesciences.org/articles/111498/elife-111498-fig7-data1-v1.zip
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Figure 7—source data 2
Original files for western blot analysis displayed in Figure 7.
- https://cdn.elifesciences.org/articles/111498/elife-111498-fig7-data2-v1.zip
Figure 7—figure supplement 1
Determination of the efficiency with which red light penetrates mouse skin under the conditions of this study.
Schematic diagram for testing the penetration of red light through the skin (a). An illuminometer was used to detect the light intensity of the LED source before and after penetrating the skin (b). (c, d) Schematic diagram illustrating the measurement of red light penetration efficiency in skin tissue (c). The skin penetration efficiency of the LED source is represented by the ratio of the illuminometer readings under direct illumination and illumination through the skin at the same distance for visible red LED sources (d).
Figure 8
Mechanism of anti-aging action of red light.
Red light can reduce SIRT4 signaling in keratinocytes, thereby reactivating lipid metabolism and increasing levels of acetyl-CoA. This promotes histone acetylation, which in turn remodels the expression of age-related inflammatory factors and genes.
Additional files
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MDAR checklist
- https://cdn.elifesciences.org/articles/111498/elife-111498-mdarchecklist1-v1.docx
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Supplementary file 1
Primer sequences used in this study.
- https://cdn.elifesciences.org/articles/111498/elife-111498-supp1-v1.docx
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Photo-downregulation of SIRT4 mitigates aging in mice by enhancing H3K9ac via fatty acid metabolism
eLife 15:RP111498.
https://doi.org/10.7554/eLife.111498.3
