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In vivo partial reprogramming alters age-associated molecular changes during physiological aging in mice

Nature Aging volume 2, pages 243–253 (2022)Cite this article

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Abstract

Partial reprogramming by expression of reprogramming factors (Oct4, Sox2, Klf4 and c-Myc) for short periods of time restores a youthful epigenetic signature to aging cells and extends the life span of a premature aging mouse model. However, the effects of longer-term partial reprogramming in physiologically aging wild-type mice are unknown. Here, we performed various long-term partial reprogramming regimens, including different onset timings, during physiological aging. Long-term partial reprogramming lead to rejuvenating effects in different tissues, such as the kidney and skin, and at the organismal level; duration of the treatment determined the extent of the beneficial effects. The rejuvenating effects were associated with a reversion of the epigenetic clock and metabolic and transcriptomic changes, including reduced expression of genes involved in the inflammation, senescence and stress response pathways. Overall, our observations indicate that partial reprogramming protocols can be designed to be safe and effective in preventing age-related physiological changes. We further conclude that longer-term partial reprogramming regimens are more effective in delaying aging phenotypes than short-term reprogramming.

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Fig. 1: Long-term partial reprogramming does not negatively impact health.
Fig. 2: Long-term but not short-term partial reprogramming reduces age acceleration in epigenetic clocks in the skin and kidney.
Fig. 3: Short-term partial reprogramming reduces interferon response gene induction in the skin and restores hair cycle gene expression.
Fig. 4: Long-term reprogramming restores metabolic gene expression and reduces inflammatory/SASP gene expression.
Fig. 5: Long-term reprogramming reduces fibrotic tissue formation during wound healing in the skin.
Fig. 6: Restoration of metabolomic and lipidomic profile in the serum following long-term partial reprogramming.

Data availability

DNA methylation and RNA-seq data are deposited in the GEO under the accession no. GSE190665 and the SuperSeries under accession no. GSE190986. The metabolomics and lipidomics raw data can be found in Supplementary Tables 8 and 9 (4F mice serum) and 10 and 11 (B6 mice serum). Other data supporting the findings of the study can be requested from the corresponding author.

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Acknowledgements

We thank M. Schwarz for administrative support. We also thank R. Russell for help with bioluminescence imaging in p16-luc mice. This study was supported by the Universidad Católica San Antonio de Murcia and Fundación Dr. Pedro Guillén. The cartoon images of mice and tissues were created with BioRender.com.

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Author notes

  1. These authors contributed equally: Kristen C. Browder, Pradeep Reddy.

Authors and Affiliations

  1. Immunology Discovery, Genentech, Inc., South San Francisco, CA, USA

    Kristen C. Browder & Heinrich Jasper

  2. Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA

    Pradeep Reddy, Mako Yamamoto, Isabel Guillen Guillen, Sanjeeb Sahu, Chao Wang, Yosu Luque, Javier Prieto, Lei Shi, Kensaku Shojima, Tomoaki Hishida, Concepcion Rodriguez Esteban & Juan Carlos Izpisua Belmonte

  3. Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Amin Haghani & Steve Horvath

  4. Altos Labs, San Diego, CA, USA

    Amin Haghani, Sanjeeb Sahu, Chao Wang, Steve Horvath & Juan Carlos Izpisua Belmonte

  5. Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA

    Zijuan Lai, Feroza K. Choudhury & Dewakar Sangaraju

  6. Microchemistry, Proteomics, Lipidomics & Next Generation Sequencing, Genentech, Inc., South San Francisco, CA, USA

    Qingling Li, Weng R. Wong, Yuxin Liang & Wendy Sandoval

  7. Universidad Católica San Antonio de Murcia, Campus de los Jerónimos, Murcia, Spain

    Estrella Nuñez Delicado

  8. Clínica CEMTRO, Madrid, Spain

    Pedro Guillen Garcia

  9. Bioinformatics, Genentech, Inc., South San Francisco, CA, USA

    Michal Pawlak & Jason A. Vander Heiden

  10. Department of Biostatistics, University of California Los Angeles, School of Public Health, Los Angeles, CA, USA

    Steve Horvath

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  1. Kristen C. Browder
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Contributions

K.B., P.R., H.J. and J.C.I.B. designed all the experiments, prepared the figures and wrote the manuscript. P.R., M.Y., I.G.G., S.S., C.W., Y. Luque, K.S., T.H., C.R.E. and J.P. performed the in vivo experiments. K.B., L.S., M.P. and J.A.V.H. performed the bioinformatics analysis. Z.L., F.K.C. and D.S. performed the metabolomics analysis. Q.L., W.R.W., and W.S. performed the lipidomics analysis. Y. Liang contributed to NGS. C.R.E., E.N.D. and P.G.G. contributed to the analysis and reagents. A.H. and S.H. analyzed the DNA methylation data.

Corresponding authors

Correspondence to Heinrich Jasper or Juan Carlos Izpisua Belmonte.

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Nature Aging thanks Jesus Avila, George Daley and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 Expression of reprogramming factors in tissues.

The expression levels of reprogramming factors (Oct4, Sox2, Klf4 and cMyc) were measured in 9 months old 4 F mice tissues after 48 hr of doxycycline treatment. n = 2 (-Dox) and n = 3 (+Dox) independent biological mice. The data are represented as mean ± SD.

Extended Data Fig. 2 Histological analysis of tissues.

Representative images of the liver, kidney, skin, spleen and lung tissues from 7 months treated long-term partial reprogramming mice were collected at the end of the treatment. The tissues from the doxycycline treatment were compared to similar age untreated and young 4 F mice. Similar phenotypes were observed in 5 pairs of untreated and treated mice. Scale bar, 50 μm (liver, kidney, skin and lung) and 100 μm (spleen). Representative images are from n = 1 mouse. Tissues were evaluated from n = 5 (4 F -Dox) and n = 5 (4 F + Dox) independent biological mice.

Extended Data Fig. 3 Epigenetic clock analysis of tissues.

Scatter plots of DNA methylation age (PredictedAge) (y-axis) versus chronological age (x-axis) of different tissues from 4F mice. DNAm age analysis is based on LUC clocks trained on either individual or pan-tissues. Kidney, Liver, Lung and Spleen: n = 19 (Control) and n = 17 (Treated). Muscle: n = 18 (Control) and n = 17 (Treated). Skin: n = 20 (Control) and n = 16 (Treated). Controls include 4F -Dox and B6 +Dox. Cor: Pearson correlation (cor); p: P-value from two-sided Student’s t-test; Err: Mean absolute error.

Extended Data Fig. 4 Epigenetic clock analysis of tissues from short-term partial reprogrammed mice.

Measurement of DNA methylation age of kidney and skin of 4F mice after short-term partial reprogramming using elastic net (EN) clocks trained on indicated tissues. n = 7 (B6 + doxycycline) and n = 3 (4F + doxycycline) independent biological mice. Age accelerations are the residuals of the predicted age regressed on the chronological age of each sample. The mean differences were examined by a two-sided Student t-test of age acceleration differences between the groups. The P values are reported in each panel. Boxes show the interquartile range of the age accelerations. The notches indicate the 95% confidence interval of the median. The whiskers represent 1.5*IQR length of the age accelerations.

Extended Data Fig. 5 Distribution of CpG sites in tissues of short-term partial reprogrammed mice.

a, Manhattan plots showing the distribution of hyper and hypomethylated CpGs in different tissues from 26 months old mice (4 F -Dox n = 3 and 4 F + Dox n = 3). The EWAS is done by linear regression model of the treatment vs the controls. The coordinates are estimated based on the alignment of Mammalian array probes to mus musculus mm10 genome. Top 15 CpGs was labeled by the neighboring genes. Red dashed line indicates P < 10-4. b, Horizontal bars showing the CpG locations in the genome of tissues. The orange color denotes hypermethylated and blue color denotes hypomethylated CpGs in treated vs control animals. Fisher’s Exact Test is used to examine the proportional change than the background; # two-sided P-value <0.05; odd ratios are reported on the bars with significant proportional change.

Extended Data Fig. 6 Epigenetic clock analysis of tissues from long-term partial reprogrammed mice.

a,b, Measurement of DNA methylation age of kidney and skin of 4F mice after long-term partial reprogramming using elastic net (EN) clocks trained on indicated tissues. a, DNA methylation age acceleration in 4F mice after seven months of treatment starting at 15 months of age. n = 7 (B6 + doxycycline) and n = 5 (4F + doxycycline) independent biological mice. b, DNA methylation age acceleration in 4F mice after ten months of treatment starting at 12 months of age. n = 7 (B6 + doxycycline) and n = 3 (4F + doxycycline) independent biological mice. c, DNA methylation age acceleration of kidney and skin of 4F mice after ten months of treatment starting at 12 months of age using Lifespan Uber Correlation (LUC) clocks trained on indicated tissues. n = 7 (B6 + doxycycline) and n = 3 (4F + doxycycline) independent biological mice. Age accelerations are the residuals of the predicted age regressed on the chronological age of each sample. The mean differences were examined by a two-sided Student t-test of age acceleration differences between the groups. The P values are reported in each panel. Boxes show the interquartile range of the age accelerations. The notches indicate the 95% confidence interval of the median. The whiskers represent 1.5*IQR length of the age accelerations.

Extended Data Fig. 7 Distribution of CpG sites in tissues of long-term partial reprogrammed mice.

a, Manhattan plots showing the distribution of hyper and hypomethylated CpGs in different tissues from 22 months old mice. n = 5 (4 F + Dox) and n = 5 (4 F -Dox) independent biological mice. The EWAS is done by linear regression model of the treatment vs the controls. The coordinates are estimated based on the alignment of Mammalian array probes to mus musculus mm10 genome. Top 15 CpGs was labeled by the neighboring genes. Red dashed line indicates P < 10-4. b, Horizontal bars showing the CpG locations in the genome of tissues. The orange color denotes hypermethylated and blue color denotes hypomethylated CpGs in treated vs control animals. # indicates positive association and *indicates negative association. Fisher’s Exact Test is used to examine the proportional change than the background; odd ratios are reported on the bars with significant proportional change. The P values (#,*<0.05, ##,**<0.01, ###,***<0.001, ****<0.0001); the odd ratio values are reported on the bars. c, The list of top hyper and hypomethylated CpGs and the closet gene. The asterisk denotes the genes differentially expressed in skin.

Extended Data Fig. 8 Transcriptomic analysis of tissues of short-term partial reprogrammed mice.

a, Transcriptional profiling of 25 months old 4 F mice after 1 month of treatment by comparing to untreated and young 4 F mice (3 mo). n = 4 (old 4 F -Dox), n = 3 (old 4 F + Dox) and n = 4 (young 4 F -Dox) independent biological mice. b, Plot of principal components (PC1 and PC2) obtained from the principal component analysis of tissues from untreated and treated male and female mice at 26 months of age and young 4 F mice. c, The list of top 20 upregulated and downregulated genes. d, A dot plot showing the downregulation of Gbp7 gene expression in treated mice and comparable to young control. e, Transcription factor motif enrichment analysis in differentially expressed genes.

Extended Data Fig. 9 Transcriptional profiling of long-term treated 4 F mice and doxycycline treated B6 mice.

a, Transcriptional profiling of 22 months old 4 F mice after 7 months of treatment by comparing to untreated B6 mice. n = 5 (B6 -Dox) and n = 5 (4 F + Dox) independent biological mice. b, Gene ontology (GO) analysis of RNA-seq data of skin showing the top upregulated and downregulated genes. DEG list cutoffs defined as P < 0.05 and LFC of 2. c, List of top downregulated and upregulated genes in the skin. d, Plot of principal components (PC1 and PC2) of tissues from 10 months treated 4 F mice analyzed at 22 months of age. n = 3 (4 F -Dox) and n = 3 (4 F + Dox) independent biological mice. e, Plot of principal components (PC1 and PC2) of the skin comparing control and treated mice. f, Volcano plots of RNA-seq data of skin generated by comparison of 5 months doxycycline treated B6 mice (control and treated) and 10 months treated 4 F mice. For B6 + /-Dox controls, n = 2 (B6 -Dox) and n = 2 (B6 + Dox) independent biological mice. For 4 F 10 month treated, n = 3 (4 F -Dox) and n = 3 (4 F + Dox) independent biological mice.

Extended Data Fig. 10 Analysis of skin and skeletal muscle regeneration after long-term partial reprogramming.

a, Representative images of immunostaining of Ki67 positive cells in the skin of 4 F mice at 22 months after long-term partial reprogramming. Scale bar, 50 μm. b, Quantification of Ki67 positive cells in the skin of 4 F mice after short-term and long-term partial reprogramming in 26 (-Dox n = 4 and +Dox n = 3) and 22 months (-Dox n = 4 and +Dox n = 4) 4 F mice, respectively. 3 sections per mice were used for quantification. c, Epidermal thickness of skin in 4 F mice at 22 months after long-term partial reprogramming. Females (-Dox n = 2 and +Dox n = 2) and Males (-Dox n = 2 and +Dox n = 2), 2 sections per mice were used for quantification. d, Representative histological images of TA muscle and quantification of muscle fiber size of Young (3-months) and 7-months treated (starting at 15 months of age until 22 months) 4 F mice 10 days after cardiotoxin injection. Scale bar, 100 μm. e, Immunostaining of Pax7 and dystrophin and quantification of Pax7+ cells in TA muscle 10 days after cardiotoxin injection n = 5 (Young), n = 6 (-Dox) and n = 5 (+Dox) independent biological mice. Scale bar, 50 μm. For all relevant figures, data are represented as mean ± SD. ****P < 0.0001 values according to two-tailed Student’s t-test.

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Browder, K.C., Reddy, P., Yamamoto, M. et al. In vivo partial reprogramming alters age-associated molecular changes during physiological aging in mice. Nat Aging 2, 243–253 (2022). https://doi.org/10.1038/s43587-022-00183-2

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