bims-proarb Biomed News
on Proteostasis in aging and regenerative biology
Issue of 2022‒03‒06
sixteen papers selected by
Rich Giadone
Harvard University
  1. Editorial: Protein Misfolding and Proteostasis Impairment in Aging and Neurodegeneration: From Spreading Studies to Therapeutic Approaches.
  2. Selective Autophagy Receptor p62/SQSTM1, a Pivotal Player in Stress and Aging.
  3. Developmentally regulated selective autophagy determines ER inheritance by gametes.
  4. Tom70-based transcriptional regulation of mitochondrial biogenesis and aging.
  5. Age-associated decline of MondoA drives cellular senescence through impaired autophagy and mitochondrial homeostasis.
  6. Effects of oligomer toxicity, fibril toxicity and fibril spreading in synucleinopathies.
  7. Don't forget to be picky - selective autophagy of protein aggregates in neurodegenerative diseases.
  8. Assessment of mitophagy in human iPSC-derived cardiomyocytes.
  9. PERK is a critical metabolic hub for immunosuppressive function in macrophages.
  10. Multi-modal profiling of human fetal liver hematopoietic stem cells reveals the molecular signature of engraftment.
  11. USP25 inhibition ameliorates Alzheimer's pathology through the regulation of APP processing and Aβ generation.
  12. Determining the structure of fleeting protein states.
  13. Premature aging in mice with error-prone protein synthesis.
  14. In vivo transcriptomic profiling using cell encapsulation identifieseffector pathways of systemic aging.
  15. Recovery Mechanism of Endoplasmic Reticulum Revealed by Fluorescence Lifetime Imaging in Live Cells.
  16. Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming.
  1. Front Aging Neurosci. 2021 ;13 830779
    Editorial: Protein Misfolding and Proteostasis Impairment in Aging and Neurodegeneration: From Spreading Studies to Therapeutic Approaches.
    Claudia Duran-Aniotz, Ines Moreno-Gonzalez, Danilo B Medinas, Rodrigo Morales.
      
    Keywords:  Alzheimer's disease; aging; neurodegeneration; protein misfolding; proteostasis
    DOI:  https://doi.org/10.3389/fnagi.2021.830779
  2. Front Cell Dev Biol. 2022 ;10 793328
    Selective Autophagy Receptor p62/SQSTM1, a Pivotal Player in Stress and Aging.
    Anita V Kumar, Joslyn Mills, Louis R Lapierre.
      Efficient proteostasis is crucial for somatic maintenance, and its decline during aging leads to cellular dysfunction and disease. Selective autophagy is a form of autophagy mediated by receptors that target specific cargoes for degradation and is an essential process to maintain proteostasis. The protein Sequestosome 1 (p62/SQSTM1) is a classical selective autophagy receptor, but it also has roles in the ubiquitin-proteasome system, cellular metabolism, signaling, and apoptosis. p62 is best known for its role in clearing protein aggregates via aggrephagy, but it has recently emerged as a receptor for other forms of selective autophagy such as mitophagy and lipophagy. Notably, p62 has context-dependent impacts on organismal aging and turnover of p62 usually reflects active proteostasis. In this review, we highlight recent advances in understanding the role of p62 in coordinating the ubiquitin-proteasome system and autophagy. We also discuss positive and negative effects of p62 on proteostatic status and their implications on aging and neurodegeneration. Finally, we relate the link between defective p62 and diseases of aging and examine the utility of targeting this multifaceted protein to achieve proteostatic benefits.
    Keywords:  aging; autophagy; neurodegenerative diseases; p62 (sequestosome 1(SQSTM1)); proteasome
    DOI:  https://doi.org/10.3389/fcell.2022.793328
  3. Autophagy. 2022 Feb 27. 1-2
    Developmentally regulated selective autophagy determines ER inheritance by gametes.
    George Maxwell Otto, Gloria Ann Brar.
      The endoplasmic reticulum (ER) carries out essential cellular functions ranging from protein trafficking to metabolite signaling. ER function is maintained in part by quality control pathways including ER degradation by selective autophagy (reticulophagy) during conditions of cellular stress. Reticulophagy is known to be important for cellular responses to starvation and protein folding stress, but no natural role during development had been identified. While investigating ER remodeling during the conserved cell differentiation process of meiosis in budding yeast, we unexpectedly observed developmentally regulated reticulophagy that was driven by expression of the autophagy receptor Atg40. This reticulophagy was coordinated with massive morphological rearrangement of the ER, including movement of most cortical ER away from the cell periphery. As meiotic reticulophagy prevents specific ER subpopulations from being inherited by gametes, we propose that it serves a quality control role, preventing deleterious material from being passed on to subsequent generations.
    Keywords:  Atg40; ERphagy; endoplasmic reticulum; gametes; meiosis; quality control; reticulophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2040315
  4. Elife. 2022 Mar 02. pii: e75658. [Epub ahead of print]11
    Tom70-based transcriptional regulation of mitochondrial biogenesis and aging.
    Qingqing Liu, Catherine E Chang, Alexandra C Wooldredge, Benjamin Fong, Brian K Kennedy, Chuankai Zhou.
      Mitochondrial biogenesis has two major steps: the transcriptional activation of nuclear genome-encoded mitochondrial proteins and the import of nascent mitochondrial proteins that are synthesized in the cytosol. These nascent mitochondrial proteins are aggregation-prone and can cause cytosolic proteostasis stress. The transcription factor-dependent transcriptional regulations and the TOM-TIM complex-dependent import of nascent mitochondrial proteins have been extensively studied. Yet, little is known regarding how these two steps of mitochondrial biogenesis coordinate with each other to avoid the cytosolic accumulation of these aggregation-prone nascent mitochondrial proteins. Here we show that in budding yeast, Tom70, a conserved receptor of the TOM complex, moonlights to regulate the transcriptional activity of mitochondrial proteins. Tom70's transcription regulatory role is conserved in Drosophila. The dual roles of Tom70 in both transcription/biogenesis and import of mitochondrial proteins allow the cells to accomplish mitochondrial biogenesis without compromising cytosolic proteostasis. The age-related reduction of Tom70, caused by reduced biogenesis and increased degradation of Tom70, is associated with the loss of mitochondrial membrane potential, mtDNA, and mitochondrial proteins. While loss of Tom70 accelerates aging and age-related mitochondrial defects, overexpressing TOM70 delays these mitochondrial dysfunctions and extends the replicative lifespan. Our results reveal unexpected roles of Tom70 in mitochondrial biogenesis and aging.
    Keywords:  S. cerevisiae; cell biology
    DOI:  https://doi.org/10.7554/eLife.75658
  5. Cell Rep. 2022 Mar 01. pii: S2211-1247(22)00171-1. [Epub ahead of print]38(9): 110444
    Age-associated decline of MondoA drives cellular senescence through impaired autophagy and mitochondrial homeostasis.
    Hitomi Yamamoto-Imoto, Satoshi Minami, Tatsuya Shioda, Yurina Yamashita, Shinsuke Sakai, Shihomi Maeda, Takeshi Yamamoto, Shinya Oki, Mizuki Takashima, Tadashi Yamamuro, Kyosuke Yanagawa, Ryuya Edahiro, Miki Iwatani, Mizue So, Ayaka Tokumura, Toyofumi Abe, Ryoichi Imamura, Norio Nonomura, Yukinori Okada, Donald E Ayer, Hidesato Ogawa, Eiji Hara, Yoshitsugu Takabatake, Yoshitaka Isaka, Shuhei Nakamura, Tamotsu Yoshimori.
      Accumulation of senescent cells affects organismal aging and the prevalence of age-associated disease. Emerging evidence suggests that activation of autophagy protects against age-associated diseases and promotes longevity, but the roles and regulatory mechanisms of autophagy in cellular senescence are not well understood. Here, we identify the transcription factor, MondoA, as a regulator of cellular senescence, autophagy, and mitochondrial homeostasis. MondoA protects against cellular senescence by activating autophagy partly through the suppression of an autophagy-negative regulator, Rubicon. In addition, we identify peroxiredoxin 3 (Prdx3) as another downstream regulator of MondoA essential for mitochondrial homeostasis and autophagy. Rubicon and Prdx3 work independently to regulate senescence. Furthermore, we find that MondoA knockout mice have exacerbated senescence during ischemic acute kidney injury (AKI), and a decrease of MondoA in the nucleus is correlated with human aging and ischemic AKI. Our results suggest that decline of MondoA worsens senescence and age-associated disease.
    Keywords:  C. elegans; MondoA; Rubicon; aging; autophagy; cellular senescence; kidney; mitochondrial homeostasis; mml-1; peroxiredoxin 3
    DOI:  https://doi.org/10.1016/j.celrep.2022.110444
  6. Cell Mol Life Sci. 2022 Mar 04. 79(3): 174
    Effects of oligomer toxicity, fibril toxicity and fibril spreading in synucleinopathies.
    Roberta Cascella, Alessandra Bigi, Nunilo Cremades, Cristina Cecchi.
      Protein misfolding is a general hallmark of protein deposition diseases, such as Alzheimer's disease or Parkinson's disease, in which different types of aggregated species (oligomers, protofibrils and fibrils) are generated by the cells. Despite widespread interest, the relationship between oligomers and fibrils in the aggregation process and spreading remains elusive. A large variety of experimental evidences supported the idea that soluble oligomeric species of different proteins might be more toxic than the larger fibrillar forms. Furthermore, the lack of correlation between the presence of the typical pathological inclusions and disease sustained this debate. However, recent data show that the β-sheet core of the α-Synuclein (αSyn) fibrils is unable to establish persistent interactions with the lipid bilayers, but they can release oligomeric species responsible for an immediate dysfunction of the recipient neurons. Reversibly, such oligomeric species could also contribute to pathogenesis via neuron-to-neuron spreading by their direct cell-to-cell transfer or by generating new fibrils, following their neuronal uptake. In this Review, we discuss the various mechanisms of cellular dysfunction caused by αSyn, including oligomer toxicity, fibril toxicity and fibril spreading.
    Keywords:  Amyloid; Lewy bodies; Neurodegeneration; Parkinson’s disease; Prion-like; Protein aggregation; Protein misfolding; Protein self-assembly; Toxic oligomers; α-Synuclein
    DOI:  https://doi.org/10.1007/s00018-022-04166-9
  7. Curr Opin Cell Biol. 2022 Feb 28. pii: S0955-0674(22)00010-2. [Epub ahead of print]75 102064
    Don't forget to be picky - selective autophagy of protein aggregates in neurodegenerative diseases.
    Anne Simonsen, Thomas Wollert.
      The homeostasis of cells depends on the selective degradation of damaged or superfluous cellular components. Autophagy is the major pathway that recognizes such components, sequesters them in de novo formed autophagosomes and delivers them to lysosomes for degradation. The recognition of specific cargo and the biogenesis of autophagosomes involve a dedicated machinery of autophagy related (ATG) proteins. Intense research over the past decades has revealed insights into the function of autophagy proteins and mechanisms that govern cargo recognition. Other aspects including the molecular mechanisms involved in the onset of human diseases are less well understood. However, autophagic dysfunctions, caused by age related decline in autophagy or mutations in ATG proteins, are directly related to a large number of human pathologies including neurodegenerative disorders. Here, we review most recent discoveries and breakthroughs in selective autophagy and its relationship to neurodegeneration.
    DOI:  https://doi.org/10.1016/j.ceb.2022.01.009
  8. Autophagy. 2022 Feb 27. 1-14
    Assessment of mitophagy in human iPSC-derived cardiomyocytes.
    Mingchong Yang, Ji-Dong Fu, Jizhong Zou, Divya Sridharan, Ming-Tao Zhao, Harpreet Singh, Judith Krigman, Mahmood Khan, Gang Xin, Nuo Sun.
      Defective mitophagy contributes to normal aging and various neurodegenerative and cardiovascular diseases. The newly developed methodologies to visualize and quantify mitophagy allow for additional progress in defining the pathophysiological significance of mitophagy in various model organisms. However, current knowledge regarding mitophagy relevant to human physiology is still limited. Model organisms such as mice might not be optimal models to recapitulate all the key aspects of human disease phenotypes. The development of the human-induced pluripotent stem cells (hiPSCs) may provide an exquisite approach to bridge the gap between animal mitophagy models and human physiology. To explore this premise, we take advantage of the pH-dependent fluorescent mitophagy reporter, mt-Keima, to assess mitophagy in hiPSCs and hiPSC-derived cardiomyocytes (hiPSC-CMs). We demonstrate that mt-Keima expression does not affect mitochondrial function or cardiomyocytes contractility. Comparison of hiPSCs and hiPSC-CMs during different stages of differentiation revealed significant variations in basal mitophagy. In addition, we have employed the mt-Keima hiPSC-CMs to analyze how mitophagy is altered under certain pathological conditions including treating the hiPSC-CMs with doxorubicin, a chemotherapeutic drug well known to cause life-threatening cardiotoxicity, and hypoxia that stimulates ischemia injury. We have further developed a chemical screening to identify compounds that modulate mitophagy in hiPSC-CMs. The ability to assess mitophagy in hiPSC-CMs suggests that the mt-Keima hiPSCs should be a valuable resource in determining the role mitophagy plays in human physiology and hiPSC-based disease models. The mt-Keima hiPSCs could prove a tremendous asset in the search for pharmacological interventions that promote mitophagy as a therapeutic target.
    Keywords:  Cardiomyocytes; cardiomyopathy; induced pluripotent stem cells; mitochondrial; mitophagy; mt-Keima
    DOI:  https://doi.org/10.1080/15548627.2022.2037920
  9. Nat Immunol. 2022 Feb 28.
    PERK is a critical metabolic hub for immunosuppressive function in macrophages.
    Lydia N Raines, Haoxin Zhao, Yuzhu Wang, Heng-Yi Chen, Hector Gallart-Ayala, Pei-Chun Hsueh, Wei Cao, Yeojung Koh, Ana Alamonte-Loya, Pu-Ste Liu, Julijana Ivanisevic, Chan-Wang Jerry Lio, Ping-Chih Ho, Stanley Ching-Cheng Huang.
      Chronic inflammation triggers compensatory immunosuppression to stop inflammation and minimize tissue damage. Studies have demonstrated that endoplasmic reticulum (ER) stress augments the suppressive phenotypes of immune cells; however, the molecular mechanisms underpinning this process and how it links to the metabolic reprogramming of immunosuppressive macrophages remain elusive. In the present study, we report that the helper T cell 2 cytokine interleukin-4 and the tumor microenvironment increase the activity of a protein kinase RNA-like ER kinase (PERK)-signaling cascade in macrophages and promote immunosuppressive M2 activation and proliferation. Loss of PERK signaling impeded mitochondrial respiration and lipid oxidation critical for M2 macrophages. PERK activation mediated the upregulation of phosphoserine aminotransferase 1 (PSAT1) and serine biosynthesis via the downstream transcription factor ATF-4. Increased serine biosynthesis resulted in enhanced mitochondrial function and α-ketoglutarate production required for JMJD3-dependent epigenetic modification. Inhibition of PERK suppressed macrophage immunosuppressive activity and could enhance the efficacy of immune checkpoint programmed cell death protein 1 inhibition in melanoma. Our findings delineate a previously undescribed connection between PERK signaling and PSAT1-mediated serine metabolism critical for promoting immunosuppressive function in M2 macrophages.
    DOI:  https://doi.org/10.1038/s41590-022-01145-x
  10. Nat Commun. 2022 Mar 01. 13(1): 1103
    Multi-modal profiling of human fetal liver hematopoietic stem cells reveals the molecular signature of engraftment.
    Kim Vanuytsel, Carlos Villacorta-Martin, Jonathan Lindstrom-Vautrin, Zhe Wang, Wilfredo F Garcia-Beltran, Vladimir Vrbanac, Dylan Parsons, Evan C Lam, Taylor M Matte, Todd W Dowrey, Sara S Kumar, Mengze Li, Feiya Wang, Anthony K Yeung, Gustavo Mostoslavsky, Ruben Dries, Joshua D Campbell, Anna C Belkina, Alejandro B Balazs, George J Murphy.
      The human hematopoietic stem cell harbors remarkable regenerative potential that can be harnessed therapeutically. During early development, hematopoietic stem cells in the fetal liver undergo active expansion while simultaneously retaining robust engraftment capacity, yet the underlying molecular program responsible for their efficient engraftment remains unclear. Here, we profile 26,407 fetal liver cells at both the transcriptional and protein level including ~7,000 highly enriched and functional fetal liver hematopoietic stem cells to establish a detailed molecular signature of engraftment potential. Integration of transcript and linked cell surface marker expression reveals a generalizable signature defining functional fetal liver hematopoietic stem cells and allows for the stratification of enrichment strategies with high translational potential. More precisely, our integrated analysis identifies CD201 (endothelial protein C receptor (EPCR), encoded by PROCR) as a marker that can specifically enrich for engraftment potential. This comprehensive, multi-modal profiling of engraftment capacity connects a critical biological function at a key developmental timepoint with its underlying molecular drivers. As such, it serves as a useful resource for the field and forms the basis for further biological exploration of strategies to retain the engraftment potential of hematopoietic stem cells ex vivo or induce this potential during in vitro hematopoietic stem cell generation.
    DOI:  https://doi.org/10.1038/s41467-022-28616-x
  11. J Clin Invest. 2022 Mar 01. pii: e152170. [Epub ahead of print]132(5):
    USP25 inhibition ameliorates Alzheimer's pathology through the regulation of APP processing and Aβ generation.
    Qiuyang Zheng, Beibei Song, Guilin Li, Fang Cai, Meiling Wu, Yingjun Zhao, LuLin Jiang, Tiantian Guo, Mingyu Shen, Huan Hou, Ying Zhou, Yini Zhao, Anjie Di, Lishan Zhang, Fanwei Zeng, Xiu-Fang Zhang, Hong Luo, Xian Zhang, Hongfeng Zhang, Zhiping Zeng, Timothy Y Huang, Chen Dong, Hong Qing, Yun Zhang, Qing Zhang, Xu Wang, Yili Wu, Huaxi Xu, Weihong Song, Xin Wang.
      Down syndrome (DS), or trisomy 21, is one of the critical risk factors for early-onset Alzheimer's disease (AD), implicating key roles for chromosome 21-encoded genes in the pathogenesis of AD. We previously identified a role for the deubiquitinase USP25, encoded on chromosome 21, in regulating microglial homeostasis in the AD brain; however, whether USP25 affects amyloid pathology remains unknown. Here, by crossing 5×FAD AD and Dp16 DS mice, we observed that trisomy 21 exacerbated amyloid pathology in the 5×FAD brain. Moreover, bacterial artificial chromosome (BAC) transgene-mediated USP25 overexpression increased amyloid deposition in the 5×FAD mouse brain, whereas genetic deletion of Usp25 reduced amyloid deposition. Furthermore, our results demonstrate that USP25 promoted β cleavage of APP and Aβ generation by reducing the ubiquitination and lysosomal degradation of both APP and BACE1. Importantly, pharmacological inhibition of USP25 ameliorated amyloid pathology in the 5×FAD mouse brain. In summary, we identified the DS-related gene USP25 as a critical regulator of AD pathology, and our data suggest that USP25 serves as a potential pharmacological target for AD drug development.
    Keywords:  Alzheimer disease; Neuroscience
    DOI:  https://doi.org/10.1172/JCI152170
  12. Nature. 2022 Mar 02.
    Determining the structure of fleeting protein states.
      
    Keywords:  Biochemistry; Molecular biology; Structural biology
    DOI:  https://doi.org/10.1038/d41586-022-00531-7
  13. Sci Adv. 2022 Mar 04. 8(9): eabl9051
    Premature aging in mice with error-prone protein synthesis.
    Dimitri Shcherbakov, Martina Nigri, Rashid Akbergenov, Margarita Brilkova, Matilde Mantovani, Patricia Isnard Petit, Amandine Grimm, Agnieszka A Karol, Youjin Teo, Adrián Cortés Sanchón, Yadhu Kumar, Anne Eckert, Kader Thiam, Petra Seebeck, David P Wolfer, Erik C Böttger.
      The main source of error in gene expression is messenger RNA decoding by the ribosome. Translational accuracy has been suggested on a purely correlative basis to positively coincide with maximum possible life span among different rodent species, but causal evidence that translation errors accelerate aging in vivo and limit life span is lacking. We have now addressed this question experimentally by creating heterozygous knock-in mice that express the ribosomal ambiguity mutation RPS9 D95N, resulting in genome-wide error-prone translation. Here, we show that Rps9 D95N knock-in mice exhibit reduced life span and a premature onset of numerous aging-related phenotypes, such as reduced weight, chest deformation, hunchback posture, poor fur condition, and urinary syndrome, together with lymphopenia, increased levels of reactive oxygen species-inflicted damage, accelerated age-related changes in DNA methylation, and telomere attrition. Our results provide an experimental link between translational accuracy, life span, and aging-related phenotypes in mammals.
    DOI:  https://doi.org/10.1126/sciadv.abl9051
  14. Elife. 2022 Mar 04. pii: e57393. [Epub ahead of print]11
    In vivo transcriptomic profiling using cell encapsulation identifieseffector pathways of systemic aging.
    Omid Mashinchian, Xiaotong Hong, Joris Michaud, Eugenia Migliavacca, Gregory Lefebvre, Christophe Boss, Filippo De Franceschi, Emmeran Le Moal, Jasmin Collerette-Tremblay, Joan Isern, Sylviane Metairon, Frederic Raymond, Patrick Descombes, Nicolas Bouche, Pura Muñoz-Cánoves, Jerome N Feige, C Florian Bentzinger.
      Sustained exposure to a young systemic environment rejuvenates aged organisms and promotes cellular function. However, due to the intrinsic complexity of tissues it remains challenging to pinpoint niche-independent effects of circulating factors on specific cell populations. Here we describe a method for the encapsulation of human and mouse skeletal muscle progenitors in diffusible polyethersulfone hollow fiber capsules that can be used to profile systemic aging in vivo independent of heterogeneous short-range tissue interactions. We observed that circulating long-range signaling factors in the old systemic environment lead to an activation of Myc and E2F transcription factors, induce senescence and suppress myogenic differentiation. Importantly, in vitro profiling using young and old serum in 2D culture does not capture all pathways deregulated in encapsulated cells in aged mice. Thus, in vivo transcriptomic profiling using cell encapsulation allows for the characterization of effector pathways of systemic aging with unparalleled accuracy.
    Keywords:  cell biology; mouse
    DOI:  https://doi.org/10.7554/eLife.57393
  15. Anal Chem. 2022 Mar 04.
    Recovery Mechanism of Endoplasmic Reticulum Revealed by Fluorescence Lifetime Imaging in Live Cells.
    Juan Chen, Guangmei Han, Zhengjie Liu, Hong Wang, Dong Wang, Jun Zhao, Bianhua Liu, Ruilong Zhang, Zhongping Zhang.
      Endoplasmic reticulum (ER) is an important organelle of a membranous tubule network in cells for the synthesis, assembly, and modification of peptides, proteins, and enzymes. Autophagy and destruction of ER commonly occur during normal cellular activities. These processes have been studied extensively, but the spontaneous ER regeneration process is poorly understood because of the lack of molecular tools capable of distinguishing the intact, damaged, autophagic, and regenerative ER in live cells. Herein, we report a dual-localizing, environment-responsive, and lifetime-sensitive fluorescent probe for real-time monitoring ER autophagy and regeneration in live cells. Using this tool, the fluorescence lifetime imaging can quantitatively determine the degrees of ER destruction and spontaneous recovery. Significantly, we show that triglycerides supplied in lipid droplets can efficiently repair ER via the two critical pathways: (i) supplying materials for ER repair by converting triglycerides into fatty acids and diglycerides and (ii) partially inhibiting autophagy for stressed ER.
    DOI:  https://doi.org/10.1021/acs.analchem.2c00216
  16. Aging Cell. 2022 Mar 02. e13578
    Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming.
    Dafni Chondronasiou, Diljeet Gill, Lluc Mosteiro, Rocio G Urdinguio, Antonio Berenguer-Llergo, Mònica Aguilera, Sylvere Durand, Fanny Aprahamian, Nitharsshini Nirmalathasan, Maria Abad, Daniel E Martin-Herranz, Camille Stephan-Otto Attolini, Neus Prats, Guido Kroemer, Mario F Fraga, Wolf Reik, Manuel Serrano.
      The expression of the pluripotency factors OCT4, SOX2, KLF4, and MYC (OSKM) can convert somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Notably, partial and reversible reprogramming does not change cell identity but can reverse markers of aging in cells, improve the capacity of aged mice to repair tissue injuries, and extend longevity in progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome, and metabolome in naturally aged mice subject to a single period of transient OSKM expression. We found that this is sufficient to reverse DNA methylation changes that occur upon aging in the pancreas, liver, spleen, and blood. Similarly, we observed reversion of transcriptional changes, especially regarding biological processes known to change during aging. Finally, some serum metabolites and biomarkers altered with aging were also restored to young levels upon transient reprogramming. These observations indicate that a single period of OSKM expression can drive epigenetic, transcriptomic, and metabolomic changes toward a younger configuration in multiple tissues and in the serum.
    Keywords:  OSKM; Yamanaka; aging; epigenetic clocks; pluripotency; reprogramming; transcriptomic clocks
    DOI:  https://doi.org/10.1111/acel.13578
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