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Transposable elements (TEs) are DNA sequences that expand selfishly in the genome, possibly causing severe cellular damage. While normally silenced, TEs have been shown to activate during aging. DNA 5-methylcytosine (5mC) is one of the main epigenetic modifications by which TEs are silenced and has been used to train highly accurate age predictors. Yet, one common criticism of such predictors is that they lack interpretability. In this study, we investigate the changes in TE 5mC methylation that occur during aging in human blood using published methylation array data. We find that evolutionarily young long interspersed nuclear elements 1 (L1s), the only known TEs capable of autonomous transposition in humans, undergo the fastest loss of 5mC methylation, suggesting an active mechanism of de-repression. The same young L1s also showed preferential gain in chromatin accessibility but not expression. The long terminal repeat retrotransposons THE1A and THE1C also showed very rapid 5mC loss. We then show that accurate age predictors can be trained on both 5mC methylation of individual TE copies and average methylation of TE families genome wide. Lastly, we show that while old L1s gradually lose 5mC during the entire lifespan, demethylation of young L1s only happens late in life and is associated with cancer., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The establishment of aging clocks highlighted the strong link between changes in DNA methylation and aging. Yet, it is not known if other epigenetic features could be used to predict age accurately. Furthermore, previous studies have observed a lack of effect of age-related changes in DNA methylation on gene expression, putting the interpretability of DNA methylation-based aging clocks into question. In this study, we explore the use of chromatin accessibility to construct aging clocks. We collected blood from 159 human donors and generated chromatin accessibility, transcriptomic, and cell composition data. We investigated how chromatin accessibility changes during aging and constructed a novel aging clock with a median absolute error of 5.27 years. The changes in chromatin accessibility used by the clock were strongly related to transcriptomic alterations, aiding clock interpretation. We additionally show that our chromatin accessibility clock performs significantly better than a transcriptomic clock trained on matched samples. In conclusion, we demonstrate that the clock relies on cell-intrinsic chromatin accessibility alterations rather than changes in cell composition. Further, we present a new approach to construct epigenetic aging clocks based on chromatin accessibility, which bear a direct link to age-related transcriptional alterations, but which allow for more accurate age predictions than transcriptomic clocks., (© 2023. The Author(s).)

Several premature aging mouse models have been developed to study aging and identify interventions that can delay age-related diseases. Yet, it is still unclear whether these models truly recapitulate natural aging. Here, we analyzed DNA methylation in multiple tissues of four previously reported mouse models of premature aging (Ercc1, LAKI, Polg, and Xpg). We estimated DNA methylation (DNAm) age of these samples using the Horvath clock. The most pronounced increase in DNAm age could be observed in Ercc1 mice, a strain which exhibits a deficit in DNA nucleotide excision repair. Similarly, we detected an increase in epigenetic age in fibroblasts isolated from patients with progeroid syndromes associated with mutations in DNA excision repair genes. These findings highlight that mouse models with deficiencies in DNA repair, unlike other premature aging models, display accelerated epigenetic age, suggesting a strong connection between DNA damage and epigenetic dysregulation during aging., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Unlike aged somatic cells, which exhibit a decline in molecular fidelity and eventually reach a state of replicative senescence, pluripotent stem cells can indefinitely replenish themselves while retaining full homeostatic capacity. The conferment of beneficial-pluripotency related traits via in vivo partial cellular reprogramming in vivo partial reprogramming significantly extends lifespan and restores aging phenotypes in mouse models. Although the phases of cellular reprogramming are well characterized, details of the rejuvenation processes are poorly defined. To understand whether cellular reprogramming can ameliorate DNA damage, we created a reprogrammable accelerated aging mouse model with an ERCC1 mutation. Importantly, using enhanced partial reprogramming by combining small molecules with the Yamanaka factors, we observed potent reversion of DNA damage, significant upregulation of multiple DNA damage repair processes, and restoration of the epigenetic clock. In addition, we present evidence that pharmacological inhibition of ALK5 and ALK2 receptors in the TGFb pathway are able to phenocopy some benefits including epigenetic clock restoration suggesting a role in the mechanism of rejuvenation by partial reprogramming., Competing Interests: AP and AO were employed by the company EPITERNA SA. AH and SH were employed by the company Altos Labs, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Paine, Rechsteiner, Morandini, Desdín-Micó, Mrabti, Parras, Haghani, Brooke, Horvath, Seluanov, Gorbunova and Ocampo.)

The induction of cellular reprogramming via expression of the transcription factors Oct4, Sox2, Klf4 and c-Myc (OSKM) can drive dedifferentiation of somatic cells and ameliorate age-associated phenotypes in multiple tissues and organs. However, the benefits of long-term in vivo reprogramming are limited by detrimental side-effects. Here, using complementary genetic approaches, we demonstrated that continuous induction of the reprogramming factors in vivo leads to hepatic and intestinal dysfunction resulting in decreased body weight and contributing to premature death (within 1 week). By generating a transgenic reprogrammable mouse strain, avoiding OSKM expression in both liver and intestine, we reduced the early lethality and adverse effects associated with in vivo reprogramming and induced a decrease in organismal biological age. This reprogramming mouse strain, which allows longer-term continuous induction of OSKM with attenuated toxicity, can help better understand rejuvenation, regeneration and toxicity during in vivo reprogramming., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Opiate addiction has been widely documented to have negative impact on pregnancy course and outcome. Unfavorable psychosocial situation of addicted women predispose for poor processing of the physiological and psychological demands of pregnancy. Thus aim of our study was to investigate the psychological mood state of opiate addicts during pregnancy and postpartum in comparison to healthy women. In a case-controlled, prospective, longitudinal study nine pregnant opiate addicts and nine healthy pregnant women matched by age, level of education and gestational age at birth were interviewed in the third trimester of pregnancy and postpartum. Standardized questionnaires and inventories for assessment of the general psychopathology and emotional state, the perceived self-efficacy expectancy, the psychosocial adaptation to pregnancy and the fear of delivery, respectively were applied. Addicted women achieved significantly higher scores in the test assessing general psychopathology and emotional state before delivery compared to abstinent women. Interestingly this difference was unverifiable postpartum. This study reaffirms the presumption of a disadvantageous psychological condition in pregnant opiate addicts in comparison to healthy pregnant women for the first time in a prospective case-control study design.

Opiate addiction has been widely documented to have a negative impact on pregnancy course and outcome. The unfavorable psychosocial situation of addicted women predispose for poor processing of the physiological and psychological demands of pregnancy. Thus the aim of our study was to investigate the psychological mood state of opiate addicts during pregnancy and postpartum in comparison to healthy women. In a case-controlled, prospective, longitudinal study, nine pregnant opiate addicts and nine healthy pregnant women matched by age, level of education and gestational age at birth were interviewed in the third trimester of pregnancy and postpartum. Standardized questionnaires and inventories for assessment of the general psychopathology and emotional state, the perceived self-efficacy expectancy, the psychosocial adaptation to pregnancy and the fear of delivery, respectively were applied. Addicted women achieved significantly higher scores in the test assessing general psychopathology and emotional state before delivery compared to abstinent women. Interestingly this difference was unverifiable postpartum. This study reaffirms the presumption of a disadvantageous psychological condition in pregnant opiate addicts in comparison to healthy pregnant women for the first time in a prospective case-control study design.

Details for the construction of a novel, inexpensive device for the electrochemical generation of metallic emitters for field desorption mass spectrometry are described. Use of the device for the generation of cobalt and nickel emitters is demonstrated.