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H2020 European Research Council, Grant/Award Number: ERC-2014-AdG/669622; Fundación Científica Asociación Española Contra el Cáncer, Grant/Award Number: PROYE18061FERN; Ministerio de Ciencia e Innovación, Grant/Award Number: SAF2013-48256-R; the Asturias Regionla Government (PCTI) co-funding 2018- 2022/FEDER (IDI/2018/146), the Health Institute Carlos III (Plan Nacional de I+D+I) co-funding FEDER (PI18/01527)...

Aging‐related decreases in cardiac and skeletal muscle function are strongly associated with various comorbidities. Elamipretide (ELAM), a novel mitochondria‐targeted peptide, has demonstrated broad therapeutic efficacy in ameliorating disease conditions associated with mitochondrial dysfunction across both clinical and pre‐clinical models. Herein, we investigated the impact of 8‐week ELAM treatment on pre‐ and post‐measures of C57BL/6J mice frailty, skeletal muscle, and cardiac muscle function, coupled with post‐treatment assessments of biological age and affected molecular pathways. We found that health status, as measured by frailty index, cardiac strain, diastolic function, and skeletal muscle force, is significantly diminished with age, with skeletal muscle force changing in a sex‐dependent manner. Conversely, ELAM mitigated frailty accumulation and was able to partially reverse these declines, as evidenced by treatment‐induced increases in cardiac strain and muscle fatigue resistance. Despite these improvements, we did not detect statistically significant changes in gene expression or DNA methylation profiles indicative of molecular reorganization or reduced biological age in most ELAM‐treated groups. However, pathway analyses revealed that ELAM treatment showed pro‐longevity shifts in gene expression, such as upregulation of genes involved in fatty acid metabolism, mitochondrial translation, and oxidative phosphorylation, and downregulation of inflammation. Together, these results indicate that ELAM treatment is effective at mitigating signs of sarcopenia and cardiac dysfunction in an aging mouse model, but that these functional improvements occur independently of detectable changes in epigenetic and transcriptomic age. Thus, some age‐related changes in function may be uncoupled from changes in molecular biological age. The effects of the mitochondria‐targeted peptide therapeutic elamipretide on age‐related muscle function were compared with its effects on molecular biomarkers of aging. It was found that elamipretide treatment partially reverses age‐related cardiac dysfunction and skeletal muscle weakness in mice without significantly affecting muscle epigenetic or transcriptomic age.

Background Productive lifespan is a critical economic trait for both dual-purpose and dairy cows, as it determines lifetime milk production. Xinjiang Brown cattle, a dual-purpose breed widely raised in China's Xinjiang region, have a population of nearly two million and play a vital role in the local economy. However, the molecular mechanisms influencing aging and productive lifespan in Xinjiang Brown cattle remain largely unknown. In this study, we collected white blood cell (leukocyte) transcriptome data from 66 Xinjiang Brown cattle, aged 31 to 160 months, to investigate the dynamic changes in their gene expression profiles across different ages and identify genes potentially influencing their aging process. Results A total of 1140 genes were identified as exhibiting a linear change in expression with age, while 697 genes showed non-linear changes, mainly enriched in immune and disease-related pathways. Linear genes were selected using elastic network regression to construct a transcriptomic clock and estimate the biological age of each sample. Individuals with older biological ages trend to highly express aging-related genes such as S100A8 , while individuals with younger biological ages will highly express anti-aging genes such as BLVRB . We identified PGA5 , LOC789748 , ENSBTAG00000048555 , and ENSBTAG00000050566 as crucial targets for anti-aging interventions, which exhibit reduced expression in biologically younger individuals and increased expression in biologically older ones. Performing sliding window analysis on non-linear genes, we elucidated changes in the expression of candidate genes at the age of 67 months, which are predominantly associated with endocrine pathways, such as GnRH and insulin secretion. Conclusions This study characterized the age-related gene expression changes in Xinjiang Brown cattle and developed a transcriptomic clock specifically for calculating their biological age. It provides a valuable tool for assessing the aging status of Xinjiang Brown cattle and identifies key genes that may influence their aging process.

Aging is the primary risk factor for most neurodegenerative diseases, yet the cell‐type‐specific progression of brain aging remains poorly understood. Here, human cell‐type‐specific transcriptomic aging clocks are developed using high‐quality single‐nucleus RNA sequencing data from post mortem human prefrontal cortex tissue of 31 donors aged 18–94 years, encompassing 73,941 high‐quality nuclei. Distinct transcriptomic changes are observed across major cell types, including upregulation of inflammatory response genes in microglia from older samples. Aging clocks trained on each major cell type accurately predict chronological age, capture biologically relevant pathways, and remain robust in independent single‐nucleus RNA‐sequencing datasets, underscoring their broad applicability. Notably, cell‐type‐specific age acceleration is identified in individuals with Alzheimer's disease and schizophrenia, suggesting altered aging trajectories in these conditions. These findings demonstrate the feasibility of cell‐type‐specific transcriptomic clocks to measure biological aging in the human brain and highlight potential mechanisms of selective vulnerability in neurodegenerative diseases. Muralidharan and colleagues develop cell‐type‐specific transcriptomic aging clocks using single‐nucleus RNA sequencing of human post mortem prefrontal cortex samples. These clocks accurately predict age and identify distinct aging trajectories in specific brain cell types. Their method also detects accelerated aging in Alzheimer's disease and schizophrenia, offering insight into differential brain aging across health and disease.

Biological aging in people with HIV (PWH) with prolonged successful antiretroviral therapy (ART) is convoluted and poorly defined. Here, we aimed to investigate the transcriptomics age estimator (TAE) in a cohort of 178 PWH on prolonged successful ART with immune reconstitution and viral suppression from the Copenhagen Comorbidity (COCOMO) cohort. We also used 143 clinical, demographical, and lifestyle factors to identify the confounders potentially responsible or associated with age acceleration. Among the PWH, 43% had an accelerated aging process (AAP), and 21% had decelerated aging process (DAP). DAP is linked with older age, European ancestry, and higher use of tenofovir disoproxil/alafenamide fumarate. A directionally class‐based gene set enrichment analysis identified the upregulation of inflammatory pathways (e.g., cytokine and Retinoic acid‐inducible gene I (RIG‐I)‐like receptor signaling pathways) and immune response like T‐cell receptor signaling, antigen processing, and presentation in AAP and the downregulation of metabolic processes like oxidative phosphorylation, pyruvate metabolism.

The circadian clock and feeding rhythms are both important regulators of rhythmic gene expression in the liver. To further dissect the respective contributions of feeding and the clock, we analyzed differential rhythmicity of liver tissue samples across several conditions. We developed a statistical method tailored to compare rhythmic liver messenger RNA (mRNA) expression in mouse knockout models of multiple clock genes, as well as PARbZip output transcription factors (Hlf/Dbp/Tef). Mice were exposed to ad libitum or night-restricted feeding under regular light–dark cycles. During ad libitum feeding, genetic ablation of the core clock attenuated rhythmic-feeding patterns, which could be restored by the night-restricted feeding regimen. High-amplitude mRNA expression rhythms in wild-type livers were driven by the circadian clock, but rhythmic feeding also contributed to rhythmic gene expression, albeit with significantly lower amplitudes. We observed that Bmal1 and Cry1/2 knockouts differed in their residual rhythmic gene expression. Differences in mean expression levels between wild types and knockouts correlated with rhythmic gene expression in wild type. Surprisingly, in PARbZip knockout mice, the mean expression levels of PARbZip targets were more strongly impacted than their rhythms, potentially due to the rhythmic activity of the D-box–repressor NFIL3. Genes that lost rhythmicity in PARbZip knockouts were identified to be indirect targets. Our findings provide insights into the diurnal transcriptome in mouse liver as we identified the differential contributions of several core clock regulators. In addition, we gained more insights on the specific effects of the feeding–fasting cycle.

High temperature stress is one of the most severe forms of abiotic stress in alfalfa. With the intensification of climate change, the frequency of high temperature stress will further increase in the future, which will bring challenges to the growth and development of alfalfa. Therefore, untargeted metabolomic and RNA-Seq profiling were implemented to unravel the possible alteration in alfalfa seedlings subjected to different temperature stress (25 ℃, 30 ℃, 35 ℃, 40 ℃) in this study. Results revealed that High temperature stress significantly altered some pivotal transcripts and metabolites. The number of differentially expressed genes (DEGs) markedly up and down-regulated was 1876 and 1524 in T30_vs_CK, 2, 815 and 2667 in T35_vs_CK, and 2115 and 2, 226 in T40_vs_CK, respectively. The number for significantly up-regulated and down-regulated differential metabolites was 173 and 73 in T30_vs_CK, 188 and 57 in T35_vs_CK, and 220 and 66 in T40_vs_CK, respectively. It is worth noting that metabolomics and transcriptomics co-analysis characterized enriched in plant hormone signal transduction (ko04705), glyoxylate and dicarboxylate metabolism (ko00630), from which some differentially expressed genes and differential metabolites participated. In particular, the content of hormone changed significantly under T40 stress, suggesting that maintaining normal hormone synthesis and metabolism may be an important way to improve the HTS tolerance of alfalfa. The qRT-PCR further showed that the expression pattern was similar to the expression abundance in the transcriptome. This study provides a practical and in-depth perspective from transcriptomics and metabolomics in investigating the effects conferred by temperature on plant growth and development, which provided the theoretical basis for breeding heat-resistant alfalfa.

• The circadian clock plays essential roles in diverse plant biological processes, such as flowering, phytohormone biosynthesis and abiotic stress responses. The manner in which circadian clock genes regulate drought stress responses in model plants has been well established, but comparatively little is known in crop species, such as soybean, a major global crop. This paper reports that the core clock components GmLHYs, the orthologues of CCA1/LHY in Arabidopsis, negatively control drought tolerance in soybean. • The expressions of four GmLHYs were all induced by drought, and the quadruple mutants of GmLHYs demonstrated significantly improved drought tolerance. Transcriptome profiling suggested that the abscisic acid (ABA) signaling pathway is regulated by GmLHYs to respond to drought tolerance. • Genetic dissections showed that two homologous pairs of LHY1a and LHY1b redundantly control the drought response. Functional characterization of LHY1a and LHY1b in Arabidopsis and soybean further supported the notion that GmLHYs can maintain cellular homeostasis through the ABA signaling pathway under drought stress. • This study improves our understanding of the underlying molecular mechanisms on soybean drought tolerance. Furthermore, the two homologues of LHY1a and LHY1b provide alternative targets for genome editing to rapidly generate mutant alleles in elite soybean cultivars to enhance their drought tolerance.

The circadian clock is a cell-autonomous transcription–translation feedback mechanism that anticipates and adapts physiology and behavior to different phases of the day. A variety of factors including hormones, temperature, food-intake, and exercise can act on tissue-specific peripheral clocks to alter the expression of genes that influence metabolism, all in a time-of-day dependent manner. The aim of this study was to elucidate the effects of exercise timing on adipose tissue metabolism. We performed RNA sequencing on inguinal adipose tissue of mice immediately following maximal exercise or sham treatment at the early rest or early active phase. Only during the early active phase did exercise elicit an immediate increase in serum nonesterified fatty acids. Furthermore, early active phase exercise increased expression of markers of thermogenesis and mitochondrial proliferation in inguinal adipose tissue. In vitro, synchronized 3T3-L1 adipocytes showed a timing-dependent difference in Adrb2 expression, as well as a greater lipolytic activity. Thus, the response of adipose tissue to exercise is time-of-day sensitive and may be partly driven by the circadian clock. To determine the influence of feeding state on the time-of-day response to exercise, we replicated the experiment in 10-h-fasted early rest phase mice to mimic the early active phase metabolic status. A 10-h fast led to a similar lipolytic response as observed after active phase exercise but did not replicate the transcriptomic response, suggesting that the observed changes in gene expression are not driven by feeding status. In conclusion, acute exercise elicits timing-specific effects on adipose tissue to maintain metabolic homeostasis.

Biological clocks have been developed at different molecular levels and were found to be more advanced in the presence of somatic illness and mental disorders. However, it is unclear whether different biological clocks reflect similar aging processes and determinants. In ~3000 subjects, we examined whether five biological clocks (telomere length, epigenetic, transcriptomic, proteomic, and metabolomic clocks) were interrelated and associated to somatic and mental health determinants. Correlations between biological aging indicators were small (all r < 0.2), indicating little overlap. The most consistent associations of advanced biological aging were found for male sex, higher body mass index (BMI), metabolic syndrome, smoking, and depression. As compared to the individual clocks, a composite index of all five clocks showed most pronounced associations with health determinants. The large effect sizes of the composite index and the low correlation between biological aging indicators suggest that one’s biological age is best reflected by combining aging measures from multiple cellular levels.