DNA methylation profile of a rural cohort exposed to early-adversity and malnutrition: An exploratory analysis.

Barker's hypothesis affirms that undernourishment in early-life induces metabolic reprogramming that compromises organism functions later in life, leading to age-related diseases. We are exposed to environmental and social conditions that impact our life trajectories, leading to ageing phenotypes as we grow. Epigenetic mechanisms constitute the link between both external stimuli and genetic programming. Studies have focused on describing the effect of early adverse events such as trauma, famines, or childhood labor on epigenetic markers in adulthood and the elderly. However, we lack information on epigenetic programming in individuals born in rural communities from underdeveloped countries, exposed to negative influences during fetal and postnatal development, particularly chronic malnutrition. Hence, in this exploratory analysis, we characterize the epigenome of individuals and some parents from Tlaltizapan (a rural community in Mexico originally studied almost 50 years ago) and collect anthropometric data on growth and development, as well on the living conditions of the families. Our results help build a biological hypothesis indicating that most of the epigenetic age measures of the subjects are significantly different among them. Interestingly, the most affected methylated regions correspond to pathways involved in neuronal system development, reproductive behaviour, learning and memory regulation.

Promising biomarkers of human aging: In search of a multi-omics panel to understand the aging process from a multidimensional perspective.

The aging process has been linked to the occurrence of chronic diseases and functional impairments, including cancer, sarcopenia, frailty, metabolic, cardiovascular, and neurodegenerative diseases. Nonetheless, aging is highly variable and heterogeneous and represents a challenge for its characterization. In this sense, intrinsic capacity (IC) stands as a novel perspective by the World Health Organization, which integrates the individual wellbeing, environment, and risk factors to understand aging. However, there is a lack of quantitative and qualitative attributes to define it objectively. Therefore, in this review we attempt to summarize the most relevant and promising biomarkers described in clinical studies at date over different molecular levels, including epigenomics, transcriptomics, proteomics, metabolomics, and the microbiome. To aid gerontologists, geriatricians, and biomedical researchers to understand the aging process through the IC. Aging biomarkers reflect the physiological state of individuals and the underlying mechanisms related to homeostatic changes throughout an individual lifespan; they demonstrated that aging could be measured independently of time (that may explain its heterogeneity) and to be helpful to predict age-related syndromes and mortality. In summary, we highlight the areas of opportunity and gaps of knowledge that must be addressed to fully integrate biomedical findings into clinically useful tools and interventions.

Systems biology and network pharmacology of frailty reveal novel epigenetic targets and mechanisms.

Frailty is an age-associated condition, characterized by an inappropriate response to stress that results in a higher frequency of adverse outcomes (e.g., mortality, institutionalization and disability). Some light has been shed over its genetic background, but this is still a matter of debate. In the present study, we used network biology to analyze the interactome of frailty-related genes at different levels to relate them with pathways, clinical deficits and drugs with potential therapeutic implications. Significant pathways involved in frailty: apoptosis, proteolysis, muscle proliferation, and inflammation; genes as FN1, APP, CREBBP, EGFR playing a role as hubs and bottlenecks in the interactome network and epigenetic factors as HIST1H3 cluster and miR200 family were also involved. When connecting clinical deficits and genes, we identified five clusters that give insights into the biology of frailty: cancer, glucocorticoid receptor, TNF-α, myostatin, angiotensin converter enzyme, ApoE, interleukine-12 and -18. Finally, when performing network pharmacology analysis of the target nodes, some compounds were identified as potentially therapeutic (e.g., epigallocatechin gallate and antirheumatic agents); while some other substances appeared to be toxicants that may be involved in the development of this condition.

The RNA world of human ageing.

Ageing is one of the most complex processes in nature; how could we prevent the associated biological changes and chronic diseases that string along with this process, is a challenge in healthcare around the world. Recent advances in next-generation sequencing have reached a stage where it is possible to know from a specific tissue the most abundant transcripts, alternative splicing process and, non-coding RNA molecules (microRNA's, long non-coding RNA's, and circular RNAs). Moreover, our knowledge of several biological processes related to ageing such as senescence and autophagy have dramatically increased in the last years. In the present review, we attempt to summarise the latest scientific advances from the most critical studies performed in human clinical samples, specific to the RNA studies about ageing. Overall, human transcriptomics research indicates that although there are common alterations of the regular expression patterns of the energetic and oxidative metabolism, extracellular matrix regulation and inflammation pathways, ageing seems to be gender and tissue-specific in general. Additionally, there is an age-related implication in several numbers of impaired events on the normal alternative splicing process. On the other hand, there is a direct relation of several non-coding RNA molecules with age-related changes which indicates its possible use as biomarkers for diagnostics and therapeutically purposes. Together, these findings highlight the importance to continue focusing research on RNA studies to improve our knowledge in the pathophysiology of age-related diseases.

Risk assessment of Soulatrolide and Mammea (A/BA+A/BB) coumarins from Calophyllum brasiliense by a toxicogenomic and toxicological approach.

Calophyllum brasiliense (Calophyllaceae) is a tropical rain forest tree distributed in Central and South America. It is an important source of tetracyclic dipyrano coumarins (Soulatrolide) and Mammea type coumarins. Soulatrolide is a potent inhibitor of HIV-1 reverse transcriptase and displays activity against Mycobacterium tuberculosis. Meanwhile, Mammea A/BA and A/BB, pure or as a mixture, are highly active against several human leukemia cell lines, Trypanosoma cruzi and Leishmania amazonensis. Nevertheless, there are few studies evaluating their safety profile. In the present work we performed toxicogenomic and toxicological analysis for both type of compounds. Soulatrolide, and the Mammea A/BA + A/BB mixture (2.1) were slightly toxic accordingly to Lorke assay classification (DL50 > 3000 mg/kg). After a short-term administration (100 mg/kg/daily, orally, 1 week) liver toxicogenomic analysis revealed 46 up and 72 downregulated genes for Mammea coumarins, and 665 up and 1077 downregulated genes for Soulatrolide. Gene enrichment analysis identified transcripts involved in drug metabolism for both compounds. In addition, network analysis through protein-protein interactions, tissue evaluation by TUNEL assay, and histological examination revealed no tissue damage on liver, kidney and spleen after treatments. Our results indicate that both type of coumarins displayed a safety profile, supporting their use in further preclinical studies to determine its therapeutic potential.

Toxicogenomic analysis of pharmacological active coumarins isolated from Calophyllum brasiliense.

Calophyllum brasiliense (Calophyllaceae) is a tropical rain forest tree, mainly distributed in South and Central America. It is an important source of bioactive natural products like, for instance soulatrolide, and mammea type coumarins. Soulatrolide is a tetracyclic dipyranocoumarins and a potent inhibitor of HIV-1 reverse transcriptase and Mycobacterium tuberculosis. Mammea A/BA and A/BB coumarins, pure or as a mixture, are highly active against several leukemia cell lines, Trypanosoma cruzi and Leishmania amazonensis. In the present work, a toxicogenomic analysis of Soulatrolide and Mammea A/BA + A/BB (3:1) mixture was performed in order to validate the toxicological potential of this type of compounds. Soulatrolide or mixture of mammea A/BA + A/BB (3:1) was administered orally to male mice (CD-1) at dose of 100 mg/kg/daily, for 1 week. After this time, mice were sacrificed, and RNA extracted from the liver of treated animals. Transcriptomic analysis was performed using Affymetrix Mouse Gene 1.0 ST Array. Robust microarray analysis (RMA) and two way ANOVA test revealed for mammea mixture treatment 46 genes upregulated and 72 downregulated genes; meanwhile, for soulatrolide 665 were upregulated and 1077 downregulated genes. Enrichment analysis for such genes revealed that in both type of treatments genetic expression were mainly involved in drug metabolism. Overall results indicate a safety profile. The microarray data complies with MIAME guidelines and are deposited in GEO under accession number GSE72755.