This book chapter will focus on modifications to chromatin itself, how chromatin modifications are regulated, and how these modifications are deciphered by the cell to impact aging. In this chapter, we will review how chromatin modifications change with age, examine how chromatin-modifying enzymes have been shown to regulate aging and healthspan, discuss how some of these epigenetic changes are triggered and how they can regulate the lifespan of the individual and its naïve descendants, and speculate on future directions for the field.

Twenty years ago, histone lysine demethylases (KDMs) were discovered. Since their discovery, they have been increasingly studied and shown to be important across species, development, and diseases. Considerable advances have been made toward understanding their (1) enzymology, (2) role as critical components of biological complexes, (3) role in normal cellular processes and functions, (4) implications in pathological conditions, and (5) therapeutic potential. This Review covers these key relationships related to the KDM field with the awareness that numerous laboratories have contributed to this field. The current knowledge coupled with future insights will shape our understanding about cell function, development, and disease onset and progression, which will allow for novel biomarkers to be identified and for optimal therapeutic options to be developed for KDM-related diseases in the years ahead.

Trauma can impact individuals within a generation (intragenerational) and future generations (transgenerational) through a complex interplay of biological and environmental factors. This review explores the epigenetic mechanisms that have been correlated with the effects of trauma across generations, including DNA methylation, histone modifications, and non-coding RNAs. These mechanisms can regulate the expression of stress-related genes (such as the glucocorticoid receptor (NR3C1) and FK506 binding protein 5 (FKBP5) gene), linking trauma to biological pathways that may affect long-term stress regulation and health outcomes. Although research using model organisms has elucidated potential epigenetic mechanisms underlying the intergenerational effects of trauma, applying these findings to human populations remains challenging due to confounding variables, methodological limitations, and ethical considerations. This complexity is compounded by difficulties in establishing causality and in disentangling epigenetic influences from shared environmental factors. Emerging therapies, such as psychedelic-assisted treatments and mind-body interventions, offer promising avenues to address both the psychological and potential epigenetic aspects of trauma. However, translating these findings into effective interventions will require interdisciplinary methods and culturally sensitive approaches. Enriched environments, cultural reconnection, and psychosocial interventions have shown the potential to mitigate trauma's impacts within and across generations. By integrating biological, social, and cultural perspectives, this review highlights the critical importance of interdisciplinary frameworks in breaking cycles of trauma, fostering resilience, and advancing comprehensive healing across generations.

Mesenchymal stem cell (MSC) holds immense potential as candidates for cell therapy in the treatment of tendon injuries due to their remarkable ability for multiple cell differentiation. However, the proliferative and differentiation capacity of MSCs has been limited by cellular senescence during the process of expanding culture. Therefore, in this study, our aim was to maintain the beneficial properties of MSCs. We found that SETD7, a histone methyltransferase, was upregulated during ex vivo expansion of human adipose-derived mesenchymal stem cells (hAD-MSCs). Pharmacological inhibition of SETD7 with PFI-2 in hAD-MSCs cultures delayed their senescence, as evident by the diminished expression of senescent-associated genes and the maintenance of their proliferation and differentiation capacity. Upon transplantation, cell sheets derived from hAD-MSCs expanded with PFI-2 were better able to accelerate tendon repair. Therefore, the present findings reveal that SETD7 is an important target to improve the expansion of hAD-MSCs by delaying senescence, which is importance for the development of efficient stem cell-based therapeutic approaches.

Over 400 articles on the pathophysiology of brain aging, neuroaging, and neurodegeneration were reviewed, with a focus on epigenetic mechanisms and numerous non-coding RNAs. In particular, this review the accent is on microRNAs, the discovery of whose pivotal role in gene regulation was recognized by the 2024 Nobel Prize in Physiology or Medicine. Aging is not a gradual process that can be easily modeled and described. Instead, multiple temporal processes occur during aging, and they can lead to mosaic changes that are not uniform in pace. The rate of change depends on a combination of external and internal factors and can be boosted in accelerated aging. The rate can decrease in decelerated aging due to individual structural and functional reserves created by cognitive, physical training, or pharmacological interventions. Neuroaging can be caused by genetic changes, epigenetic modifications, oxidative stress, inflammation, lifestyle, and environmental factors, which are especially noticeable in space environments where adaptive changes can trigger aging-like processes. Numerous candidate molecular biomarkers specific to neuroaging need to be validated to develop diagnostics and countermeasures.

Epigenetic modifications, including posttranslational modifications of histones, are closely linked to transcriptional regulation. Trimethylated H3 lysine 4 (H3K4me3) is one of the most studied histone modifications owing to its enrichment at the start sites of transcription and its association with gene expression and processes determining cell fate, development, and disease. In this review, we focus on recent studies that have yielded insights into how levels and patterns of H3K4me3 are regulated, how H3K4me3 contributes to the regulation of specific phases of transcription such as RNA polymerase II initiation, pause-release, heterogeneity, and consistency. The conclusion from these studies is that H3K4me3 by itself regulates gene expression and its precise regulation is essential for normal development and preventing disease.

The burgeoning field of environmental epigenetics has revealed the malleability of the epigenome and uncovered numerous instances of its sensitivity to environmental influences; however, pinpointing specific mechanisms that tie together environmental triggers, epigenetic pathways, and organismal responses has proven difficult. This article describes how Caenorhabditis elegans can fill this gap, serving as a useful model for the discovery of molecular epigenetic mechanisms that are conserved in humans.

Recent results show that environmental stressors such as methylmercury, arsenite, starvation, heat, bacterial infection, and mitochondrial inhibitors can all have profound effects on the epigenome, with some insults showing epigenetic and organismal effects for multiple generations. In some cases, the pathways connecting the stressor to epigenetic pathways and organismal responses have been elucidated. For example, a small RNA from the bacterial pathogen Pseudomonas aeruginosa induces transgenerational learned avoidance by activating the RNA interference PIWI-interacting RNA pathways across generations to downregulate, via Cer1 retrotransposon particles and histone methylation, maco-1, a gene that functions in sensory neurons to regulate chemotaxis. Mitochondrial inhibitors seem to have a profound effect on both the DNA methylation mark 6mA and histone methylation, and may act within mitochondrial DNA (mtDNA) to regulate mitochondrial stress response genes. Transgenerational transcriptional responses to alcohol have also been worked out at the single-nucleus resolution in C. elegans, demonstrating its utility when combined with modern sequencing technologies. These recent studies highlight how C. elegans can serve as a bridge between biochemical in vitro experiments and the more associative findings of epidemiological studies in humans to unveil possible mechanisms of environmental influence on the epigenome. The nematode is particularly well-suited to transgenerational experiments thanks to its rapid generation time and ability to self-fertilize. These studies have revealed connections between the various epigenetic mechanisms, and so studies in C. elegans that take advantage of recent advancements in sequencing technologies, including single-cell techniques, to gain unprecedented resolution of the whole epigenome across development and generations will be critical.

Hematopoiesis within the bone marrow (BM) is a complex and tightly regulated process predominantly influenced by immune factors. Aging, diabetes, and obesity are significant contributors to BM niche damage, which can alter hematopoiesis and lead to the development of clonal hematopoiesis of intermediate potential (CHIP). Genetic/epigenetic alterations during aging could influence BM niche reorganization for hematopoiesis or clonal hematopoiesis. CHIP is driven by mutations in genes such as Tet2, Dnmt3a, Asxl1, and Jak2, which are associated with age-related hematological malignancies.

This literature review aims to provide an updated exploration of the functional aspects of BM niche cells within the hematopoietic microenvironment in the context of age-related hematological malignancies. The review specifically focuses on how immunological stressors modulate different signaling pathways that impact hematopoiesis.

An extensive review of recent studies was conducted, examining the roles of various BM niche cells in hematopoietic stem cell (HSC) trafficking and the development of age-related hematological malignancies. Emphasis was placed on understanding the influence of immunological stressors on these processes.

Recent findings reveal a significant microheterogeneity and temporal stochasticity of niche cells across the BM during hematopoiesis. These studies demonstrate that niche cells, including mesenchymal stem cells, osteoblasts, and endothelial cells, exhibit dynamic interactions with HSCs, significantly influenced by the BM microenvironment as the age increases. Immunosurveillance plays a crucial role in maintaining hematopoietic homeostasis, with alterations in immune signaling pathways contributing to the onset of hematological malignancies. Novel insights into the interaction between niche cells and HSCs under stress/aging conditions highlight the importance of niche plasticity and adaptability.

The involvement of age-induced genetic/epigenetic alterations in BM niche cells and immunological stressors in hematopoiesis is crucial for understanding the development of age-related hematological malignancies. This comprehensive review provides new insights into the complex interplay between niche cells and HSCs, emphasizing the potential for novel therapeutic approaches that target niche cell functionality and resilience to improve hematopoietic outcomes in the context of aging and metabolic disorders.

This review introduces novel concepts regarding the plasticity and adaptability of BM niche cells in response to immunological stressors and epigenetics. It proposes that targeted therapeutic strategies aimed at enhancing niche cell resilience could mitigate the adverse effects of aging, diabetes, and obesity on hematopoiesis and clonal hematopoiesis. Additionally, the review suggests that understanding the precise temporal and spatial dynamics of niche-HSC interactions and epigenetics influence may lead to innovative treatments for age-related hematological malignancies.

Variations of individual lifespans within genetically identical populations in homogenous environments are remarkable, with the cause largely unknown. Here, we show the expression dynamic of the Caenorhabditis elegans fatty acid elongase ELO-6 during aging predicts individual longevity in isogenic populations. elo-6 expression is reduced with age. ELO-6 expression level exhibits obvious variation between individuals in mid-aged worms and is positively correlated with lifespan and health span. Interventions that prolong longevity enhance ELO-6 expression stability during aging, indicating ELO-6 is also a populational lifespan predictor. Differentially expressed genes between short-lived and long-lived isogenic worms regulate lifespan and are enriched for PQM-1 binding sites. pqm-1 in young to mid-aged adults causes individual ELO-6 expression heterogeneity and restricts health span and life span. Thus, our study identifies ELO-6 as a predictor of individual and populational lifespan and reveals the role of pqm-1 in causing individual health span variation in the mid-aged C. elegans.

Vitamin B12 is an essential nutritional co-factor for the folate and methionine cycles, which together constitute one-carbon metabolism. Here, we show that dietary uptake of vitamin B12 modulates cell fate decisions controlled by the conserved RAS/MAPK signaling pathway in C. elegans. A bacterial diet rich in vitamin B12 increases vulval induction, germ cell apoptosis and oocyte differentiation. These effects are mediated by different one-carbon metabolites in a tissue-specific manner. Vitamin B12 enhances via the choline/phosphatidylcholine metabolism vulval induction by down-regulating fat biosynthesis genes and increasing H3K4 tri-methylation, which results in increased expression of RAS/MAPK target genes. Furthermore, the nucleoside metabolism and H3K4 tri-methylation positively regulate germ cell apoptosis and oocyte production. Using mammalian cells carrying different activated KRAS and BRAF alleles, we show that the effects of methionine on RAS/MAPK-regulated phenotype are conserved in mammals. Our findings suggest that the vitamin B12-dependent one-carbon metabolism is a limiting factor for diverse RAS/MAPK-induced cellular responses.

Loss of protein homeostasis (proteostasis) is a common hallmark of aging and age-associated diseases. Considered as the guardian of proteostasis, the proteostasis network (PN) acts to preserve the functionality of proteins during their lifetime. However, its activity declines with age, leading to disease manifestation. While reactive oxygen species (ROS) were traditionally considered culprits in this process, recent research challenges this view. While harmful at high concentrations, moderate ROS levels protect the cell against age-mediated onset of proteotoxicity by activating molecular chaperones, stress response pathways, and autophagy. This review explores the nuanced roles of ROS in proteostasis and discusses the most recent findings regarding the redox regulation of the PN and its potential in extending healthspan and delaying age-related pathologies.

The ability of mitochondria to coordinate stress responses across tissues is critical for health. In C. elegans, neurons experiencing mitochondrial stress elicit an inter-tissue signaling pathway through the release of mitokine signals, such as serotonin or the Wnt ligand EGL-20, which activate the mitochondrial unfolded protein response (UPRMT) in the periphery to promote organismal health and lifespan. We find that germline mitochondria play a surprising role in neuron-to-periphery UPRMT signaling. Specifically, we find that germline mitochondria signal downstream of neuronal mitokines, Wnt and serotonin, and upstream of lipid metabolic pathways in the periphery to regulate UPRMT activation. We also find that the germline tissue itself is essential for UPRMT signaling. We propose that the germline has a central signaling role in coordinating mitochondrial stress responses across tissues, and germline mitochondria play a defining role in this coordination because of their inherent roles in germline integrity and inter-tissue signaling.

Body size is a fundamental trait that drives multiple evolutionary and ecological patterns. Caenorhabditis inopinata is a fig-associated nematode that is exceptionally large relative to other members of the genus, including Caenorhabditis elegans. We previously showed that C. inopinata is large primarily due to postembryonic cell size expansion that occurs during the larval-to-adult transition. Here, we describe gene expression patterns in C. elegans and C. inopinata throughout this developmental period to understand the transcriptional basis of body size change. We performed RNA-seq in both species across the L3, L4, and adult stages. Most genes are differentially expressed across all developmental stages, consistent with C. inopinata's divergent ecology and morphology. We also used a model comparison approach to identify orthologues with divergent dynamics across this developmental period between the 2 species. This included genes connected to neurons, behavior, stress response, developmental timing, and small RNA/chromatin regulation. Multiple hypodermal collagens were also observed to harbor divergent developmental dynamics across this period, and genes important for molting and body morphology were also detected. Genes associated with transforming growth factor β signaling revealed idiosyncratic and unexpected transcriptional patterns given their role in body size regulation in C. elegans. This widespread transcriptional divergence between these species is unexpected and maybe a signature of the ecological and morphological divergence of C. inopinata. Alternatively, transcriptional turnover may be the rule in the Caenorhabditis genus, indicative of widespread developmental system drift among species. This work lays the foundation for future functional genetic studies interrogating the bases of body size evolution in this group.

Ribosome heterogeneity has emerged as an important regulatory control feature for determining which proteins are synthesized, however, the influence of age on ribosome heterogeneity is not fully understood. Whether mRNA transcripts are selectively translated in young versus old cells and whether dysregulation of this process drives organismal aging is unknown. Here we examined the role of ribosomal RNA (rRNA) methylation in maintaining appropriate translation as organisms age. In a directed RNAi screen, we identified the 18S rRNA N6'-dimethyl adenosine (m6,2A) methyltransferase, dimt-1, as a regulator of C. elegans lifespan and stress resistance. Lifespan extension induced by dimt-1 deficiency required a functional germline and was dependent on the known regulator of protein translation, the Rag GTPase, raga-1, which links amino acid sensing to the mechanistic target of rapamycin complex (mTORC)1. Using an auxin-inducible degron tagged version of dimt-1, we demonstrate that DIMT-1 functions in the germline after mid-life to regulate lifespan. We further found that knock-down of dimt-1 leads to selective translation of transcripts important for stress resistance and lifespan regulation in the C. elegans germline in mid-life including the cytochrome P450 daf-9, which synthesizes a steroid that signals from the germline to the soma to regulate lifespan. We found that dimt-1 induced lifespan extension was dependent on the daf-9 signaling pathway. This finding reveals a new layer of proteome dysfunction, beyond protein synthesis and degradation, as an important regulator of aging. Our findings highlight a new role for ribosome heterogeneity, and specific rRNA modifications, in maintaining appropriate translation later in life to promote healthy aging.

Histone H3/H4 chaperone anti-silencing function 1 (ASF1) is a conserved factor mediating nucleosomal assembly and disassembly, playing crucial roles in processes such as replication, transcription, and DNA repair. Nevertheless, its involvement in aging has remained unclear. Here, we utilized the model organism Caenorhabditis elegans to demonstrate that the loss of UNC-85, the homolog of ASF1, leads to a shortened lifespan in a multicellular organism. Furthermore, we show that UNC-85 is required for epigenome-mediated longevity, as knockdown of the histone H3 lysine K4 methyltransferase ash-2 does not extend the lifespan of unc-85 mutants. In this context, we found that the longevity-promoting ash-2 RNA interference enhances UNC-85 activity by increasing its nuclear localization. Finally, our data indicate that the loss of UNC-85 increases the activity of one-carbon metabolism, and that downregulation of the one-carbon metabolism component dao-3/MTHFD2 partially rescues the short lifespan of unc-85 mutants. Together, these findings reveal UNC-85/ASF1 as a modulator of the central metabolic pathway and a factor regulating a pro-longevity response, thus shedding light on a mechanism of how nucleosomal maintenance associates with aging.

This review article critically examines the pivotal role of chromatin organization in gene regulation, cellular differentiation, disease progression and aging. It explores the dynamic between the euchromatin and heterochromatin, coded by a complex array of histone modifications that orchestrate essential cellular processes. We discuss the pathological impacts of chromatin state misregulation, particularly in cancer and accelerated aging conditions such as progeroid syndromes, and highlight the innovative role of epigenetic therapies and artificial intelligence (AI) in comprehending and harnessing the histone code toward personalized medicine. In the context of aging, this review explores the use of AI and advanced machine learning (ML) algorithms to parse vast biological datasets, leading to the development of predictive models for epigenetic modifications and providing a framework for understanding complex regulatory mechanisms, such as those governing cell identity genes. It supports innovative platforms like CEFCIG for high-accuracy predictions and tools like GridGO for tailored ChIP-Seq analysis, which are vital for deciphering the epigenetic landscape. The review also casts a vision on the prospects of AI and ML in oncology, particularly in the personalization of cancer therapy, including early diagnostics and treatment optimization for diseases like head and neck and colorectal cancers by harnessing computational methods, AI advancements and integrated clinical data for a transformative impact on healthcare outcomes.

Ribosome heterogeneity has emerged as an important regulatory control feature for determining which proteins are synthesized, however, the influence of age on ribosome heterogeneity is not fully understood. Whether mRNA transcripts are selectively translated in young versus old cells and whether dysregulation of this process drives organismal aging is unknown. Here we examined the role of ribosomal RNA (rRNA) methylation in maintaining appropriate translation as organisms age. In a directed RNAi screen, we identified the 18S rRNA N6'-dimethyl adenosine (m6,2A) methyltransferase, dimt-1, as a regulator of C. elegans lifespan and stress resistance. Lifespan extension induced by dimt-1 deficiency required a functional germline and was dependent on the known regulator of protein translation, the Rag GTPase, raga-1, which links amino acid sensing to the mechanistic target of rapamycin complex (mTORC)1. Using an auxin-inducible degron tagged version of dimt-1, we demonstrate that DIMT-1 functions in the germline after mid-life to regulate lifespan. We further found that knock-down of dimt-1 leads to selective translation of transcripts important for stress resistance and lifespan regulation in the C. elegans germline in mid-life including the cytochrome P450 daf-9, which synthesizes a steroid that signals from the germline to the soma to regulate lifespan. We found that dimt-1 induced lifespan extension was dependent on the daf-9 signaling pathway. This finding reveals a new layer of proteome dysfunction, beyond protein synthesis and degradation, as an important regulator of aging. Our findings highlight a new role for ribosome heterogeneity, and specific rRNA modifications, in maintaining appropriate translation later in life to promote healthy aging.

Recently, various studies have shown that epigenetic changes are associated with aging and age-related diseases. Both animal and human models have revealed that epigenetic processes are involved in aging mechanisms. These processes happen at multiple levels and include histone modification, DNA methylation, and changes in noncoding RNA expression. Consequently, changes in the organization of chromatin and DNA accessibility lead to the regulation of gene expression. With increasing awareness of the pivotal function of epigenetics in the aging process, researchers' attention has been drawn to how these epigenetic changes can be modified to prevent, stop, or reverse aging, senescence, and age-related diseases. Among various agents that can affect epigenetic, polyphenols are well-known phytochemicals found in fruits, vegetables, and plants. Polyphenols are found to modify epigenetic-related mechanisms in various diseases and conditions, such as metabolic disorders, obesity, neurodegenerative diseases, cancer, and cardiovascular diseases. Resveratrol (RSV) is a member of the stilbene subgroup of polyphenols which is derived from various plants, such as grapes, apples, and blueberries. Therefore, herein, we aim to summarize how RSV affects different epigenetic processes to change aging-related mechanisms. Furthermore, we discuss its roles in age-related diseases, such as Alzheimer's, Parkinson's, osteoporosis, and cardiovascular diseases.

S-adenosylmethionine (SAM) was a methyl donor for modifying histones, which had crucial roles in lipid accumulation, tissue injury, and immune responses. SAM fluctuation might be linked to variations in histone methylation. However, the underlying molecular mechanisms of whether the SAM diet influenced the immune response via histone modification remained obscure. In this study, we utilized the Caenorhabditis elegans as a model to investigate the role of SAM diet in innate immunity. We found that 50 μM SAM increased resistance to Gram-negative pathogen Pseudomonas aeruginosa PA14 by reducing the bacterial burden in the intestine. Furthermore, through the genetic screening in C. elegans, we found that SAM functioned in germline to enhance innate immunity via an H3K4 methyltransferase complex to upregulate the immune response genes, including irg-1 and T24B8.5. Intriguingly, SAM also protected mice from P. aeruginosa PA14 infection by reducing the bacterial burden in lung. These findings provided insight into the mechanisms of molecular connections among SAM diet, histone modifications and innate immunity.

The gonad has become a central organ for understanding aging in C. elegans, as removing the proliferating stem cells in the germline results in significant lifespan extension. Similarly, when starvation in late larval stages leads to the quiescence of germline stem cells the adult nematode enters reproductive diapause, associated with an extended lifespan. This review summarizes recent advancements in identifying the mechanisms behind gonad-mediated lifespan extension, including comparisons with other nematodes and the role of lipid signaling and transcriptional changes. Given that the gonad also mediates lifespan regulation in other invertebrates and vertebrates, elucidating the underlying mechanisms may help to gain new insights into the mechanisms and evolution of aging.

One of the major challenges that remain in the fields of aging and lifespan determination concerns the precise roles that reactive oxygen species (ROS) play in these processes. ROS, including superoxide and hydrogen peroxide, are constantly generated as byproducts of aerobic metabolism, as well as in response to endogenous and exogenous cues. While ROS accumulation and oxidative damage were long considered to constitute some of the main causes of age-associated decline, more recent studies reveal a signaling role in the aging process. In fact, accumulation of ROS, in a spatiotemporal manner, can trigger beneficial cellular responses that promote longevity and healthy aging. In this review, we discuss the importance of timing and compartmentalization of external and internal ROS perturbations in organismal lifespan and the role of redox regulated pathways.

Aging causes numerous age-related diseases, leading the human species to death. Nevertheless, rejuvenating strategies based on cell epigenetic modifications are a possible approach to counteract disease progression while getting old. Cell reprogramming of adult somatic cells toward pluripotency ought to be a promising tool for age-related diseases. However, researchers do not have control over this process as cells lose their fate, and cause potential cancerous cells or unexpected cell phenotypes. Direct and partial reprogramming were introduced in recent years with distinctive applications. Although direct reprogramming makes cells lose their identity, it has various applications in regeneration medicine. Temporary and regulated in vivo overexpression of Yamanaka factors has been shown in several experimental contexts to be achievable and is used to rejuvenate mice models. This regeneration can be accomplished by altering the epigenetic adult cell signature to the signature of a younger cell. The greatest advantage of partial reprogramming is that this method does not allow cells to lose their identity when they are resetting their epigenetic clock. It is a regimen of short-term Oct3/4, Sox2, Klf4, and c-Myc expression in vivo that prevents full reprogramming to the pluripotent state and avoids both tumorigenesis and the presence of unwanted undifferentiated cells. We know that many neurological age-related diseases, such as Alzheimer's disease, stroke, dementia, and Parkinson's disease, are the main cause of death in the last decades of life. Therefore, scientists have a special tendency regarding neuroregeneration methods to increase human life expectancy.

Epigenetic mechanisms are crucial in regulating gene expression. These mechanisms include DNA methylation and histone modifications, like methylation, acetylation, and phosphorylation. DNA methylation is associated with gene expression suppression; however, histone methylation can stimulate or repress gene expression depending on the methylation pattern of lysine or arginine residues on histones. These modifications are key factors in mediating the environmental effect on gene expression regulation. Therefore, their aberrant activity is associated with the development of various diseases. The current study aimed to review the significance of DNA and histone methyltransferases and demethylases in developing various conditions, like cardiovascular diseases, myopathies, diabetes, obesity, osteoporosis, cancer, aging, and central nervous system conditions. A better understanding of the epigenetic roles in developing diseases can pave the way for developing novel therapeutic approaches for affected patients.

Transient events during development can exert long-lasting effects on organismal lifespan. Here we demonstrate that exposure of Caenorhabditis elegans to reactive oxygen species during development protects against amyloid-induced proteotoxicity later in life. We show that this protection is initiated by the inactivation of the redox-sensitive H3K4me3-depositing COMPASS complex and conferred by a substantial increase in the heat-shock-independent activity of heat shock factor 1 (HSF-1), a longevity factor known to act predominantly during C. elegans development. We show that depletion of HSF-1 leads to marked rearrangements of the organismal lipid landscape and a significant decrease in mitochondrial β-oxidation and that both lipid and metabolic changes contribute to the protective effects of HSF-1 against amyloid toxicity. Together, these findings link developmental changes in the histone landscape, HSF-1 activity and lipid metabolism to protection against age-associated amyloid toxicities later in life.

Body size is a fundamental trait that drives multiple evolutionary and ecological patterns. Caenorhabditis inopinata is a fig-associated nematode that is exceptionally large relative to other members of the genus, including C. elegans. We previously showed that C. inopinata is large primarily due to postembryonic cell size expansion that occurs during the larval-to-adult transition. Here, we describe gene expression patterns in C. elegans and C. inopinata throughout this developmental period to understand the transcriptional basis of body size change. We performed RNA-seq in both species across the L3, L4, and adult stages. Most genes are differentially expressed across all developmental stages, consistent with C. inopinata's divergent ecology and morphology. We also used a model comparison approach to identify orthologs with divergent dynamics across this developmental period between the two species. This included genes connected to neurons, behavior, stress response, developmental timing, and small RNA/chromatin regulation. Multiple hypodermal collagens were also observed to harbor divergent developmental dynamics across this period, and genes important for molting and body morphology were also detected. Genes associated with TGF-β signaling revealed idiosyncratic and unexpected transcriptional patterns given their role in body size regulation in C. elegans. Widespread transcriptional divergence between these species is unexpected and may be a signature of the ecological and morphological divergence of C. inopinata. Alternatively, transcriptional turnover may be the rule in the Caenorhabditis genus, indicative of widespread developmental system drift among species. This work lays the foundation for future functional genetic studies interrogating the bases of body size evolution in this group.

Loss of function during aging is accompanied by transcriptional drift, altering gene expression and contributing to a variety of age-related diseases. CREB-regulated transcriptional coactivators (CRTCs) have emerged as key regulators of gene expression that might be targeted to promote longevity. Here we define the role of the Caenorhabditis elegans CRTC-1 in the epigenetic regulation of longevity. Endogenous CRTC-1 binds chromatin factors, including components of the COMPASS complex, which trimethylates lysine 4 on histone H3 (H3K4me3). CRISPR editing of endogenous CRTC-1 reveals that the CREB-binding domain in neurons is specifically required for H3K4me3-dependent longevity. However, this effect is independent of CREB but instead acts via the transcription factor AP-1. Strikingly, CRTC-1 also mediates global histone acetylation levels, and this acetylation is essential for H3K4me3-dependent longevity. Indeed, overexpression of an acetyltransferase enzyme is sufficient to promote longevity in wild-type worms. CRTCs, therefore, link energetics to longevity by critically fine-tuning histone acetylation and methylation to promote healthy aging.

Loss of transcription-coupled histone H3 lysine 36 trimethylation (H3K36me3) contributes to shorter lifespans in eukaryotes. However, the molecular mechanism of the decline of H3K36me3 during aging remains poorly understood. Here, we report that the degradation of the methyltransferase Set2 is the cause of decreased H3K36me3 levels during chronological aging in budding yeast. We show that Set2 protein degradation during cellular senescence and chronological aging is mainly mediated by the ubiquitin-conjugating E2 enzyme Ubc3 and the E3 ligase Bre1. Lack of Bre1 or abolishment of the ubiquitination stabilizes Set2 protein, sustains H3K36me3 levels at the aging-related gene loci, and upregulates their gene expression, thus leading to extended chronological lifespan. We further illustrate that Gcn5-mediated Set2 acetylation is a prerequisite for Bre1-catalyzed Set2 polyubiquitination and proteolysis during aging. We propose that two sequential post-translational modifications regulate Set2 homeostasis, suggesting a potential strategy to target the Gcn5-Bre1-Set2 axis for intervention of longevity.

Genetic and epigenetic changes, oxidative stress and inflammation influence the rate of aging, which diseases, lifestyle and environmental factors can further accelerate. In accelerated aging (AA), the biological age exceeds the chronological age.

The objective of this study is to reappraise the AA concept critically, considering its weaknesses and limitations.

We reviewed more than 300 recent articles dealing with the physiology of brain aging and neurodegeneration pathophysiology.

(1) Application of the AA concept to individual organs outside the brain is challenging as organs of different systems age at different rates. (2) There is a need to consider the deceleration of aging due to the potential use of the individual structure-functional reserves. The latter can be restored by pharmacological and/or cognitive therapy, environment, etc. (3) The AA concept lacks both standardised terminology and methodology. (4) Changes in specific molecular biomarkers (MBM) reflect aging-related processes; however, numerous MBM candidates should be validated to consolidate the AA theory. (5) The exact nature of many potential causal factors, biological outcomes and interactions between the former and the latter remain largely unclear.

Although AA is commonly recognised as a perspective theory, it still suffers from a number of gaps and limitations that assume the necessity for an updated AA concept.

Aging affects nearly all aspects of our cells, from our DNA to our proteins to how our cells handle stress and communicate with each other. Age-related chromatin changes are of particular interest because chromatin can dynamically respond to the cellular and organismal environment, and many modifications at chromatin are reversible. Changes at chromatin occur during aging, and evidence from model organisms suggests that chromatin factors could play a role in modulating the aging process itself, as altering proteins that work at chromatin often affect the lifespan of yeast, worms, flies, and mice. The field of chromatin and aging is rapidly expanding, and high-resolution genomics tools make it possible to survey the chromatin environment or track chromatin factors implicated in longevity with precision that was not previously possible. In this review, we discuss the state of chromatin and aging research. We include examples from yeast, Drosophila, mice, and humans, but we particularly focus on the commonly used aging model, the worm Caenorhabditis elegans, in which there are many examples of chromatin factors that modulate longevity. We include evidence of both age-related changes to chromatin and evidence of specific chromatin factors linked to longevity in core histones, nuclear architecture, chromatin remodeling, and histone modifications.

The ability of mitochondria to coordinate stress responses across tissues is critical for health. In C. elegans , neurons experiencing mitochondrial stress elicit an inter-tissue signaling pathway through the release of mitokine signals, such as serotonin or the WNT ligand EGL-20, which activate the mitochondrial unfolded protein response (UPR MT ) in the periphery to promote organismal health and lifespan. We find that germline mitochondria play a surprising role in neuron-to-peripheral UPR MT signaling. Specifically, we find that germline mitochondria signal downstream of neuronal mitokines, like WNT and serotonin, and upstream of lipid metabolic pathways in the periphery to regulate UPR MT activation. We also find that the germline tissue itself is essential in UPR MT signaling. We propose that the germline has a central signaling role in coordinating mitochondrial stress responses across tissues, and germline mitochondria play a defining role in this coordination because of their inherent roles in germline integrity and inter-tissue signaling.

Heritable non-genetic information can regulate a variety of complex phenotypes. However, what specific non-genetic cues are transmitted from parents to their descendants are poorly understood. Here, we perform metabolic methyl-labeling experiments to track the heritable transmission of methylation from ancestors to their descendants in the nematode Caenorhabditis elegans (C. elegans). We find heritable methylation in DNA, RNA, proteins, and lipids. We find that parental starvation elicits reduced fertility, increased heat stress resistance, and extended longevity in fed, naïve progeny. This intergenerational hormesis is accompanied by a heritable increase in N6'-dimethyl adenosine (m6,2A) on the 18S ribosomal RNA at adenosines 1735 and 1736. We identified DIMT-1/DIMT1 as the m6,2A and BUD-23/BUD23 as the m7G methyltransferases in C. elegans that are both required for intergenerational hormesis, while other rRNA methyltransferases are dispensable. This study labels and tracks heritable non-genetic material across generations and demonstrates the importance of rRNA methylation for regulating epigenetic inheritance.

Aging is considered the deterioration of physiological functions along with an increased mortality rate. This scientific review focuses on the central importance of genomic instability during the aging process, encompassing a range of cellular and molecular changes that occur with advancing age. In particular, this revision addresses the genetic and epigenetic alterations that contribute to genomic instability, such as telomere shortening, DNA damage accumulation, and decreased DNA repair capacity. Furthermore, the review explores the epigenetic changes that occur with aging, including modifications to histones, DNA methylation patterns, and the role of non-coding RNAs. Finally, the review discusses the organization of chromatin and its contribution to genomic instability, including heterochromatin loss, chromatin remodeling, and changes in nucleosome and histone abundance. In conclusion, this review highlights the fundamental role that genomic instability plays in the aging process and underscores the need for continued research into these complex biological mechanisms.

Protein lysine acetylation is a dynamic post-translational modification (PTM) that regulates a wide spectrum of cellular events including aging. General control nonderepressible 5 (GCN5) is a highly conserved lysine acetyltransferase (KAT). However, the acetylation substrates of GCN5 in vivo remain poorly studied, and moreover, how lysine acetylation changes with age and the contribution of KATs to aging remain to be addressed. Here, using Drosophila, we perform label-free quantitative acetylomic analysis, identifying new substrates of GCN5 in the adult and aging process. We further characterize the dynamics of protein acetylation with age, which exhibits a trend of increase. Since the expression of endogenous fly Gcn5 progressively increases during aging, we reason that, by combining the substrate analysis, the increase in acetylation with age is triggered, at least in part, by GCN5. Collectively, our study substantially expands the atlas of GCN5 substrates in vivo, provides a resource of protein acetylation that naturally occurs with age, and demonstrates how individual KAT contributes to the aging acetylome.

The ageing process begins at birth. It is a life-long process, and its exact origins are still unknown. Several hypotheses attempt to describe the normal ageing process, including hormonal imbalance, formation of reactive oxygen species, DNA methylation & DNA damage accumulation, loss of proteostasis, epigenetic alterations, mitochondrial dysfunction, senescence, inflammation, and stem cell depletion. With increased lifespan in elderly individuals, the prevalence of age-related diseases including, cancer, diabetes, obesity, hypertension, Alzheimer's, Alzheimer's disease and related dementias, Parkinson's, and other mental illnesses are increased. These increased age-related illnesses, put tremendous pressure & burden on caregivers, family members, and friends who are living with patients with age-related diseases. As medical needs evolve, the caregiver is expected to experience an increase in duties and challenges, which may result in stress on themselves, and impact their own family life. In the current article, we assess the biological mechanisms of ageing and its effect on body systems, exploring lifestyle and ageing, with a specific focus on age-related disorders. We also discussed the history of caregiving and specific challenges faced by caregivers in the presence of multiple comorbidities. We also assessed innovative approaches to funding caregiving, and efforts to improve the medical system to better organize chronic care efforts, while improving the skill and efficiency of both informal and formal caregivers. We also discussed the role of caregiving in end-of-life care. Our critical analysis strongly suggests that there is an urgent need for caregiving in aged populations and support from local, state, and federal agencies.

Previous studies show a woman's pregnancy is correlated with post-reproductive longevity, and nulliparity is associated with higher risk of incident heart failure, suggesting pregnancy likely exerts a cardioprotection. We previously reported a cardioprotective phenomenon termed myocardial hypertrophic preconditioning, but it is unknown whether pregnancy-induced physiological hypertrophic preconditioning (PHP) can also protect the heart against subsequent pathological hypertrophic stress. We aimed to clarify the phenomenon of PHP and its mechanisms. The pluripara mice whose pregnancy-induced physiological hypertrophy regressed and the nulliparous mice underwent angiotensin II (Ang II) infusion or transverse aortic constriction (TAC). Echocardiography, invasive left ventricular hemodynamic measurement and histological analysis were used to evaluate cardiac remodeling and function. Silencing or overexpression of Foxo3 by adeno-associated virus was used to investigate the role of FoxO3a involved in the antihypertrophic effect. Compared with nulliparous mice, pathological cardiac hypertrophy induced by Ang II infusion, or TAC was significantly attenuated and heart failure induced by TAC was markedly improved in mice with PHP. Activation of FoxO3a was significantly enhanced in the hearts of postpartum mice. FoxO3a inhibited myocardial hypertrophy by suppressing signaling pathway of phosphorylated glycogen synthase kinase-3β (p-GSK3β)/β-catenin/Cyclin D1. Silencing or overexpression of Foxo3 attenuated or enhanced the anti-hypertrophic effect of PHP in mice with pathological stimulation. Our findings demonstrate that PHP confers resistance to subsequent hypertrophic stress and slows progression to heart failure through activation of FoxO3a/GSK3β pathway.

The proper transfer of genetic information from DNA to RNA to protein is essential for cell-fate control, development, and health. Methylation of DNA, RNAs, histones, and non-histone proteins is a reversible post-synthesis modification that finetunes gene expression and function in diverse physiological processes. Aberrant methylation caused by genetic mutations or environmental stimuli promotes various diseases and accelerates aging, necessitating the development of therapies to correct the disease-driver methylation imbalance. In this Review, we summarize the operating system of methylation across the central dogma, which includes writers, erasers, readers, and reader-independent outputs. We then discuss how dysregulation of the system contributes to neurological disorders, cancer, and aging. Current small-molecule compounds that target the modifiers show modest success in certain cancers. The methylome-wide action and lack of specificity lead to undesirable biological effects and cytotoxicity, limiting their therapeutic application, especially for diseases with a monogenic cause or different directions of methylation changes. Emerging tools capable of site-specific methylation manipulation hold great promise to solve this dilemma. With the refinement of delivery vehicles, these new tools are well positioned to advance the basic research and clinical translation of the methylation field.

Aging is accompanied by homeostatic and functional dysregulation of multiple immune cell subsets. Group 3 innate lymphoid cells (ILC3s) constitute a heterogeneous cell population that plays pivotal roles in intestinal immunity. In this study, we found that ILC3s in aged mice exhibited dysregulated homeostasis and function, leading to bacterial and fungal infection susceptibility. Moreover, our data revealed that the enrichment of the H3K4me3 modification in effector genes of aged gut CCR6+ ILC3s was specifically decreased compared to young mice counterparts. Disruption of Cxxc finger protein 1 (Cxxc1) activity, a key subunit of H3K4 methyltransferase, in ILC3s led to similar aging-related phenotypes. An integrated analysis revealed Kruppel-like factor 4 (Klf4) as a potential Cxxc1 target. Klf4 overexpression partially restored the differentiation and functional defects seen in both aged and Cxxc1-deficient intestinal CCR6+ ILC3s. Therefore, these data suggest that targeting intestinal ILC3s may provide strategies to protect against age-related infections.

In the last decade epigenetics has come to the fore as a discipline which is central to biogerontology. Age associated epigenetic changes are routinely linked with pathologies, including cardiovascular disease, cancer, and Alzheimer's disease; moreover, epigenetic clocks are capable of correlating biological age with chronological age in many species including humans. Recent intriguing empirical observations also suggest that inherited epigenetic effects could influence lifespan/longevity in a variety of organisms. If this is the case, an imperative exists to reconcile lifespan/longevity associated inherited epigenetic processes with the evolution of ageing. This review will critically evaluate inherited epigenetic effects from an evolutionary perspective. The overarching aim is to integrate the evidence which suggests epigenetic inheritance modulates lifespan/longevity with the main evolutionary theories of ageing.

Pulmonary hypertension is characterized by pulmonary arterial remodeling that results in increased pulmonary vascular resistance, right ventricular failure, and premature death. It is a threat to public health globally. Autophagy, as a highly conserved self-digestion process, plays crucial roles with autophagy-related (ATG) proteins in various diseases. The components of autophagy in the cytoplasm have been studied for decades and multiple studies have provided evidence of the importance of autophagic dysfunction in pulmonary hypertension. The status of autophagy plays a dynamic suppressive or promotive role in different contexts and stages of pulmonary hypertension development. Although the components of autophagy have been well studied, the molecular basis for the epigenetic regulation of autophagy is less understood and has drawn increasing attention in recent years. Epigenetic mechanisms include histone modifications, chromatin modifications, DNA methylation, RNA alternative splicing, and non-coding RNAs, which control gene activity and the development of an organism. In this review, we summarize the current research progress on epigenetic modifications in the autophagic process, which have the potential to be crucial and powerful therapeutic targets against the autophagic process in pulmonary hypertension development.

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent neuromuscular disorders. The disease is linked to copy number reduction and/or epigenetic alterations of the D4Z4 macrosatellite on chromosome 4q35 and associated with aberrant gain of expression of the transcription factor DUX4, which triggers a pro-apoptotic transcriptional program leading to muscle wasting. As today, no cure or therapeutic option is available to FSHD patients. Given its centrality in FSHD, blocking DUX4 expression with small molecule drugs is an attractive option. We previously showed that the long non protein-coding RNA DBE-T is required for aberrant DUX4 expression in FSHD. Using affinity purification followed by proteomics, here we identified the chromatin remodeling protein WDR5 as a novel DBE-T interactor and a key player required for the biological activity of the lncRNA. We found that WDR5 is required for the expression of DUX4 and its targets in primary FSHD muscle cells. Moreover, targeting WDR5 rescues both cell viability and myogenic differentiation of FSHD patient cells. Notably, comparable results were obtained by pharmacological inhibition of WDR5. Importantly, WDR5 targeting was safe to healthy donor muscle cells. Our results support a pivotal role of WDR5 in the activation of DUX4 expression identifying a druggable target for an innovative therapeutic approach for FSHD.

Citrus fruit has long been considered a healthy food, but its role and detailed mechanism in lifespan extension are not clear. Here, by using the nematode C. elegans, we identified that nomilin, a bitter-taste limoloid that is enriched in citrus, significantly extended the animals' lifespan, healthspan, and toxin resistance. Further analyses indicate that this ageing inhibiting activity depended on the insulin-like pathway DAF-2/DAF-16 and nuclear hormone receptors NHR-8/DAF-12. Moreover, the human pregnane X receptor (hPXR) was identified as the mammalian counterpart of NHR-8/DAF-12 and X-ray crystallography showed that nomilin directly binds with hPXR. The hPXR mutations that prevented nomilin binding blocked the activity of nomilin both in mammalian cells and in C. elegans. Finally, dietary nomilin supplementation improved healthspan and lifespan in D-galactose- and doxorubicin-induced senescent mice as well as in male senescence accelerated mice prone 8 (SAMP8) mice, and induced a longevity gene signature similar to that of most longevity interventions in the liver of bile-duct-ligation male mice. Taken together, we identified that nomilin may extend lifespan and healthspan in animals via the activation of PXR mediated detoxification functions.