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Key Points Widespread epigenomic remodelling, at the level of DNA or histone protein modification, has been observed during ageing across species and cell types. Some epigenetic states can function as 'molecular clocks'. The experimental perturbation of chromatin modifiers can influence the lifespan of model organisms. Environmental inputs, such as diet, physical activity, hormones or pheromones, have been linked to remodelling of the epigenome as well as to changes in lifespan. Chromatin may thus act as a molecular integrator of environmental exposures. Random epigenetic changes, or epimutations, throughout life may trigger increases in transcriptional and genomic instability. The unique regulation of chromatin in germline cells might protect these cells more than somatic cells during ageing. Some ageing or age-related phenotypes, such as lifespan, fertility and stress resistance, may be inherited through successive generations in model organisms, through non-genetic mechanisms. The use of epigenetic drugs or epigenome-editing technologies may be a promising avenue for age-related therapeutics. The chromatin-based epigenetic changes that occur during ageing and the role of chromatin modifiers in lifespan have recently been highlighted. The importance of epigenome remodelling by environmental stimuli for transcriptional and genomic stability is emerging, and such remodelling could provide new targets to counter ageing or age-related diseases. Ageing is affected by both genetic and non-genetic factors. Here, we review the chromatin-based epigenetic changes that occur during ageing, the role of chromatin modifiers in modulating lifespan and the importance of epigenetic signatures as biomarkers of ageing. We also discuss how epigenome remodelling by environmental stimuli affects several aspects of transcription and genomic stability, with important consequences for longevity, and outline epigenetic differences between the 'mortal soma' and the 'immortal germ line'. Finally, we discuss the inheritance of characteristics of ageing and potential chromatin-based strategies to delay or reverse hallmarks of ageing or age-related diseases.

Healthy aging can be promoted by enhanced metabolic fitness and physical capacity. Mitochondria are chief metabolic organelles with strong implications in aging that also coordinate broad physiological functions, in part, using peptides that are encoded within their independent genome. However, mitochondrial-encoded factors that actively regulate aging are unknown. Here, we report that mitochondrial-encoded MOTS-c can significantly enhance physical performance in young (2 mo.), middle-age (12 mo.), and old (22 mo.) mice. MOTS-c can regulate (i) nuclear genes, including those related to metabolism and proteostasis, (ii) skeletal muscle metabolism, and (iii) myoblast adaptation to metabolic stress. We provide evidence that late-life (23.5 mo.) initiated intermittent MOTS-c treatment (3x/week) can increase physical capacity and healthspan in mice. In humans, exercise induces endogenous MOTS-c expression in skeletal muscle and in circulation. Our data indicate that aging is regulated by genes encoded in both of our co-evolved mitochondrial and nuclear genomes. Exercise has beneficial effects on metabolism and overall physiologic fitness in aged organisms. Here the authors show that MOTS-c is a mitochondrial-encoded exercise-induced peptide that regulates skeletal muscle metabolism and improves healthspan of older mice.

Chromatin modifiers regulate lifespan in several organisms, raising the question of whether changes in chromatin states in the parental generation could be incompletely reprogrammed in the next generation and thereby affect the lifespan of descendants. The histone H3 lysine 4 trimethylation (H3K4me3) complex, composed of ASH-2, WDR-5 and the histone methyltransferase SET-2, regulates Caenorhabditis elegans lifespan. Here we show that deficiencies in the H3K4me3 chromatin modifiers ASH-2, WDR-5 or SET-2 in the parental generation extend the lifespan of descendants up until the third generation. The transgenerational inheritance of lifespan extension by members of the ASH-2 complex is dependent on the H3K4me3 demethylase RBR-2, and requires the presence of a functioning germline in the descendants. Transgenerational inheritance of lifespan is specific for the H3K4me3 methylation complex and is associated with epigenetic changes in gene expression. Thus, manipulation of specific chromatin modifiers only in parents can induce an epigenetic memory of longevity in descendants. Epigenetic inheritance of longevity It is known that simple traits — flower characteristics in plants and eye colour in Drosophila , for instance — can be inherited in a transgenerational manner. This Article demonstrates the transgenerational epigenetic inheritance of a complex trait: acquired longevity in the roundworm Caenorhabditis elegans . The manipulation of H3K4me3 chromatin modifiers of the ASH-2 complex in the parental generation extends the lifespan of the descendents for three subsequent generations. These findings imply that chromatin changes in parents might not be entirely reset between generations, and provide the first evidence for epigenetic inheritance of lifespan. The H3K4me3 regulatory complex is conserved in mammals, but more work is needed to determine whether manipulations of the complex have a heritable effect on longevity in mammals.

How an individual's longevity is affected by the opposite sex is still largely unclear. In the nematode Caenorhabditis elegans, the presence of males accelerated aging and shortened the life span of individuals of the opposite sex (hermaphrodites), including long-lived or sterile hermaphrodites. The male-induced demise could occur without mating and required only exposure of hermaphrodites to medium in which males were once present. Such communication through pheromones or other diffusible substances points to a nonindividual autonomous mode of aging regulation. The male-induced demise also occurred in other species of nematodes, suggesting an evolutionary conserved process whereby males may induce the disposal of the opposite sex to save resources for the next generation or to prevent competition from other males.

The mammalian innate immune system is sex-dimorphic. Neutrophils are the most abundant leukocyte in humans and represent innate immunity’s first line of defense. We previously found that primary mouse bone marrow neutrophils show widespread sex-dimorphism throughout life, including at the transcriptional level. Extracellular matrix [ECM]-related terms were observed among the top sex-dimorphic genes. Since the ECM is emerging as an important regulator of innate immune responses, we sought to further investigate the transcriptomic profile of primary mouse bone marrow neutrophils at both the bulk and single-cell level to understand how biological sex may influence ECM component expression in neutrophils throughout life. Here, using curated gene lists of ECM components and unbiased weighted gene co-expression network analysis [WGCNA], we find that multiple ECM-related gene sets show widespread female-bias in expression in primary mouse neutrophils. Since many immune-related diseases ( e . g ., rheumatoid arthritis) are more prevalent in females, our work may provide insights into the pathogenesis of sex-dimorphic inflammatory diseases.

Long interspersed element 1 (LINE-1; L1) are a family of transposons that occupy ~17% of the human genome. Though a small number of L1 copies remain capable of autonomous transposition, the overwhelming majority of copies are degenerate and immobile. Nevertheless, both mobile and immobile L1s can exert pleiotropic effects (promoting genome instability, inflammation, or cellular senescence) on their hosts, and L1’s contributions to aging and aging diseases is an area of active research. However, because of the cell type-specific nature of transposon control, the catalogue of L1 regulators remains incomplete. Here, we employ an eQTL approach leveraging transcriptomic and genomic data from the GEUVADIS and 1000Genomes projects to computationally identify new candidate regulators of L1 RNA levels in lymphoblastoid cell lines. To cement the role of candidate genes in L1 regulation, we experimentally modulate the levels of top candidates in vitro , including IL16 , STARD5 , HSD17B12 , and RNF5 , and assess changes in TE family expression by Gene Set Enrichment Analysis (GSEA). Remarkably, we observe subtle but widespread upregulation of TE family expression following IL16 and STARD5 overexpression. Moreover, a short-term 24-hour exposure to recombinant human IL16 was sufficient to transiently induce subtle, but widespread, upregulation of L1 subfamilies. Finally, we find that many L1 expression-associated genetic variants are co-associated with aging traits across genome-wide association study databases. Our results expand the catalogue of genes implicated in L1 RNA control and further suggest that L1-derived RNA contributes to aging processes. Given the ever-increasing availability of paired genomic and transcriptomic data, we anticipate this new approach to be a starting point for more comprehensive computational scans for regulators of transposon RNA levels.

Neutrophils are the most abundant human white blood cell and constitute a first line of defense in the innate immune response. Neutrophils are short-lived cells and thus the impact of organismal aging on neutrophil biology, especially as a function of biological sex, remains poorly understood. Here, we describe a multi-omic resource of mouse primary bone-marrow neutrophils from young and old female and male mice, at the transcriptomic, metabolomic and lipidomic levels. We identify widespread regulation of neutrophil ‘omics’ landscapes with organismal aging and biological sex. In addition, we leverage our resource to predict functional differences, including changes in neutrophil responses to activation signals. This dataset represents a large multi-omics resource for neutrophils across sex and ages and identifies neutrophil characteristics that could be targeted to improve immune responses as a function of sex and/or age. Lu and colleagues generated a transcriptomic, lipidomic and metabolomic atlas of primary bone-marrow mouse neutrophils with organismal aging and across biological sexes, revealing lifelong sex-dimorphic neutrophil functional regulation.

Although aging is a conserved phenomenon across evolutionary distant species, aspects of the aging process have been found to differ between males and females of the same species. Indeed, observations across mammalian studies have revealed the existence of longevity and health disparities between sexes, including in humans (i.e. with a female or male advantage). However, the underlying mechanisms for these sex differences in health and lifespan remain poorly understood, and it is unclear which aspects of this dimorphism stem from hormonal differences (i.e. predominance of estrogens vs. androgens) or from karyotypic differences (i.e. XX vs. XY sex chromosome complement). In this review, we discuss the state of the knowledge in terms of sex dimorphism in various aspects of aging and in human age-related diseases. Where the interplay between sex differences and age-related differences has not been explored fully, we present the state of the field to highlight important future research directions. We also discuss various dietary, drug or genetic interventions that were shown to improve longevity in a sex-dimorphic fashion. Finally, emerging tools and models that can be leveraged to decipher the mechanisms underlying sex differences in aging are also briefly discussed.

Microglia, the brain’s resident macrophages, maintain brain homeostasis and respond to injury and infection. During aging they undergo functional changes, but the underlying mechanisms and their contributions to neuroprotection versus neurodegeneration are unclear. Previous studies suggested that microglia are sex dimorphic, so we compared microglial aging in mice of both sexes. RNA-sequencing of hippocampal microglia revealed more aging-associated changes in female microglia than male microglia, and more sex differences in old microglia than young microglia. Pathway analyses and subsequent validation assays revealed a stronger AKT-mTOR-HIF1α-driven shift to glycolysis among old female microglia and indicated that C3a production and detection was elevated in old microglia, especially in females. Recombinant C3a induced AKT-mTOR-HIF1α signaling and increased the glycolytic and phagocytic activity of young microglia. Single cell analyses attributed the aging-associated sex dimorphism to more abundant disease-associated microglia (DAM) in old female mice than old male mice, and evaluation of an Alzheimer’s Disease mouse model revealed that the metabolic and complement changes are also apparent in the context of neurodegenerative disease and are strongest in the neuroprotective DAM2 subset. Collectively, our data implicate autocrine C3a-C3aR signaling in metabolic reprogramming of microglia to neuroprotective DAM during aging, especially in females, and also in Alzheimer’s Disease.

Aging is associated with increased monocyte production and altered monocyte function. Classical monocytes are heterogenous and a shift in their subset composition may underlie some of their apparent functional changes during aging. We have previously shown that mouse granulocyte‐monocyte progenitors (GMPs) produce “neutrophil‐like” monocytes (NeuMo), whereas monocyte‐dendritic cell progenitors (MDPs) produce monocyte‐derived dendritic cell (moDC)‐producing monocytes (DCMo). Here, we demonstrate that classical monocytes from the bone marrow of old male and female mice have higher expression of DCMo signature genes (H2‐Aa, H2‐Ab1, H2‐Eb1, Cd74), and that more classical monocytes express MHCII and CD74 protein. Moreover, we show that bone marrow MDPs and classical monocytes from old mice yield more moDC. We also demonstrate higher expression of Aw112010 in old monocytes and that Aw112010 lncRNA activity regulates MHCII induction in macrophages, which suggests that elevated Aw112010 levels may underlie increased MHCII expression during monocyte aging. Finally, we show that classical monocyte expression of MHCII is also elevated during healthy aging in humans. Thus, aging‐associated changes in monocyte production may underlie altered monocyte function and have implications for aging‐associated disorders. During aging, monocyte‐dendritic cell progenitors (MDPs) in bone marrow produce more MHCII‐expressing classical monocytes (DCMo) and more monocyte‐derived DCs (moDC). Classical monocyte expression of the lncRNA AW112010 also increases during aging in mice and AW112010 promotes MHCII expression.