Unveiling the molecular landscape of cognitive aging: insights from polygenic risk scores, DNA methylation, and gene expression.

BACKGROUND: Aging represents a significant risk factor for the occurrence of cerebral small vessel disease, associated with white matter (WM) lesions, and to age-related cognitive alterations, though the precise mechanisms remain largely unknown. This study aimed to investigate the impact of polygenic risk scores (PRS) for WM integrity, together with age-related DNA methylation, and gene expression alterations, on cognitive aging in a cross-sectional healthy aging cohort. The PRSs were calculated using genome-wide association study (GWAS) summary statistics for magnetic resonance imaging (MRI) markers of WM integrity, including WM hyperintensities, fractional anisotropy (FA), and mean diffusivity (MD). These scores were utilized to predict age-related cognitive changes and evaluate their correlation with structural brain changes, which distinguish individuals with higher and lower cognitive scores. To reduce the dimensionality of the data and identify age-related DNA methylation and transcriptomic alterations, Sparse Partial Least Squares-Discriminant Analysis (sPLS-DA) was used. Subsequently, a canonical correlation algorithm was used to integrate the three types of omics data (PRS, DNA methylation, and gene expression data) and identify an individual "omics" signature that distinguishes subjects with varying cognitive profiles. RESULTS: We found a positive association between MD-PRS and long-term memory, as well as a correlation between MD-PRS and structural brain changes, effectively discriminating between individuals with lower and higher memory scores. Furthermore, we observed an enrichment of polygenic signals in genes related to both vascular and non-vascular factors. Age-related alterations in DNA methylation and gene expression indicated dysregulation of critical molecular features and signaling pathways involved in aging and lifespan regulation. The integration of multi-omics data underscored the involvement of synaptic dysfunction, axonal degeneration, microtubule organization, and glycosylation in the process of cognitive aging. CONCLUSIONS: These findings provide valuable insights into the biological mechanisms underlying the association between WM coherence and cognitive aging. Additionally, they highlight how age-associated DNA methylation and gene expression changes contribute to cognitive aging.

The chromatin accessibility and transcriptomic landscape of the aging mice cochlea and the identification of potential functional super-enhancers in age-related hearing loss.

BACKGROUND: Presbycusis, also referred to as age-related hearing loss (ARHL), is a condition that results from the cumulative effects of aging on an individual's auditory capabilities. Given the limited understanding of epigenetic mechanisms in ARHL, our research focuses on alterations in chromatin-accessible regions. METHODS: We employed assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) in conjunction with unique identifier (UID) mRNA-seq between young and aging cochleae, and conducted integrated analysis as well as motif/TF-gene prediction. Additionally, the essential role of super-enhancers (SEs) in the development of ARHL was identified by comparative analysis to previous research. Meanwhile, an ARHL mouse model and an aging mimic hair cell (HC) model were established with a comprehensive identification of senescence phenotypes to access the role of SEs in ARHL progression. RESULTS: The control cochlear tissue exhibited greater chromatin accessibility than cochlear tissue affected by ARHL. Furthermore, the levels of histone 3 lysine 27 acetylation were significantly depressed in both aging cochlea and aging mimic HEI-OC1 cells, highlighting the essential role of SEs in the development of ARHL. The potential senescence-associated super-enhancers (SASEs) of ARHL were identified, most of which exhibited decreased chromatin accessibility. The majority of genes related to the SASEs showed obvious decreases in mRNA expression level in aging HCs and was noticeably altered following treatment with JQ1 (a commonly used SE inhibitor). CONCLUSION: The chromatin accessibility in control cochlear tissue was higher than that in cochlear tissue affected by ARHL. Potential SEs involved in ARHL were identified, which might provide a basis for future therapeutics targeting SASEs related to ARHL.

Human determinants of age-dependent patterns of death from infection.

Regardless of microbial virulence (i.e., the global infection-fatality ratio), age generally drives the prevalence of death from infection in unvaccinated humans. Four mortality patterns are recognized: the common U- and L-shaped curves of endemic infections and the unique W- and J-shaped curves of pandemic infections. We suggest that these patterns result from different sets of human genetic and immunological determinants. In this model, it is the interplay between (1) monogenic genotypes affecting immunity to primary infection that preferentially manifest early in life and related genotypes or their phenocopies, including auto-antibodies, which manifest later in life and (2) the occurrence and persistence of adaptive, acquired immunity to primary or cross-reactive infections, which shapes the age-dependent pattern of human deaths from infection.

Cellular Senescence and Inflammaging in the Bone: Pathways, Genetics, Anti-Aging Strategies and Interventions.

Advancing age is associated with several age-related diseases (ARDs), with musculoskeletal conditions impacting millions of elderly people worldwide. With orthopedic conditions contributing towards considerable number of patients, a deeper understanding of bone aging is the need of the hour. One of the underlying factors of bone aging is cellular senescence and its associated senescence associated secretory phenotype (SASP). SASP comprises of pro-inflammatory markers, cytokines and chemokines that arrest cell growth and development. The accumulation of SASP over several years leads to chronic low-grade inflammation with advancing age, also known as inflammaging. The pathways and molecular mechanisms focused on bone senescence and inflammaging are currently limited but are increasingly being explored. Most of the genes, pathways and mechanisms involved in senescence and inflammaging coincide with those associated with cancer and other ARDs like osteoarthritis (OA). Thus, exploring these pathways using techniques like sequencing, identifying these factors and combatting them with the most suitable approach are crucial for healthy aging and the early detection of ARDs. Several approaches can be used to aid regeneration and reduce senescence in the bone. These may be pharmacological, non-pharmacological and lifestyle interventions. With increasing evidence towards the intricate relationship between aging, senescence, inflammation and ARDs, these approaches may also be used as anti-aging strategies for the aging bone marrow (BM).

Reduced PIN1 expression in neocortical and limbic brain regions in female Alzheimer's patients correlates with cognitive and neuropathological phenotypes.

Women have a higher incidence of Alzheimer's disease (AD), even after adjusting for increased longevity. Thus, there is an urgent need to identify genes that underpin sex-associated risk of AD. PIN1 is a key regulator of the tau phosphorylation signaling pathway; however, potential differences in PIN1 expression, in males and females, are still unknown. We analyzed brain transcriptomic datasets focusing on sex differences in PIN1 mRNA levels in an aging and AD cohort, which revealed reduced PIN1 levels primarily within females. We validated this observation in an independent dataset (ROS/MAP), which also revealed that PIN1 is negatively correlated with multiregional neurofibrillary tangle density and global cognitive function in females only. Additional analysis revealed a decrease in PIN1 in subjects with mild cognitive impairment (MCI) compared with aged individuals, again driven predominantly by female subjects. Histochemical analysis of PIN1 in AD and control male and female neocortex revealed an overall decrease in axonal PIN1 protein levels in females. These findings emphasize the importance of considering sex differences in AD research.

Aging aggravates aortic aneurysm and dissection via miR-1204-MYLK signaling axis in mice.

The mechanism by which aging induces aortic aneurysm and dissection (AAD) remains unclear. A total of 430 participants were recruited for the screening of differentially expressed plasma microRNAs (miRNAs). We found that miR-1204 is significantly increased in both the plasma and aorta of elder patients with AAD and is positively correlated with age. Cell senescence induces the expression of miR-1204 through p53 interaction with plasmacytoma variant translocation 1, and miR-1204 induces vascular smooth muscle cell (VSMC) senescence to form a positive feedback loop. Furthermore, miR-1204 aggravates angiotensin II-induced AAD formation, and inhibition of miR-1204 attenuates ß-aminopropionitrile monofumarate-induced AAD development in mice. Mechanistically, miR-1204 directly targets myosin light chain kinase (MYLK), leading to the acquisition of a senescence-associated secretory phenotype (SASP) by VSMCs and loss of their contractile phenotype. MYLK overexpression reverses miR-1204-induced VSMC senescence, SASP and contractile phenotypic changes, and the decrease of transforming growth factor-ß signaling pathway. Our findings suggest that aging aggravates AAD via the miR-1204-MYLK signaling axis.

A multiomic atlas of the aging hippocampus reveals molecular changes in response to environmental enrichment.

Aging involves the deterioration of organismal function, leading to the emergence of multiple pathologies. Environmental stimuli, including lifestyle, can influence the trajectory of this process and may be used as tools in the pursuit of healthy aging. To evaluate the role of epigenetic mechanisms in this context, we have generated bulk tissue and single cell multi-omic maps of the male mouse dorsal hippocampus in young and old animals exposed to environmental stimulation in the form of enriched environments. We present a molecular atlas of the aging process, highlighting two distinct axes, related to inflammation and to the dysregulation of mRNA metabolism, at the functional RNA and protein level. Additionally, we report the alteration of heterochromatin domains, including the loss of bivalent chromatin and the uncovering of a heterochromatin-switch phenomenon whereby constitutive heterochromatin loss is partially mitigated through gains in facultative heterochromatin. Notably, we observed the multi-omic reversal of a great number of aging-associated alterations in the context of environmental enrichment, which was particularly linked to glial and oligodendrocyte pathways. In conclusion, our work describes the epigenomic landscape of environmental stimulation in the context of aging and reveals how lifestyle intervention can lead to the multi-layered reversal of aging-associated decline.

Nur77 improves ovarian function in reproductive aging mice by activating mitophagy and inhibiting apoptosis.

Reproductive aging not only affects the fertility and physical and mental health of women but also accelerates the aging process of other organs. There is an urgent need newfor novel mechanisms, targets, and drugs to break the vicious cycle of mitochondrial dysfunction, redox imbalance, and germ cell apoptosis associated with ovarian aging. Autophagy, recognized as a longevity mechanism, has recently become a focal point in anti-aging research. Although mitophagy is a type of autophagy, its role and regulatory mechanisms in ovarian aging, particularly in age-related ovarian function decline, remain unclear. Nerve growth factor inducible gene B (Nur77) is an early response gene that can be stimulated by oxidative stress, DNA damage, metabolism, and inflammation. Recent evidence recommends that decreased expression of Nur77 is associated with age-related myocardial fibrosis, renal dysfunction, and Parkinson's disease; however, its association with ovarian aging has not been studied yet. We herein identified Nur77 as a regulator of germ cell senescence, apoptosis, and mitophagy and found that overexpression of Nur77 can activate mitophagy, improve oxidative stress, reduce apoptosis, and ultimately enhance ovarian reserve in aged mice ovaries. Furthermore, we discovered an association between Nur77 and the AKT pathway through String and molecular docking analyses. Experimental confirmation revealed that the AKT/mTOR signaling pathway is involved in the regulation of Nur77 in ovarian function. In conclusion, our results suggest Nur77 as a promising target for preventing and treating ovarian function decline related to reproductive aging.

MIAMI-AD (Methylation in Aging and Methylation in AD): an integrative knowledgebase that facilitates explorations of DNA methylation across sex, aging, and Alzheimer's disease.

Alzheimer's disease (AD) is a common neurodegenerative disorder with a significant impact on aging populations. DNA methylation (DNAm) alterations have been implicated in both the aging processes and the development of AD. Given that AD affects more women than men, it is also important to explore DNAm changes that occur specifically in each sex. We created MIAMI-AD, a comprehensive knowledgebase containing manually curated summary statistics from 98 published tables in 38 studies, all of which included at least 100 participants. MIAMI-AD enables easy browsing, querying, and downloading DNAm associations at multiple levels-at individual CpG, gene, genomic regions, or genome-wide, in one or multiple studies. Moreover, it also offers tools to perform integrative analyses, such as comparing DNAm associations across different phenotypes or tissues, as well as interactive visualizations. Using several use case examples, we demonstrated that MIAMI-AD facilitates our understanding of age-associated CpGs in AD and the sex-specific roles of DNAm in AD. This open-access resource is freely available to the research community, and all the underlying data can be downloaded. MIAMI-AD facilitates integrative explorations to better understand the interplay between DNAm across aging, sex, and AD. Database URL: https://miami-ad.org/.

miR-146a Decreases Inflammation and ROS Production in Aged Dermal Fibroblasts.

Aging is associated with a decline in the functionality of various cell types, including dermal fibroblasts, which play a crucial role in maintaining skin homeostasis and wound healing. Chronic inflammation and increased reactive oxygen species (ROS) production are hallmark features of aging, contributing to impaired wound healing. MicroRNA-146a (miR-146a) has been implicated as a critical regulator of inflammation and oxidative stress in different cell types, yet its role in aged dermal fibroblasts and its potential relevance to wound healing remains poorly understood. We hypothesize that miR-146a is differentially expressed in aged dermal fibroblasts and that overexpression of miR-146a will decrease aging-induced inflammatory responses and ROS production. Primary dermal fibroblasts were isolated from the skin of 17-week-old (young) and 88-week-old (aged) mice. Overexpression of miR-146a was achieved through miR-146a mimic transfection. ROS were detected using a reliable fluorogenic marker, 2,7-dichlorofluorescin diacetate. Real-time PCR was used to quantify relative gene expression. Our investigation revealed a significant reduction in miR-146a expression in aged dermal fibroblasts compared to their younger counterparts. Moreover, aged dermal fibroblasts exhibited heightened levels of inflammatory responses and increased ROS production. Importantly, the overexpression of miR-146a through miR-146a mimic transfection led to a substantial reduction in inflammatory responses through modulation of the NF-kB pathway in aged dermal fibroblasts. Additionally, the overexpression of miR-146a led to a substantial decrease in ROS production, achieved through the downregulation of NOX4 expression in aged dermal fibroblasts. These findings underscore the pivotal role of miR-146a in mitigating both inflammatory responses and ROS production in aged dermal fibroblasts, highlighting its potential as a therapeutic target for addressing age-related skin wound healing.

Perturbation of METTL1-mediated tRNA N7- methylguanosine modification induces senescence and aging.

Cellular senescence is characterized by a decrease in protein synthesis, although the underlying processes are mostly unclear. Chemical modifications to transfer RNAs (tRNAs) frequently influence tRNA activity, which is crucial for translation. We describe how tRNA N7-methylguanosine (m7G46) methylation, catalyzed by METTL1-WDR4, regulates translation and influences senescence phenotypes. Mettl1/Wdr4 and m7G gradually diminish with senescence and aging. A decrease in METTL1 causes a reduction in tRNAs, especially those with the m7G modification, via the rapid tRNA degradation (RTD) pathway. The decreases cause ribosomes to stall at certain codons, impeding the translation of mRNA that is essential in pathways such as Wnt signaling and ribosome biogenesis. Furthermore, chronic ribosome stalling stimulates the ribotoxic and integrative stress responses, which induce senescence-associated secretory phenotype. Moreover, restoring eEF1A protein mitigates senescence phenotypes caused by METTL1 deficiency by reducing RTD. Our findings demonstrate that tRNA m7G modification is essential for preventing premature senescence and aging by enabling efficient mRNA translation.

Dietary restriction promote sperm remodeling in aged roosters based on transcriptome analysis.

BACKGROUND: The breeder rooster has played a pivotal role in poultry production by providing high-quality semen. Typically, fertility peaks between 30 and 40 weeks of age and then declines rapidly from 45 to 55 weeks of age. Research into improving fertility in aging roosters is essential to extend their productive life. While progress has been made, enhancing fertility in aging roosters remains a significant challenge. METHODS: To identify the genes related to promoting sperm remodeling in aged Houdan roosters, we combined changes in testis and semen quality with transcriptome sequencing (RNA-seq) to analyze the synchrony of semen quality and testis development. In this study, 350-day-old Houdan breeder roosters were selected for RNA-seq analysis in testis tissues from induced molting roosters (D group) and non-induced molting roosters (47DG group). All analyses of differentially expressed genes (DEGs) and functional enrichment were performed. Finally, we selected six DEGs to verify the accuracy of the sequencing by qPCR. RESULTS: Compared with the 47DG group, sperm motility (P < 0.05), sperm density (P < 0.01), and testis weight (P < 0.05) were significantly increased in roosters in the D group. Further RNA-seq analysis of the testis between the D group and 47DG group identified 61 DEGs, with 21 up-regulated and 40 down-regulated. Functional enrichment analysis showed that the DEGs were primarily enriched in the cytokine-cytokine receptor interaction, Wnt signaling pathway, MAPK signaling pathway, TGF-ß signaling pathway, and focal adhesion pathway. The qRT-PCR results showed that the expression trend of these genes was consistent with the sequencing results. WNT5A, FGFR3, AGTR2, TGFß2, ROMO1, and SLC26A7 may play a role in testis development and spermatogenesis. This study provides fundamental data to enhance the reproductive value of aging roosters.

Five years of change in adult twins: longitudinal changes of genetic and environmental influence on epigenetic clocks.

BACKGROUND: Epigenetic clocks were known as promising biomarkers of aging, including original clocks trained by individual CpG sites and principal component (PC) clocks trained by PCs of CpG sites. The effects of genetic and environmental factors on epigenetic clocks are still unclear, especially for PC clocks. METHODS: We constructed univariate twin models in 477 same-sex twin pairs from the Chinese National Twin Registry (CNTR) to estimate the heritability of five epigenetic clocks (GrimAge, PhenoAge, DunedinPACE, PCGrimAge, and PCPhenoAge). Besides, we investigated the longitudinal changes of genetic and environmental influences on epigenetic clocks across 5 years in 134 same-sex twin pairs. RESULTS: Heritability of epigenetic clocks ranged from 0.45 to 0.70, and those for PC clocks were higher than those for original clocks. For five epigenetic clocks, the longitudinal stability was moderate to high and was largely due to genetic effects. The genetic correlations between baseline and follow-up epigenetic clocks were moderate to high. Special unique environmental factors emerged both at baseline and at follow-up. PC clocks showed higher longitudinal stability and unique environmental correlations than original clocks. CONCLUSIONS: For five epigenetic clocks, they have the potential to identify aging interventions. High longitudinal stability is mainly due to genetic factors, and changes of epigenetic clocks over time are primarily due to changes in unique environmental factors. Given the disparities in genetic and environmental factors as well as longitudinal stability between PC and original clocks, the results of studies with original clocks need to be further verified with PC clocks.

Causal effects of denture wearing on epigenetic age acceleration and the mediating pathways: a mendelian randomization study.

BACKGROUND: The epigenetic-age acceleration (EAA) represents the difference between chronological age and epigenetic age, reflecting accelerated biological aging. Observational studies suggested that oral disorders may impact DNA methylation patterns and aging, but their causal relationship remains largely unexplored. This study aimed to investigate potential causal associations between dental traits and EAA, as well as to identify possible mediators. METHODS: Using summary statistics of genome-wide association studies of predominantly European ancestry, we conducted univariable and multivariable Mendelian randomization (MR) to estimate the overall and independent effects of ten dental traits (dentures, bleeding gums, painful gums, loose teeth, toothache, ulcers, periodontitis, number of teeth, and two measures of caries) on four EAA subtypes (GrimAge acceleration [GrimAA], PhenoAge acceleration [PhenoAA], HannumAge acceleration [HannumAA] and intrinsic EAA [IEAA]), and used two-step Mendelian randomization to evaluate twelve potential mediators of the associations. Comprehensive sensitivity analyses were used to verity the robustness, heterogeneity, and pleiotropy. RESULTS: Univariable inverse variance weighted MR analyses revealed a causal effect of dentures on greater GrimAA (ß: 2.47, 95% CI: 0.93-4.01, p = 0.002), PhenoAA (ß: 3.00, 95% CI: 1.15-4.85, p = 0.001), and HannumAA (ß: 1.96, 95% CI: 0.58-3.33, p = 0.005). In multivariable MR, the associations remained significant after adjusting for periodontitis, caries, number of teeth and bleeding gums. Three out of 12 aging risk factors were identified as mediators of the association between dentures and EAA, including body mass index, body fat percentage, and waist circumference. No evidence for reverse causality and pleiotropy were detected (p > 0.05). CONCLUSIONS: Our findings supported the causal effects of genetic liability for denture wearing on epigenetic aging, with partial mediation by obesity. More attention should be paid to the obesity-monitoring and management for slowing EAA among denture wearers.

DNA Methylation-derived biological age and long-term mortality risk in subjects with type 2 diabetes.

BACKGROUND: Individuals with type 2 diabetes (T2D) face an increased mortality risk, not fully captured by canonical risk factors. Biological age estimation through DNA methylation (DNAm), i.e. the epigenetic clocks, is emerging as a possible tool to improve risk stratification for multiple outcomes. However, whether these tools predict mortality independently of canonical risk factors in subjects with T2D is unknown. METHODS: Among a cohort of 568 T2D patients followed for 16.8 years, we selected a subgroup of 50 subjects, 27 survived and 23 deceased at present, passing the quality check and balanced for all risk factors after propensity score matching. We analyzed DNAm from peripheral blood leukocytes using the Infinium Human MethylationEPIC BeadChip (Illumina) to evaluate biological aging through previously validated epigenetic clocks and assess the DNAm-estimated levels of selected inflammatory proteins and blood cell counts. We tested the associations of these estimates with mortality using two-stage residual-outcome regression analysis, creating a reference model on data from the group of survived patients. RESULTS: Deceased subjects had higher median epigenetic age expressed with DNAmPhenoAge algorithm (57.49 [54.72; 60.58] years. vs. 53.40 [49.73; 56.75] years; p = 0.012), and accelerated DunedinPoAm pace of aging (1.05 [1.02; 1.11] vs. 1.02 [0.98; 1.06]; p = 0.012). DNAm PhenoAge (HR 1.16, 95% CI 1.05-1.28; p = 0.004) and DunedinPoAm (HR 3.65, 95% CI 1.43-9.35; p = 0.007) showed an association with mortality independently of canonical risk factors. The epigenetic predictors of 3 chronic inflammation-related proteins, i.e. CXCL10, CXCL11 and enRAGE, C-reactive protein methylation risk score and DNAm-based estimates of exhausted CD8 + T cell counts were higher in deceased subjects when compared to survived. CONCLUSIONS: These findings suggest that biological aging, as estimated through existing epigenetic tools, is associated with mortality risk in individuals with T2D, independently of common risk factors and that increased DNAm-surrogates of inflammatory protein levels characterize deceased T2D patients. Replication in larger cohorts is needed to assess the potential of this approach to refine mortality risk in T2D.

Achilles' spear: A new therapeutic target for age-related diseases.

The role of the senescence-associated secretory phenotype (SASP) in the development of age-related diseases is significant, and its control promises to have a tremendous positive impact on health. A recent study has identified a new mechanism for SASP regulation, titled miMOMP. Failure to regulate SASP would dramatically increase the risk of various age-related health problems. Nonetheless, we have not completely comprehended how to modulate SASP. In this commentary, we summarise the specific mechanisms by which miMOMP regulates SASP and outline possible future research directions. Moreover, potential risks and obstacles to the clinical translation of miMOMP are also presented.

Developing transcriptomic signatures as a biomarker of cellular senescence.

Cellular senescence is a cell fate driven by different types of stress, where damaged cells exit from the cell cycle and, in many cases, develop an inflammatory senescence-associated secretory phenotype (SASP). Senescence has often been linked to driving aging and the onset of multiple diseases conferred by the harmful SASP, which disrupts tissue homeostasis and impairs the regular function of many tissues. This phenomenon was first observed in vitro when fibroblasts halted replication after approximately 50 population doublings. In addition to replication-induced senescence, factors such as DNA damage and oncogene activation can induce cellular senescence both in culture and in vivo. Despite their contribution to aging and disease, identifying senescent cells in vivo has been challenging due to their heterogeneity. Although senescent cells can express the cell cycle inhibitors p16Ink4a and/or p21Cip1 and exhibit SA-ß-gal activity and evidence of a DNA damage response, there is no universal biomarker for these cells, regardless of inducer or cell type. Recent studies have analyzed the transcriptomic characteristics of these cells, leading to the identification of signature gene sets like CellAge, SeneQuest, and SenMayo. Advancements in single-cell and spatial RNA sequencing now allow for analyzing senescent cell heterogeneity within the same tissue and the development of machine learning algorithms, e.g., SenPred, SenSig, and SenCID, to discover cellular senescence using RNA sequencing data. Such insights not only deepen our understanding of the genetic pathways driving cellular senescence, but also promote the development of its quantifiable biomarkers. This review summarizes the current knowledge of transcriptomic signatures of cellular senescence and their potential as in vivo biomarkers.

The association between sleep quality and accelerated epigenetic aging with metabolic syndrome in Korean adults.

BACKGROUND: Healthy sleep is vital for maintaining optimal mental and physical health. Accumulating evidence suggests that sleep loss and disturbances play a significant role in the biological aging process, early onset of disease, and reduced lifespan. While numerous studies have explored the association between biological aging and its drivers, only a few studies have examined its relationship with sleep quality. In this study, we investigated the associations between sleep quality and epigenetic age acceleration using whole blood samples from a cohort of 692 Korean adults. Sleep quality of each participant was assessed using the validated Pittsburgh Sleep Quality Index (PSQI), which encompassed seven domains: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbance, use of sleep medication, and daytime dysfunction. Four epigenetic age accelerations (HorvathAgeAccel, HannumAgeAccel, PhenoAgeAccel, and GrimAgeAccel) and the pace of aging, DunedinPACE, were investigated for epigenetic aging estimates. RESULTS: Among the 692 participants (good sleepers [n = 441, 63.7%]; poor sleepers [n = 251, 36.3%]), DunedinPACE was positively correlated with PSQI scores in poor sleepers ( γ =0.18, p < 0.01). GrimAgeAccel ( ß =0.18, p = 0.02) and DunedinPACE ( ß =0.01, p < 0.01) showed a statistically significant association with PSQI scores only in poor sleepers by multiple linear regression. In addition, every one-point increase in PSQI was associated with a 15% increase in the risk of metabolic syndrome (MetS) among poor sleepers (OR = 1.15, 95% CI = 1.03-1.29, p = 0.011). In MetS components, a positive correlation was observed between PSQI score and fasting glucose ( γ = 0.19, p < 0.01). CONCLUSIONS: This study suggests that worsening sleep quality, especially in poor sleepers, is associated with accelerated epigenetic aging for GrimAgeAccel and DundinePACE with risk of metabolic syndrome. This finding could potentially serve as a promising strategy for preventing age-related diseases in the future.