Longevity Papers

The epidemiological observational studies unveiled that aging is one of the risk factors for liver fibrosis, and the hepatic tissues in the elderly harbor more fibrotic lesions when compared to those in young people. Previous investigations found that TGFβ1 was elevated with aging and promoted liver fibrosis. However, the underlying mechanisms of aging and liver fibrosis remain largely unknown.

A new DNA methylation biomarker, Dunedin Pace of Aging Calculated from the Epigenome (DunedinPACE), is associated with healthy lifespan in several European ancestry cohorts. Few studies have examined the relation between dietary quality and DunedinPACE in African American and White adults with longitudinal assessments. To assess the relationship between diet quality and DunedinPACE, we used longitudinal data from African American and White 30-64 year old adults living above and below poverty. Participants' DunedinPACE scores and dietary assessments were calculated at two time points, approximately 5 years apart. Numbers of participants (n = 421; mean age 49 years) were balanced by race, sex, and poverty status. Diet quality was assessed using two different dietary indexes: Dietary Inflammatory Index (DII) and Healthy Eating Index-2010 (HEI). Linear mixed model regression examined the longitudinal association of DunedinPACE with DII and HEI adjusted by age, race, poverty status, BMI, and smoking status. Initial mean values of DII were 3.34 (SD = 2.16) and HEI was 40.67 (SD = 11.69), indicating a pro-inflammatory dietary pattern and low diet quality in this cohort. The initial mean DunedinPACE score was 1.07. We found that a higher DII score was associated with higher DunedinPACE score (β = 0.009; p < 0.001), higher HEI score was associated with lower DunedinPACE score (β =  - 0.001; p = 0.032), and that these relationships were consistent over time. Overall, lower dietary quality was associated with a faster pace of aging captured by DunedinPACE score. Our findings demonstrate the independent contribution of diet quality to healthy aging-related epigenetic mechanisms.

Advances in single-cell sequencing have deepened our understanding of cellular identities. However, because they inherently capture only static snapshots, after which no further observations are possible, we cannot compare past and present profiles within the same cell. Thus, multi-time-point whole-genome profiling at single-cell resolution has been a long-standing goal. Here, we introduce the History Tracing-sequencing (HisTrac-seq) platform, which enzymatically labels genomic DNA adenine to bookmark gene regulatory statuses. This first enabled the profiling of transcriptomic and epigenetic states in the mouse brain over a period of two months. Furthermore, extending HisTrac-seq to single-cell multi-omics sequencing, we demonstrated the simultaneous mapping of past and present profiles of the same single cells. Analyzing over 93,000 cells, we discovered unexpected, drastic cell identity transitions on a large scale (identity jumps). This phenomenon was previously unobservable with current technologies and revealed a hidden layer of developmental plasticity. HisTrac-seq offers a powerful approach to temporal-multi-omics for disentangling dynamic biological processes involved in development, plasticity, aging, and disease progression.

Cellular senescence, stable cell cycle arrest that can be triggered in normal cells in response to various intrinsic and extrinsic stressors, has been highlighted as one of the most important mechanisms involved in kidney diseases. It not only serves as a fundamental biological process promoting normal organogenesis and successful wound repair but also contributes to organ dysfunction, tissue fibrosis, and the generalized aging phenotype. Moreover, senescent cells exhibit reduced regenerative capacity, which impairs renal function recovery from injuries. Importantly, senescent cells are involved in immune regulation via secreting a diverse array of proinflammatory and profibrotic factors known as senescence-associated secretory phenotype (SASP) with autocrine, paracrine, and endocrine activities. Thus, eliminating detrimental senescent cells or inhibiting SASP production holds great promise for developing innovative therapeutic strategies for kidney diseases. In this review, we summarize the current knowledge of the intricate mechanisms and hallmarks of cellular senescence in kidney diseases and emphasize novel therapeutic targets, including epigenetic regulators, G protein-coupled receptors, and lysosome-related proteins. Particularly, we highlight the recently identified senotherapeutics, which provide new therapeutic strategies for treating kidney diseases.

In youth, energy deprivation primarily results from fasting. Because inconsistent nutrient availability is common for most organisms, natural selection has provided mechanisms that detect nutrient-deprived states, followed by adaptive responses that increase the likelihood of survival until nutrients are restored. Organisms respond to fasting first by oxidizing the cellular cytoplasm, then by activating redox-sensitive kinases - namely the c-Jun N-terminal kinases (henceforth collectively termed JNK) and AMP-activated protein kinase (AMPK) - and Foxo transcription factors (henceforth referred to collectively as Foxo). Together, JNK, AMPK and Foxo induce autophagy. This fasting response is beneficial because autophagy supplies substrates for metabolism that replace missing nutrients and enhances removal of damaged organelles such as mitochondria, which increases lifespan and enhances survival through the fast. Although this response is adaptive in the context of acute nutrient deprivation, it can have harmful consequences when activated chronically. Here, I propose that cells from old organisms are constitutively energy deprived because of lifetime accumulation of dysfunctional mitochondria. As a result, these cells reactivate the fasting response seen in youth. Hence, old organisms constitutively oxidize the cellular cytoplasm and activate JNK, AMPK, Foxo and, finally, autophagy. However, because energy deprivation in old age is driven by mitochondrial insufficiency rather than nutrient deprivation, this response fails to restore ATP production and becomes chronic and deleterious. I suggest that many age-related pathologies, such as oxidative stress, neurodegeneration and sarcopenia, result from aberrant activation of the fasting response.

Aging is an intrinsic biological decline marked by multidimensional alterations spanning molecular, cellular, tissue, and organ levels. One hallmark of aging is the progressive deterioration of immune function, a condition referred to as immunosenescence. This process often involves a persistent, mild, and non-infectious inflammatory state across the body, commonly described as inflammaging. The regulation of age-related immune and inflammatory processes is critically influenced by epigenetic mechanisms, such as alterations in DNA methylation patterns, histone modifications, chromatin structure reorganization, and the regulatory actions of non-coding RNAs. Recent research has increasingly focused on the regulatory roles of post-translational modifications (PTMs), including histone methylation, acetylation, ubiquitination, and O-GlcNAcylation, have been widely recognized as fundamental modulators of immunoinflammatory processes in aging. In this review, we provide a comprehensive overview of histone modification-mediated mechanisms involved in the regulation of immunosenescence. We further highlight their functional roles from the perspective of immune inflammation and explore potential therapeutic strategies targeting histone modifications to mitigate immunosenescence.

Metabolic changes can play a critical role in the structural and functional decline of the aging cardiovascular system. In this review, we examine how key metabolic pathways and regulatory mechanisms influence cardiovascular aging, highlighting recent studies into metabolic flexibility, mitochondrial function, nutrient sensing, and energy utilization in the aging heart. Potential metabolic-based interventions to mitigate cardiac aging are also discussed.

Physical activity (PA) and sedentary behavior (SB) are two key lifestyle factors with profound implications for bone health across the lifespan. While PA is recognized for its positive effects on bone mineral density (BMD) and fracture prevention, emerging evidence highlights the detrimental consequences of prolonged sedentary time, independent of PA levels. This review synthesizes current knowledge on the impact of PA and SB on bone health outcomes, focusing on BMD and fracture risk in children, adolescents, adults, and older populations. A selection of epidemiological studies, systematic reviews, and meta-analyses was analyzed to explore the associations between movement behaviors and bone health indicators across different life stages. Particular attention was given to studies objectively measuring SB and PA and to the substitution effects of sedentary time with light or moderate-to-vigorous PA. In children and adolescents, higher levels of SB are associated with lower BMD, particularly at weight-bearing sites, while participation in weight-bearing and impact-loading PA positively influences bone mass accrual. In adults and older individuals, regular PA, including moderate-to-vigorous intensity weight-bearing PA and resistance training activities, is consistently linked to greater BMD and reduced fracture risk. Conversely, high sedentary time is associated with lower BMD and increased fracture incidence, particularly among frail or pre-frail individuals. Importantly, replacing sedentary time with even light-intensity PA yields measurable benefits for bone health, particularly among older adults and postmenopausal women, and may contribute to a reduced risk of fractures, although evidence remains limited. Promoting PA while minimizing SB should be central to clinical practice and public health policies aimed at maximizing and preserving skeletal health and preventing osteoporotic fractures, across the lifespan. Early intervention, continuous promotion across life stages, and adherence to WHO guidelines offer an effective, evidence-based framework for lifelong bone health maintenance.

Both mosaic loss of the Y chromosome (mLOY) and frailty are related to human aging. However, their relationship and the potential mediating effect of mLOY on the association between frailty and mortality risk remain understudied. A total of 8947 middle-aged and older male adults from the Dongfeng-Tongji cohort were included in this study. Causes of death were tracked till the end of year 2018. Frailty index (FI) was calculated by 34 deficits and categorized into three groups: robust (FI ≤ 0.10), prefrail (0.10< FI < 0.25), and frail (FI ≥ 0.25). mLOY was estimated by genotyping data and presented as the proportion of leukocytes with mLOY. Cox proportional hazards regressions were used to assess the associations of mLOY with risk of mortality. Mediation effects of mLOY were estimated under a counterfactual-based framework. In this prospective study, the prevalence of prefrail and frail participants were 50.2% and 29.0%, respectively. Compared to the robust participants, frail males exhibited significantly increased level of mLOY [β (95%CI) =1.15 (0.62, 1.68)]. Frailty and mLOY showed significant associations with increased mortality risks, and mLOY may mediate a separate 27.3%, 53.9%, and 23.5% of the association of frailty with the risks of death from all causes, cancer, and other causes. These relationships were confined to males aged ≥65 years. These findings unveiled the relationships of frailty with mLOY and the mediation role of mLOY in the frailty-mortality association among older males aged ≥65 years. Our results highlighted the importance of mLOY during male aging.

After stroke, microglia and hematogenous macrophages, together referred to as MΦ, clear dead cells and cellular debris in the infarcted brain through phagocytosis as an essential part of the recovery process. However, the phagocytic capability of MΦ declines with age. Furthermore, aged MΦ become overactivated in response to stroke, enhancing secondary brain injury. In this study, we demonstrated that by reversing the age-related dysfunctions in MΦ through activating the retinoid x receptor (RXR), the recovery after stroke in the aged brain could be improved. Using RNA sequencing, we compared the transcriptomes between MΦ isolated from the brains of young and aged male mice. We observed higher levels of pro-inflammatory genes and lower levels of phagocytosis-facilitating genes (

The mitochondrial transcription factor A (TFAM) is essential for mitochondrial genome maintenance. It binds to mitochondrial DNA (mtDNA) and determines the abundance, packaging and stability of the mitochondrial genome. Because its function is tightly associated with mtDNA, TFAM has a protective role in mitochondrial diseases and supportive studies demonstrate reversal of disease phenotypes by TFAM overexpression. In addition, TFAM deficiency has been shown to cause release of mtDNA into the cytosol and activation of the cGAS/STING innate immune response pathway. As such, TFAM presents as a unique target for therapeutic intervention, but limited efforts for activators have been reported. Herein we disclose novel TFAM small molecule modulators with sub-micromolar activity. Our results demonstrate that these compounds result in increase of TFAM protein levels and mtDNA copy number. This results in inhibition of a mtDNA stress-mediated inflammatory response by preventing mtDNA escape into the cytosol. Furthermore, we see beneficial effects in cellular disease models in which boosting TFAM activity has been advanced as a disease modifying strategy including improved energetics in MELAS cybrid cells and a decrease of fibrotic markers in Systemic Sclerosis (SSc) fibroblasts. These results highlight the therapeutic potential of using small molecule TFAM activators in indications characterized by mitochondrial dysfunction.

Aging is a series of adverse changes over time that increases mortality risk. Several hypotheses have been proposed to explain aging, including Leslie Orgel's Error-Catastrophe Theory, which asserts that translation errors erode the translational machinery, become self-amplifying, and eventually lead to death. Evidence for the theory is scarce, especially regarding intra-specific fidelity-longevity correlations. Here, we demonstrate that the correlation can be hidden by the constrained evolution of translational fidelity, but remains detectable in long-lived samples. Measuring the lifespan and translational fidelity of a panel of BY × RM yeast recombinant haploid progenies, we validate the fidelity-longevity correlation. QTL analyses reveal that both fidelity and longevity are most strongly associated with a locus encoding vacuolar protein sorting-associated protein 70(VPS70). Replacing VPS70 in BY by its RM allele reduces translation error by ~8.0% and extends lifespan by ~8.9% through a vacuole-dependent mechanism. Our results support the impact of translational fidelity on intra-specific longevity variation.

Aging is increasingly understood not as the passive accumulation of molecular damage, but as the cumulative cost of unresolved physiological adaptation under bioenergetic constraint. This review introduces Exposure-Related Malnutrition (ERM) as a mechanistically grounded and clinically actionable phenotype of early maladaptation. ERM arises from sustained metabolic strain during chronic stress exposure and manifests not through overt weight loss or nutrient deficiency, but through subtle, multisystem declines in physical, cognitive, and regenerative capacity. These include fatigue, impaired recovery, cognitive slowing, immune dysregulation, chronic pain, anabolic resistance, and reproductive decline-features often missed by classical malnutrition criteria. We propose a unifying framework-Respond → Adapt → Resolve-to model the trajectory of stress response and resolution, emphasizing the critical role of bioenergetic availability in shaping divergent outcomes. When metabolic substrates are insufficient, resolution fails and the system defaults to a trade-off state, prioritizing immediate survival over long-term maintenance. ERM represents this inflection point: a reversible, energy-constrained condition that precedes frailty and chronic disease. We review interconnected mechanisms-including neuroendocrine activation, immune reprogramming, skeletal muscle catabolism, translational suppression, and mitochondrial distress-that create a self-perpetuating loop of maladaptive adaptation. We map ERM onto key hallmarks of aging, propose a multidimensional staging model, and outline clinical strategies to detect and reverse ERM using dynamic biomarkers, functional assessments, and circadian-aligned lifestyle interventions. By reframing aging as a failure of adaptive resolution, this framework offers a novel lens to extend healthspan-via early detection of metabolic compromise and restoration of resilience before functional decline becomes irreversible.

Calorie restriction (CR) improves health and longevity. CR induces a periodic fasting cycle in mammals; our study compares CR with unanticipated fasting (F), when the food is unexpectedly withheld. F induces hepatic steatosis, whereas CR reduces it; surprisingly, the difference is not due to hepatic β-oxidation. Liver transcriptome analysis identifies fatty acid transporters (Slc27a1 and Slc27a2), triglyceride (TAG) synthesis (Gpat4), and lipid storage (Plin2 and Cidec) genes to be upregulated only in F, in agreement with hepatic steatosis. The circadian clock and anticipated fasting contribute to preventing fasting-associated hepatic steatosis in CR. Mechanistically, the Slc27a1, Plin2, and Cidec genes are upregulated, and liver TAGs accumulate in circadian clock mutant mice on CR or if wild-type CR mice miss their anticipated meal. The results highlight the similarities and differences between F and CR, suggesting that circadian clock-dependent gating of transcriptional response to fasting controls lipid homeostasis and prevents hepatic steatosis.

Cannabidiol (CBD), a non-psychoactive cannabinoid, has been studied for its various health-promoting effects recently. This study investigates the effects of dietary CBD to the circadian clock of Drosophila melanogaster as a model animal and its many physiological effect to flies. We showed that CBD extended the period of locomotor activity in a dose-dependent manner, suggesting its influence on the circadian clock. Additionally, CBD improved sleep quality and extended lifespan under starvation conditions. The study also revealed enhanced rhythmicity in Close Proximity (CP) rhythm and increased eggs reproduction with dietary CBD supplementation. Furthermor, CBD attenuates age-related motor dysfunction in wild-type and Parkinson's disease (PD) model in Drosophila. These findings strongly suggest that appropriate amount of CBD affects the circadian rhythms, sleep, life span, CP rhythm, egg reproduction and motor function of Drosophila melanogaster, and providing a basic data for exploring its potential applications in managing circadian-related disorders in other animals.

The progressive loss of cerebral white matter during aging contributes to cognitive decline, but whether reduced blood flow is a cause or a consequence remains debatable. Using deep multi-photon imaging in mice, we examined microvascular networks perfusing myelinated tissues in cortical layer 6 and the corpus callosum. We identified sparse, wide-reaching venules, termed principal cortical venules, which exclusively drain deep tissues and resemble the vasculature at the human cortex and U-fiber interface. Aging led to selective constriction and rarefaction of capillaries in deep branches of principal cortical venules. This resulted in mild hypoperfusion that was associated with microgliosis, astrogliosis and demyelination in deep tissues, but not the upper cortex. Induction of comparable hypoperfusion in adult mice using carotid artery stenosis triggered a similar tissue pathology specific to layer 6 and the corpus callosum. Thus, impaired capillary-venous drainage is a contributor to hypoperfusion and a potential therapeutic target for preserving blood flow to white matter during aging.

Proteostasis, or protein homeostasis, is a tightly regulated network of cellular pathways essential for maintaining proper protein folding, trafficking, and degradation. Neurons are particularly vulnerable to proteostasis collapse due to their post-mitotic and long-lived nature and thus represent a unique cell type to understand the dynamics of proteostasis throughout development, maturation, and aging. Here, we utilized a dual-species co-culture model of human excitatory neurons and mouse glia to investigate cell type-specific, age-related changes in the proteostasis network using data-independent acquisition (DIA) LC-MS/MS proteomics. We quantified branch-specific unfolded protein response (UPR) activation by monitoring curated effector proteins downstream of the ATF6, IRE1/XBP1s, and PERK pathways, enabling a comprehensive, unbiased evaluation of UPR dynamics during neuronal aging. Species-specific analysis revealed that aging neurons largely preserved proteostasis, although they showed some signs of collapse, primarily in ER-to-Golgi transport mechanisms. However, these changes were accompanied by upregulation of proteostasis-related machinery and activation of the ATF6 branch, as well as maintenance of the XBP1s and PERK branches of the UPR with age. In contrast, glia exhibited broad downregulation of proteostasis factors and UPR components, independent of neuronal presence. Furthermore, we quantified stimulus-specific modulation of select UPR branches in aged neurons exposed to pharmacologic ER stressors. These findings highlight distinct, cell-type-specific stress adaptations during aging and provide a valuable proteomic resource for dissecting proteostasis and UPR regulation in the aging brain.

Biological age estimation, derived from physiological signatures such as brain activity, is emerging as a valuable biomarker for health and well-being. Discrepancies between biological and chronological age have been linked to multiple physical, mental, and cognitive health outcomes. However, current approaches primarily focus on MRI-based measurements, which are costly, challenging to obtain, and contraindicated for certain populations. This study explores polysomnographic (PSG) sleep signals, which capture activity from multiple physiological systems, as an accessible alternative for biological age prediction. Sleep serves as an ideal platform for age prediction due to its standardized data collection protocols, abundant public data resources, and the presence of well-documented age-related changes in sleep architecture. Additionally, the proliferation of consumer sleep monitoring tools offers potential for widespread application and longitudinal analysis. We trained transformer-based neural network models on over 10,000 nights of PSG data and performed rigorous internal and external validation. Our best models achieved age predictions with an absolute error of 5-10 years from just a single physiological time series input and were especially accurate with respect to certain stages of sleep (specifically, N2). Electroencephalography (EEG) signals were essential for capturing sleep architecture changes that correlate with age, while electrocardiogram (ECG) signals, although less accurate overall, tended to overestimate age in association with health conditions such as elevated blood pressure, higher body mass index, and sleep apnea. Despite strong performance, generalization beyond the training dataset remains a challenge (age prediction errors increase between internal validation and external data by at least 3 to 5 years). These findings show that noninvasive sleep-derived electrophysiological signals, particularly EEG, can rival MRI-based age prediction models in accuracy-while offering lower cost, greater accessibility, and broader applicability.

A strong regenerative capacity is a hallmark of youth. From the tadpole's tail to the mammalian brain, young animals of many species can repair or regrow damaged tissues more effectively than older animals. Here, we take a broad perspective on ageing, inclusive of the transition from the developmental processes of embryogenesis through maturation to adulthood, as well as the processes that occur as an animal reaches the end of its lifespan. In some cases, the loss of regenerative capacity occurs once development is complete, and in others it occurs in the latter part of the animal's life. Regardless, the loss of regenerative capacity is caused by a failure to activate genes required for successful regeneration. This, in part, can be attributed to restructuring of the epigenome.

Aging can be understood as a consequence of the declining force of natural selection with age. Consistent with this, the antagonistic pleiotropy theory of aging proposes that aging arises from trade-offs that favor early growth and reproduction. However, evidence supporting antagonistic pleiotropy in humans remains limited.

Cellular senescence is a major contributor to aging-related degenerative diseases, including Alzheimer's disease (AD), but much less is known about the key cell types and pathways driving senescence mechanisms in the brain. We hypothesized that dysregulated cholesterol metabolism is central to cellular senescence in AD. We analyzed single-cell RNA-seq data from the ROSMAP and SEA-AD cohorts to uncover cell type-specific senescence pathologies. In ROSMAP snRNA-seq data (982,384 nuclei from postmortem prefrontal cortex), microglia emerged as central contributors to AD-associated senescence phenotypes among non-neuronal cells. Homeostatic, inflammatory, phagocytic, lipid-processing, and neuronal-surveillance microglial states were associated with AD-related senescence in both ROSMAP (152,459 microglia nuclei from six brain regions) and SEA-AD (82,486 microglia nuclei) via integrative analysis. We assessed top senescence-associated bioprocesses and demonstrated that senescent microglia exhibit altered cholesterol-related processes and dysregulated cholesterol metabolism. We identified three gene co-expression modules representing cholesterol-related senescence signatures in postmortem brains. To validate these findings, we applied these signatures to snRNA-seq data from iPSC-derived microglia（iMGs) exposed to myelin, Aβ, apoptotic neurons, and synaptosomes. Treatment with AD-related substrates altered cholesterol-associated senescence signatures in iMGs. This study provides the first human evidence that dysregulated cholesterol metabolism in microglia drives cellular senescence in AD. Targeting cholesterol pathways in senescent microglia is an attractive strategy to attenuate AD progression.

Cardiorespiratory fitness (CRF) is a strong predictor of mortality and non-communicable disease risk, but its underlying molecular mechanisms are poorly understood. In this study, we identified CRF associated metabolomics (n=30,010) and proteomics (n=4,235) signatures in UK Biobank participants. These signatures were validated in an independent sample of UK participants with data on metabolomics (n=198,871) and proteomics (n=29,961) to investigate prospective associations with all-cause mortality and non-communicable diseases. Our findings reveal that higher CRF is characterized by downregulation of pathways related to inflammation, triglyceride metabolism, glycolysis, and vascular dysfunction, and upregulation of pathways related to cholesterol transport, apolipoprotein particle size, and cytoskeletal remodeling. Leveraging these insights, we developed two novel metabolic CRF signatures, one metabolomic and one proteomic, that robustly reflect CRF levels (R2: 0.49-0.60). Over an average of 9 years of follow-up, we observed 27,659 cases of all-cause mortality. Across the discovery and validation cohorts, we found that the metabolomic CRF signature was strongly associated with a 34-39% lower risk of all-cause mortality and markedly reduced risk of type 2 diabetes (89-91%), cardiovascular disease (35-39%), and colorectal cancer (32-54%). Additionally, the proteomic CRF signature was associated with a 17% lower risk of all-cause mortality, and with a 22-39% lower risk of type 2 diabetes and cardiovascular disease. Together, these findings suggest that circulating metabolites and proteins can capture the physiological imprint of CRF and may serve as indirect biomarkers for predicting mortality and non-communicable disease risk.

Using 100 technical replicate samples from two adult buccal cohorts, we compared technical methylation variability and signal strength between the Infinium MethylationEPIC v2.0 array and the Twist Human Methylome Panel across 753,648 shared CpGs. Twist methylation sequencing showed skewed methylation distributions and fewer highly correlated CpGs than MethylationEPIC arrays. Variance analysis revealed a skew toward higher signal strength in MethylationEPIC datasets, with a subset of CpGs showing high signal strength in both methylation sequencing and array datasets. Despite these biases, four principal component (PC) trained epigenetic clocks (pcHorvath1, pcHorvath2, pcHannum, and pcDNAm PhenoAge) were robust across both technologies, even with missing data. While pcHannum and pcDNAm PhenoAge were similarly reproducible with mean absolute replicate difference (MRD) values ranging from 1.014 years to 1.194 years, pcHorvath1 was more reproducible in arrays (MRD = 0.459 years) than methylation sequencing (MRD = 2.320 years) and pcHorvath2 was more reproducible in methylation sequencing (MRD = 0.760 years) than arrays (MRD = 1.011 years). Furthermore, original non-PC versions of these clocks were less reproducible in Twist datasets and, as an example of this, MRD for uncorrected clocks went as high as 15.498 years in arrays and as high as 20.180 years in methylation sequencing. Obvious differences in age prediction were also observed in original clocks compared to their PC-trained versions across both technologies (with a mean absolute difference ranging from 4.492 years to 46.724 years). This underscores the need for careful selection of epigenetic clocks and technology-specific adjustments when optimizing for accuracy and reproducibility.

Navigational skills are essential for interacting with our environment, supported by multiple types of spatial representations. We investigated age-related differences in spatial memory using a virtual reality task that manipulated viewpoints between the encoding and retrieval of one or four-object locations. The task investigates compensatory mechanisms in aging, specifically how spatial updating via self-motion affects spatial memory. We tested 21 young adults (ages 19-36) and 23 older adults (ages 63-80). The task involved three movement conditions: same-viewpoint condition, where participants walked away and returned to the same viewpoint; shifted-viewpoint (walking) condition where participants walked to a different viewpoint, enabling continuous updates of their egocentric representations through self-motion; and shifted-viewpoint (teleport) condition where participants teleported to the other viewpoint, involving both a virtual translation and rotation of the participant's view. Retrieval was tested by asking participants to place each object at its previously seen location. Average displacement error was affected by age group, object configuration, and movement condition, with an interaction between age and movement condition. Differences in movement conditions were primarily driven by older participants, who were most accurate from the same viewpoint. In shifted-viewpoint conditions, teleportation-where self-motion cues were absent-led to significantly greater errors than walking in the older group. Our results highlight the role of spatial updating in supporting spatial memory and suggest that age-related decline in allocentric representations can be mitigated by continuous updating of egocentric representations by self-motion. We speculate that the use of spatial updating might be impaired early in the progression to Alzheimer's dementia due to entorhinal cortical pathology. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

While it is well-documented that plasma oxytocin (OXT) levels decline with age, the underlying mechanisms remain elusive. This study aimed to elucidate the physiological mechanisms contributing to this age-related decrease in plasma OXT and the possible use of OXT supplementation on improving age-related decline of neural function. Comparing young (9 weeks) and aged (> 45 weeks) mice, aged mice showed reduced plasma OXT levels, an increase in the inflammation marker hs-CRP, and decreased OXT-positive neurons in the hypothalamus. Aged mice showed signs of epigenetic changes in the hypothalamus as indicated by decreased ten-eleven translocation (TET) family mRNA expression, decreased 5-hydroxymethylcytosine (5hmC) positive neurons, and downregulated mitochondrial respiratory complex IV (COX IV) expression. Nasal application of OXT (10 μg/day) for 10 days to aged mice resulted in normalized plasma OXT and inflammation levels and a recovery of OXT-positive neurons, TET2 mRNA levels, 5hmC positive neurons, and COX IV expression. Directly confirming a role for OXTR signaling, TET2, COX IV, and 5hmC in the hypothalamus and hippocampus were also found to be decreased in oxytocin receptor (OXTR) null mice, compared with age-matched WT mice. Furthermore, we show that methylation as a result of aging decreases OXT production in hypothalamic neurons, thereby reducing circulating plasma OXT levels, which can be reversed by nasal OXT treatment. The data presented here suggest that aging, DNA methylation, mitochondrial dysfunction, inflammation, and senescence are interconnected in a vicious cycle, which can be successfully interrupted by OXT treatment.

Antioxidant decline is crucial to driving age-related macular degeneration (AMD). Ferroptosis, a regulated cell death mediated by iron-dependent hydroxyl radical-catalyzed phospholipid peroxidation through the Fenton reaction, is implicated in various chronic degenerative diseases. Here, we show that superoxide activates ferroptosis in retinal pigment epithelium (RPE) cells via the Haber-Weiss reaction, thereby contributing to dry AMD. We silenced manganese superoxide dismutase (MnSOD/SOD2) in RPE cells and exposed the cells to blue light to induce ferroptosis by increasing superoxide anions. Additionally, MnSOD deficiency triggered the Hsp70-linked ubiquitin-dependent degradation of GPX4, further aggravating ferroptosis. We validated blue light-induced ferroptosis in the RPE layer as a driver of the dry AMD phenotype in Sod2