Longevity Papers

Somatic stem cells are characterized by their low overall protein-synthesis rates, a feature implicated in driving their stemness. However, how aging reshapes the translational landscape of stem cells remains poorly understood. Here, we present an in vivo single-cell ribosome profiling strategy to monitor tissue-wide translational landscapes of the epidermis during aging. By implementing ribosomal elongation-inhibited cell isolation and switching to RNase I, we expand the applicability of single-cell ribosome profiling to in vivo systems and facilitate the evaluation of triplet periodicity, a hallmark of high-quality data. Leveraging this strategy, we document the in vivo translational landscapes of the major epidermal cell types, outline cell-type-specific translational efficiencies, and identify a pronounced translational reprogramming of AP-1 subunits specifically in aged epidermal stem cells. Our study illustrates the power of in vivo single-cell ribosome profiling to map cell-type-specific translational programs and offers a scalable strategy for tissue-wide interrogation of translational landscapes.

Diabetic kidney disease (DKD) is a major disease characterized by early albuminuria and heightened risk of renal deterioration. Increased reactive oxygen species (ROS) production, especially in glomeruli, plays an important role in the progression of DKD. ROS also cause activation of Apoptosis signal-regulating kinase 1 (ASK-1), which is implicated in various organ injuries. However, the detailed mechanisms remain unclear. This study investigates ASK-1 activation in advanced DKD and its underlying mechanisms using GS442172, an ASK-1 inhibitor. In the DKD mouse model, activation of ASK-1 was observed. Although inhibition of ASK-1 activation improved hyperpermeability in glomerular endothelial cells. ASK-1 inhibition significantly reduced glomerular injury and albuminuria, while also attenuating tubular damage and interstitial fibrosis. RNA-seq analysis revealed an aging phenotype associated with ASK-1 activation in DKD. In vitro experiments demonstrated ASK-1 activation-induced cellular senescence in tubular cells via redox signaling. These results suggested that the critical role of ASK-1 activation in DKD pathogenesis, implicating glomerular injury, tubular damage, and cellular senescence. ASK-1 inhibitors are promising therapeutic strategies to mitigate the progression of DKD.

Given the potential fundamental function of osteal macrophages in bone pathophysiology, we study here their precise function in experimental osteoporosis. Gene profiling of osteal macrophages from ovariectomized mice demonstrated the upregulation of genes that were involved in oxidative stress, cell senescence, and apoptotic process. A single-cell RNA-Seq analysis revealed that osteal macrophages were heterogeneously clustered into 6 subsets that expressed proliferative, inflammatory, antiinflammatory, and efferocytosis gene signatures. Importantly, postmenopausal mice exhibited an increase in subset 3 that showed a typical gene signature of cell senescence and inflammation. These findings suggest that the decreased production of estrogen due to postmenopausal condition altered the osteal macrophage subsets, resulting in a shift toward cell senescence and inflammatory conditions in the bone microenvironment. Furthermore, adoptive macrophage transfer onto calvarial bone was performed, and mice that received oxidatively stressed macrophages exhibited greater osteolytic lesions than control macrophages, suggesting the role of these cells in the development of inflammaging in the bone microenvironment. Consistently, depletion of senescent cells and the oxidatively stressed macrophage subset alleviated the excessive bone loss in postmenopausal mice. Our data provided insight into the pathogenesis of osteoporosis and shed light on a therapeutic approach for the treatment or prevention of postmenopausal osteoporosis.

The cellular metabolism of macrophages depends on tissue niches and can control macrophage inflammatory or resolving phenotypes. Yet, the identity of signals within tissue niches that control macrophage metabolism is not well understood. Here, using single-cell RNA sequencing of macrophages in early mouse wounds, we find that, rather than gene expression of canonical inflammatory or resolving polarization markers, metabolic gene expression defines distinct populations of early wound macrophages. Single-cell secretomics and transcriptomics identify inflammatory and resolving cytokines expressed by early wound macrophages, and we show that these signals drive metabolic inputs and mitochondrial metabolism in an age-dependent manner. We show that aging alters the metabolome of early wound macrophages and rewires their metabolism from mitochondria to glycolysis. We further show that macrophage-derived Chi3l3 and IGF-1 can induce metabolic inputs and mitochondrial mass/metabolism in aged and bone marrow-derived macrophages. Together, these findings reveal that macrophage-derived signals drive the mitochondrial metabolism of macrophages within early wounds in an age-dependent manner and have implications for inflammatory diseases, chronic injuries, and age-related inflammatory diseases. In BriefThis study reveals that macrophage subsets in early inflammatory stages of skin wound healing are defined by their metabolic profiles rather than polarization phenotype. Using single-cell secretomics, we establish key macrophage cytokines that comprise the in vivo wound niche and drive mitochondrial-based metabolism. Aging significantly alters macrophage heterogeneity and increases glycolytic metabolism, which can be restored to OxPHOS-based metabolism with young niche cytokines. These findings highlight the importance of the tissue niche in driving macrophage phenotypes, with implications for aging-related impairments in wound healing. HighlightsO_LISingle cell transcriptional analysis reveals that reveals that metabolic gene expression identifies distinct macrophage populations in early skin wounds. C_LIO_LISingle-cell secretomic data show that young macrophages contribute to the wound bed niche by secreting molecules such as IGF-1 and Chi3l3. C_LIO_LIOld wound macrophages display altered metabolomics, elevated glycolytic metabolism and glucose uptake, and reduced lipid uptake and mitochondrial mass/metabolism. C_LIO_LIChi3l3 but not IGF-1 secretion is altered in macrophages in an age dependent manner. C_LIO_LIChi3l3 can restore mitochondrial mass/metabolism in aged macrophages. C_LI

Epigenetic modification plays a key role in {beta} cell senescence. In the regulation of gene expression, there is a complex and close relationship between DNA methylation and histone modification. In order to explore its specific mechanism in T2DM {beta} cell senescence, we used postbisulfite aptamer labeling of genome-wide bisulfite-SEQ, chromatin immunocoprecipitation-SEQ, RNA-SEQ, CRISPR/Cas9 TETs knockout, RNA interference, TET2 inhibitors, lentiviral overexpression, and gene knockout mouse models. Our study found that demethylase TET2 was localized in the islets of mice, and the expression level increased with age. TET2 knockout in pancreatic {beta} cells can hypermethylate PTEN, up-regulate MOF and enrich H4K16ac, and reduce the level of aging markers. This study confirmed that TET2-mediated PTEN DNA methylation can promote a new mechanism of {beta} cell senescence by regulating H4K16ac, providing a new molecular mechanism and therapeutic target for T2DM {beta} cell senescence therapy.

Ancient humans used dietary plants and herbs to treat disease and to pursue eternal life. Today, phytochemicals in dietary plants and herbs have been shown to be the active ingredients, some of which have antiaging and longevity-promoting effects. Here, we summarize 210 antiaging phytochemicals in dietary plants and herbs, systematically classify them into 8 groups. We found that all groups of phytochemicals can be categorized into six areas that regulate organism longevity: ROS levels, nutrient sensing network, mitochondria, autophagy, gut microbiota, and lipid metabolism. We review the role of these processes in aging and the molecular mechanism of the health benefits through phytochemical-mediated regulation. Among these, how phytochemicals promote longevity through the gut microbiota and lipid metabolism is rarely highlighted in the field. Our understanding of the mechanisms of phytochemicals based on the above six aspects may provide a theoretical basis for the further development of antiaging drugs and new insights into the promotion of human longevity.

Age-related frailty and reduced physical activity contribute to a degenerative loss of muscle mass, function, and strength, which is known as sarcopenia. Increasing evidence has shown that vitamin D has beneficial effects on the muscle health. However, the molecular mechanisms of vitamin D have not been fully elucidated. In this study, we aimed to demonstrate whether vitamin D can overcome muscle atrophy due to aging, especially with respect to the regulation of myokines.

The dynamical nature of gait increases fall risk for older adults as the Center of Mass (COM) is constantly displaced inside and outside the Base of Support (BOS). Foot placement and leg joint moments are the primary mechanisms controlling dynamic balance. The Margin of Stability (MOS) quantifies the distance between the COM dynamical state and the BOS. While research examined how aging affects the relationship between foot placement and MOS, the relationship to leg moments is unexamined. Examining this relationship would elucidate whether aging increases fall risk from changes in the joint moments controlling the COM. Fourteen older (66.9 ± 4.3 years) and sixteen young (26.3 ± 3.6 years) adults walked along a 12m path for three trials. The MOS, hip and ankle moments in sagittal and frontal planes were analyzed. For the knee, only the sagittal plane was analyzed. MOS was calculated as the distance between the extrapolated-COM and the Center of Pressure per step. Statistical Parametric Mapping independent t-tests assessed group differences. Cross-correlation quantified MOS and joint moment relationships per plane during single-stance. No group differences in walking speed were observed. A larger frontal plane MOS, hip abduction and ankle eversion moment occurred for older adults. Cross-correlation demonstrated moderate and strong relationships for the hip-MOS for both groups in the sagittal plane. Older adults had a larger sagittal plane hip-MOS correlation than young adults. The larger mediolateral MOS in older adults may indicate attempts to avoid lateral balance loss by shifting their COM away from their BOS lateral boundaries during single-stance. However, this strategy moves the COM toward the BOS medial borders potentially pre-maturely terminating the contralateral swing phase during medial destabilization. The stronger sagittal plane hip-MOS relationship in older adults may reflect increased coupling between hip moments and the COM to control dynamic balance.

Over the past decade, ageing clocks have become widely adopted as important tools for understanding biological ageing and have been redefining notions of "pro-longevity" lifestyles. However, this work is still at an early stage. Some leisure activities, such as arts and cultural engagement (ACEng) have never been studied at all, while others such as physical activity (PA) have only received scant attention. In particular, there is little understanding of whether frequency of engagement or diversity (which provides access to more active ingredients) is more important. This study used 3,354 adults in the UK Household Longitudinal Study - a large, nationally-representative cohort study, which includes six derived epigenetic clocks. We used a doubly robust estimation using the inverse-probability-weighted regression adjustment estimator adjusted for demographic, socioeconomic, behavioural and health covariates, data collection gaps and technical covariates of epigenetic clocks. ACEng and PA were related to slower biological ageing in the PhenoAge and DunedinPoAm clocks, although not to the other measured clocks, with comparable effect sizes between ACEng and PA (Lin, Horvath2018, Horvath2013 and Hannum). For ACEng, diversity and frequency of engagement were related to DunedinPoAm, while for PhenoAge, there was a slightly clearer relationship for frequency than diversity. For PA, higher levels of frequency, diversity, and activeness were related to DunedinPoAm, while only the highest diversity and activeness were related to PhenoAge. These findings were all stronger amongst middle-aged and older adults. This was the first study to show a relationship between ACEng and epigenetic ageing, with comparable effect sizes to PA, suggesting the value of its exploration alongside other lifestyle factors. Decelerations in ageing clocks, including those within our study, have been demonstrated to have clinical (as well as statistical) importance, supporting future exploration as to whether lifestyle changes have any value to slowing or potentially reversing epigenetic ageing.

Loss of proteostasis is well documented during physiological aging and depends on the progressive decline in the activity of two major degradative mechanisms: the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway. This decline in proteostasis is exacerbated in age-associated neurodegenerative diseases, such as Parkinson's Disease (PD). In PD, patients develop an accumulation of aggregated proteins and dysfunctional mitochondria, which leads to ROS production, neuroinflammation and neurodegeneration. We recently reported that inhibition of the deubiquitinating enzyme USP14, which is known to enhance both the UPS and autophagy, increases lifespan and rescues the pathological phenotype of two Drosophila models of PD. Studies on the effects of USP14 inhibition in mammalian neurons have not yet been conducted. To close this gap, we exploited iNeurons differentiated from human embryonic stem cells (hESCs), and investigated the effect of inhibiting USP14 in these cultured neurons. Quantitative global proteomics analysis performed following genetic ablation or pharmacological inhibition of USP14 demonstrated that USP14 loss of function specifically promotes mitochondrial autophagy in iNeurons. Biochemical and imaging data also showed that USP14 inhibition enhances mitophagy. The mitophagic effect of USP14 inhibition proved to be PINK1/Parkin- independent, instead relying on expression of the mitochondrial E3 Ubiquitin Ligase MITOL/MARCH5. Notably, USP14 inhibition normalized the mitochondrial defects of Parkin KO human neurons.

Dysregulation of energy metabolism is a fundamental contributor to all the hallmarks of brain aging. Melatonin, primarily secreted by the pineal gland, is closely associated with molecules and signaling pathways that sense and affect energy metabolism. However, the impact of melatonin on age-related mRNA expression in the hippocampus of mice at different ages remains poorly understood.

Accumulation of the age pigment lipofuscin represents a ubiquitous hallmark of the aging process. However, our knowledge about cellular effects of lipofuscin accumulation is potentially flawed, because previous research mainly utilized highly artificial methods of lipofuscin generation. In order to address this tremendous problem, we developed a convenient protocol for isolation of authentic lipofuscin from human and equine cardiac tissue in high purity and quantity. Isolated lipofuscin aggregates contained elevated concentrations of proline and metals such as calcium or iron. The material was readily incorporated by fibroblasts and caused cell death at low concentrations (LC

This study aims to investigate the relationships between the Chinese Healthy Eating Index (CHEI), psychological balance, depressive symptoms, and cognitive function in the rural older population. Additionally, it examines the impact of CHEI on cognitive function and the potential chain mediating roles of psychological balance and depressive symptoms.

Brain functional modular organization changes with age. Considering the brain as a dynamic system, recent studies have suggested that time-varying connectivity provides more information on brain functions. However, the spontaneous reconfiguration of modular brain structures over time during aging remains poorly understood. In this study, we investigated the age-related dynamic modular reconfiguration using resting-state functional MRI data (615 participants, aged 18-88 years) from Cam-CAN. We employed a graph-based modularity analysis to investigate modular variability and the transition of nodes from one module to another in modular brain networks across the adult lifespan. Results showed that modular structure exhibits both linear and nonlinear age-related trends. The modular variability is higher in early and late adulthood, with higher modular variability in the association networks and lower modular variability in the primary networks. In addition, the whole-brain transition matrix showed that the times of transition from other networks to the dorsal attention network were the largest. Furthermore, the modular structure was closely related to the number of cognitive components and memory-related cognitive performance, suggesting a potential contribution to flexibility cognitive function. Our findings highlighted the notable dynamic characteristics in large-scale brain networks across the adult lifespan, which enhanced our understanding of the neural substrate in various cognitions during aging. These findings also provided further evidence that dedifferentiation and compensation are the outcomes of functional brain interactions.

Abdominal aortic aneurysms (AAAs) are a degenerative aortic disease and associated with hallmarks of aging, such as mitophagy. Despite this, the exact associations among mitophagy, aging, and AAA progression remain unknown. In our study, gene expression analysis of human AAA tissue revealed downregulation of mitophagy pathways, mitochondrial structure, and function-related proteins. Human proteomic analyses identified decreased levels of mitophagy mediators PINK1 and Parkin. Aged mice and, separately, a murine AAA model showed reduced mitophagy in aortic vascular smooth muscle cells (VSMCs) and PINK1 and Parkin expression. Parkin knockdown in VSMCs aggravated AAA dilation in murine models, with elevated mitochondrial ROS and impaired mitochondrial function. Importantly, inhibiting USP30, an antagonist of the PINK1/Parkin pathway, increased mitophagy in VSMCs, improved mitochondrial function, and reduced AAA incidence and growth. Our study elucidates a critical mechanism that proposes AAAs as an age-associated disease with altered mitophagy, introducing new potential therapeutic approaches.

Mitochondrial dysfunction and oxidative stress are hallmarks of pathophysiological processes in age-related neurodegenerative diseases including Parkinsons, Alzheimers and Huntingtons diseases. Neuronal cells are highly vulnerable to mitochondrial stress, however, the cellular and molecular mechanisms underlying the enhanced vulnerability are not well understood. Previously, we demonstrated that the novel PKC isoform PKC{delta} is highly expressed in dopamin(DA)ergic neurons and plays a key role in inducing apoptotic cell death during neurotoxic stress via caspase-3-mediated proteolytic activation. Herein, we further uncovered a key downstream molecular event of PKC{delta} signaling following mitochondrial dysfunction that governs neuronal cell death by dissembling nuclear architecture. Exposing N27 DAergic cell line to the mitochondrial complex-1 inhibitor tebufenpyrad induced PKC{delta} phosphorylation at the T505 activation loop accompanied by caspase-3-dependent proteolytic activation of the kinase. Subcellular analysis using high-resolution 3D confocal microscopy revealed that proteolytically activated cleaved PKC{delta} translocates to the nuclear compartment, colocalizing with Lamin B1. Electron microscopy also enabled the visualization of nuclear membrane damage triggered by subjecting the DAergic neuronal cells by Tebufenpyrad (Tebu) toxicity. In silico analyses identified that the threonine site on Lamin B1 (T575) is likely phosphorylated by PKC{delta}, suggesting that Lamin B1 serves as a key downstream target of the kinase. Interestingly, N27 DAergic cells stably expressing the PKC{delta} proteolytic cleavage site-resistant mutant failed to induce nuclear damage, PKC{delta} activation, and Lamin B1 phosphorylation. Furthermore, CRISPR/Cas9-based stable knockdown of PKC{delta} greatly attenuated Tebu-induced Lamin B1 phosphorylation. Also, studies using Lamin B1T575G mutated at phosphorylation and PKC{delta}-{Delta}NLS-overexpressing N27 cells showed that PKC{delta} activation and translocation to the nuclear membrane are critically required for phosphorylating Lamin B1 at T575 to induce nuclear membrane damage during Tebu insult. Additionally, Tebu failed to induce Lamin B1 damage and Lamin B1 phosphorylation in organotypic midbrain slices cultured from PKC{delta}-/- mouse pups. More importantly, we observed higher PKC{delta} activation, Lamin B1 phosphorylation and Lamin B1 loss in nigral DAergic neurons from the postmortem brains of PD patients as compared to age-matched healthy control brains, thus providing translational relevance of our finding. Collectively, our data reveal that PKC{delta} functions as a Lamin B1 kinase to disassemble the nuclear membrane during the neuronal cell death process triggered by mitochondrial stress. This mechanistic insight may have important implications for the etiology of age-related neurodegenerative diseases resulting from mitochondrial dysfunction as well as for the development of novel treatment strategies.

Breast aging encompasses intricate molecular and cellular changes that elevate cancer risk. Our study profiled DNA methylation and gene expression of 181 normal breast samples and systematically evaluated eight epigenetic clocks. We found that clocks trained using breast tissues demonstrate improved age prediction in normal breast tissue, and bias universally exists in epigenetic clocks, necessitating a proper definition of age acceleration. Cell composition analysis revealed significant age-related alterations and highlighted its distinct associations with age acceleration, including increased luminal epithelial and myoepithelial cells and reduced adipocytes and immune cells, connecting age acceleration to carcinogenesis from a cell compositional perspective. Additionally, CpG sites associated with age acceleration were enriched for estrogen receptor binding sites, providing a mechanistic link between estrogen exposure, accelerated aging, and cancer. These findings highlight the importance of cellular heterogeneity in epigenetic age estimates and the potential of age acceleration to guide for risk stratification and prevention strategies.

The black goji berry (Lycium ruthenicum Murr.) is known for its abundance of high-quality natural antioxidants, particularly anthocyanins. Black goji berry anthocyanins (BGA) are receiving increasing attention because of their high safety and beneficial biological activities. Studies have shown that oxidative stress is a key factor affecting aging, whereas antioxidants are critical preventive and delaying strategies.

Convolutional Neural Networks (CNNs) are proven to be effective when data are homogeneous such as images, or when there is a relationship between consecutive data such as time series data. Although CNNs are not famous for tabular data, we show that we can use them in longitudinal data, where individuals' information is recorded over a period and therefore there is a relationship between them. This study considers the English Longitudinal Study of Ageing (ELSA) survey, conducted every two years. We use one-dimensional convolutional neural networks (1D-CNNs) to forecast mortality using socio-demographics, diseases, mobility impairment, Activities of Daily Living (ADLs), Instrumental Activities of Daily Living (IADLs), and lifestyle factors. As our dataset is highly imbalanced, we try different over and undersampling methods and find that over-representing the small class improves the results. We also try our model with different activation functions. Our results show that swish nonlinearity outperforms other functions.

Average age is increasing worldwide, raising the public health burden of age-related diseases, as more resources will be required to manage treatments. Phenotypic Age is a score that can be useful to provide an estimate of the probability of developing aging-related conditions, and prevention of such conditions could be performed efficiently studying the mechanisms leading to an increased phenotypic age. The objective of this study is to characterize the mechanisms that lead to aging acceleration from the interactions among socio-demographic factors, health predispositions and biological phenotypes.

Sarcopenia is a prevalent muscle disorder in old people leading to higher fracture rate, mortality, and other adverse clinical outcomes. Evidence indicates that short-chain fatty acids (SCFAs), which are beneficial gut microbial metabolites, were reduced in old people with sarcopenia. This study aimed to determine whether the use of SCFAs as a supplement can be a therapeutic strategy of sarcopenia in a pre-clinical model.

Individual's aging rates vary across organs. However, there are few methods for assessing aging at organ levels and whether they contribute differently to mortalities remains unknown. We analyzed data from 45,821 adults in the UK Biobank, using plasma proteomics and machine learning to estimate biological ages for 12 major organs. The differences between biological age and chronological age, referred to as "age gaps," were calculated for each organ. Partial correlation analyses were used to assess the association between age gaps and modifiable factors. Adjusted multivariable Cox regression models were applied to examine the association of age gaps with all-cause mortality, cause-specific mortalities, and cancer-specific mortalities. We reveal a complex network of varied associations between multi-organ aging and modifiable factors. All age gaps increase the risk of all-cause mortality by 6-60%. The risk of death varied from 5.54 to 29.18 times depending on the number of aging organs. Cause-specific mortalities are associated with certain organs' aging. For mental diseases mortality, and nervous system mortality, only brain aging exhibited a significant increased risk of HR 2.38 (per SD, 95% CI: 2.06-2.74) and 1.99 (per SD, 95% CI: 1.84-2.16), respectively. Age gaps of stomach were also a specific indicator for gastric cancer. Eventually, we find that an organ's biological age selectively influences the aging of other organ systems. Our study demonstrates that accelerated aging in specific organs increases the risk of mortality from various causes. This provides a potential tool for early identification of at-risk populations, offering a relatively objective method for precision medicine.

The mechanisms contributing to age-related deterioration of the female reproductive system are complex, however aberrant protein homeostasis is a major contributor. We elucidated exceptionally stable proteins, structures, and macromolecules that persist in mammalian ovaries and gametes across the reproductive lifespan. Ovaries exhibit localized structural and cell-type-specific enrichment of stable macromolecules in both the follicular and extrafollicular environments. Moreover, ovaries and oocytes both harbor a panel of exceptionally long-lived proteins, including cytoskeletal, mitochondrial, and oocyte-derived proteins. The exceptional persistence of these long-lived molecules suggest a critical role in lifelong maintenance and age-dependent deterioration of reproductive tissues.

Motor skills are essential for daily functioning and serve as key indicators of healthy development and aging. However, existing assessments of motor skill are inaccessible to the public and do not directly measure the quality of the movement. Here, we developed a convenient and robust measure of motor skill that uses a smartphone app to provide on-the-spot assessment in just 15 seconds. To validate our method, we asked 1675 participants between the ages of three to eighty-eight years old to trace circles at a fixed rhythm with a smartphone, which was either held in the hand or strapped to the ankle. Motor skill was quantified by the smartphone app using an algorithm that calculated the variability in the accelerations trajectory. Our assessment revealed significant changes in the skill of the hands and feet with age and practice. The variability of the hands and feet linearly decreased and matured in the mid-teens, but it regressed gradually thereafter. Laterality, or the difference in the motor skill between the left and right limbs, increased with age as the non-dominant hand and foot regressed faster in the elderly. Motor practice affected both skill and laterality as left-handers who were forced to write with their right-hand during childhood had a tell-tale sign of stronger right-handedness and, surprisingly, right-footedness. Our assessment aims to democratize motor skill assessment, making it accessible for professionals and users of all ages.

Prior studies using global cognitive measures have shown that social connectedness is linked with cognitive performance. We investigate the role of different social network dimensions on performance across distinct cognitive domains among dementia-free middle-aged and older rural Indians.

Bipolar disorder (BD) has been linked to accelerated aging processes, with many studies suggesting that drugs used to treat BD may modulate pathways related to aging. This systematic review aimed to determine whether FDA-approved pharmacotherapies for BD have reported effects on aging biomarkers across clinical and preclinical studies. We conducted searches in PubMed and PsychINFO and followed PRISMA guidelines. Out of 6400 records identified, 19 studies met the inclusion criteria. Most preclinical studies tested the effects of BD drugs, especially lithium, on lifespan and telomere biology in cell and animal models. Clinical studies predominantly focused on lithium, evaluating aging markers like telomere length, telomerase, mitochondrial DNA copy number, and epigenetic age acceleration in individuals with BD. Findings indicate that chronic lithium treatment is associated with modulatory effects on aging biomarkers, particularly increased telomere length and telomerase activity. Conversely, some negative results were also reported. Limited evidence suggests potential aging-modulating properties of other mood stabilizers like valproic acid and lamotrigine, evidencing that further investigation is required. Despite variability across studies, the overall findings support the notion that pharmacotherapies used in BD present many effects of aging biomarkers. However, the field is still developing, with a clear emphasis on lithium and a lack of standardized methods to evaluate aging biomarkers in clinical samples. Further research exploring the anti-accelerated aging effects of BD drugs beyond lithium, their mechanisms of action, and potential synergistic effects is warranted.

Tea flower polysaccharides (TFPS) have prominent anti-aging effect. In this study, we used an animal model of aging induced by D-galactose in mice to investigate the effect of TFPS on reducing inflammatory factors, lowering oxidative stress levels, and inhibiting oxidative damage to microglia from the perspective of regulating gut microbiota. The results showed that TFPS could improve the homeostasis of gut microbiota in aging mice, reduce the ratio of

Senescence impairs liver physiology, mitochondrial function and circadian regulation, resulting in systemic metabolic dysregulation. Given the limited research on the effects of combined exercise on an ageing liver, this study aimed to evaluate its impact on liver metabolism, circadian rhythms and mitochondrial function in senescence-accelerated mouse-prone 8 (SAMP8) and senescence-accelerated mouse-resistant 1 (SAMR1) mice. Histological, reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunoblotting analyses were conducted, supplemented by transcriptomic data sets and AML12 hepatocyte studies. Sedentary SAMP8 mice exhibited decreased muscle strength, reduced mitochondrial complex I levels and increased lipid droplet accumulation. In contrast, combined exercise mitigated muscle strength loss, upregulated proteins involved in mitochondrial complexes (CIII, CIV, CV) and increased Bmal1 messenger RNA (mRNA) expression in the liver. These molecular adaptations are associated with healthier liver phenotypes and may influence metabolic function and cellular longevity. Notably, elevated lipid content in aged mice was reduced post-exercise, indicating liver benefits even after a relatively short intervention. The combined exercise regimen did not improve aerobic capacity, likely due to the low volume and brief duration of running. Moreover, no significant effects were observed in SAMR1 mice, possibly because the training intensity was insufficient for younger, healthier animals. These findings underscore the potential of combined strength and endurance exercise to attenuate age-related liver dysfunction, particularly in ageing populations.

Cysteine is an amino acid present in thiol proteins and often dictates their secondary structures. Although considered nonessential, cysteine may be essential for patients with certain metabolic diseases and can reduce the requirement for dietary methionine. Cysteine and some of its derivatives, such as N-acetylcysteine, are considered antioxidants and widely used in animal aging studies. To provide insights into the potential anti-aging effects of cysteine, we systematically reviewed and performed a meta-analysis to investigate the impact of cysteine supplementation on lifespan using three model organisms: mice, nematodes, and fruit flies. A total of 13 mouse studies, 13 C. elegans studies, and 5 Drosophila studies were included in the analysis. The findings revealed that cysteine supplementation significantly reduced the risk of mortality in mice and C. elegans. Subgroup analysis showed consistent results across different starting times and administration methods and revealed adverse effects of high doses on worms and a lack of effect in nondisease mouse models. Similar to mice, the effects of cysteine supplementation on Drosophila were not statistically significant, except in transgenic flies. The study identified certain limitations, including the quality of the included studies and the potential for publication bias. We also discussed uncertainties in the underlying molecular mechanisms and the clinical application of dietary cysteine.

Cellular senescence, an irreversible cell cycle arrest with secretory phenotype, is a hallmark of skin aging. Regenerative exosome-based approaches, such as topical human platelet extract (HPE), are emerging to target age-related skin dysfunction.

With the growth of the aging population, age-related diseases have become a heavy global burden, particularly cardiovascular and cerebrovascular diseases (CVDs). Endothelial cell (EC) senescence constitutes an essential factor in the development of CVDs, prompting increased focus on strategies to alleviate or reverse EC senescence.

The relationship between possible sarcopenia and mortality remains ambiguous within Asian populations. To clarify this, we investigated the association in older adults residing in Chinese communities. Utilizing data from the China Health and Retirement Longitudinal Study, this population-based cohort study included individuals aged ≥ 60 years, followed from 2011 to 2012 through 2020. Possible sarcopenia was defined in accordance with the Asian Working Group on Sarcopenia 2019 criteria, and Cox proportional hazards regression was used to analyze its impact on mortality, while exploratory analyses were conducted to investigate the associations of possible sarcopenia with chronic diseases, functional independence, and hospitalization frequency. The study encompassed 5,160 participants (median age: 66 years), nearly half of whom (48.8%) were identified with possible sarcopenia. Over a 9-year follow-up period, there were 1216 recorded deaths. Analysis indicated that individuals with possible sarcopenia faced a significantly elevated mortality risk compared to their counterparts (HR: 1.79, 95% CI: 1.58-2.03; P < 0.001). Further, subgroup analyses confirmed a strong association between possible sarcopenia and all-cause mortality across various subgroups, including those related to sex, obesity status, and living environment. Additionally, exploratory analyses revealed that possible sarcopenia was significantly associated with an increased likelihood of heart disease (OR = 1.18, 95% CI: 1.03-1.34, P = 0.014) and stroke (OR = 1.41, 95% CI: 1.19-1.68, P < 0.001), as well as reduced functional independence (β = -0.17, 95% CI: -0.24--0.10, P < 0.001). Possible sarcopenia was also associated with a higher frequency of hospitalizations at baseline (Exp(β) = 1.50, 95% CI: 1.25-1.81, P < 0.001), although this association was no longer significant during the follow-up period. In conclusion, in Chinese community-dwelling older adults, possible sarcopenia was associated with an increased risk of all-cause mortality, several chronic diseases, and functional dependence. Thus, alleviating or preventing possible sarcopenia may improve health outcomes and extend the lifespan of these individuals.

Proteins occurring in significantly high concentrations in cellular environments (over 100 mg/ml) and functioning in crowded cytoplasm, often face the prodigious challenges of aggregation which are the pathological hallmark of aging and are critically responsible for a wide spectrum of rising human diseases. Here, we combine a joint-venture of complementary wet-lab experiment and molecular simulation to discern the potential ability of adenosine triphosphate (ATP) as solubilizer of protein aggregates. We show that ATP prevents both condensation of aggregation-prone intrinsically disordered protein Aβ40 and promotes dissolution of preformed aggregates. Computer simulation links ATP's solubilizing role to its ability to modulate protein's structural plasticity by unwinding protein conformation. We show that ATP is positioned as a superior biological solubilizer of protein aggregates over traditional chemical hydrotropes, potentially holding promises in therapeutic interventions in protein-aggregation-related diseases. Going beyond its conventional activity as energy currency, the amphiphilic nature of ATP enables its protein-specific interaction that would enhance ATP's efficiency in cellular processes.

The female reproductive lifespan is highly dependent on egg quality, especially the presence of a normal number of chromosomes in an egg, known as euploidy. Mistakes in meiosis leading to egg aneuploidy are frequent in humans. Yet, knowledge of the precise genetic landscape that causes egg aneuploidy in women is limited, as phenotypic data on the frequency of human egg aneuploidy are difficult to obtain and therefore absent in public genetic datasets. Here, we identify genetic determinants of reproductive aging via egg aneuploidy in women using a biobank of individual maternal exomes linked with maternal age and embryonic aneuploidy data. Using the exome data, we identified 404 genes bearing variants enriched in individuals with pathologically elevated egg aneuploidy rates. Analysis of the gene ontology and protein-protein interaction network implicated genes encoding the kinesin protein family in egg aneuploidy. We interrogate the causal relationship of the human variants within candidate kinesin genes via experimental perturbations and demonstrate that motor domain variants increase aneuploidy in mouse oocytes. Finally, using a knock-in mouse model, we validate that a specific variant in kinesin KIF18A accelerates reproductive aging and diminishes fertility. These findings reveal additional functional mechanisms of reproductive aging and shed light on how genetic variation underlies individual heterogeneity in the female reproductive lifespan, which might be leveraged to predict reproductive longevity. Together, these results lay the groundwork for the noninvasive biomarkers for egg quality, a first step toward personalized fertility medicine.

Importance: Schizophrenia is associated with increased age-related morbidity, mortality, and frailty, which are not entirely explained by behavioral factors. Prior studies using epigenetic clocks have suggested that schizophrenia is associated with accelerated aging, however these studies have primarily used unidimensional clocks that summarize aging as a single "biological age" score. Objective: This meta-analysis uses multidimensional epigenetic clocks that split aging into multiple scores to analyze biological aging in schizophrenia. These novel clocks may provide more granular insights into the mechanistic relationships between schizophrenia, epigenetic aging, and premature morbidity and mortality. Study selection: Selected studies included patients with schizophrenia-spectrum disorders and non- psychiatric controls with available DNA methylation data. Seven cross-sectional datasets were available for this study, with a total sample size of 1,891 patients with schizophrenia and 1,881 controls. Data extraction and synthesis: Studies were selected by consensus Meta-analyses were performed using fixed-effect models. Main outcomes and measures: We analyzed multidimensional epigenetic clocks, including causality- enriched CausAge clocks, physiological system-specific SystemsAge clocks, RetroelementAge, DNAmEMRAge, and multi omics-informed OMICmAge. Meta-analyses examined clock associations with schizophrenia disease status and clozapine use, after accounting for age and sex. Results: Overall SystemsAge, CausAge, DNAmEMRAge, and OMICmAge scores demonstrated increased epigenetic aging in patients with schizophrenia after strict multiple-comparison testing. Ten of the eleven SystemsAge sub-clocks corresponding to different physiological systems demonstrated increased aging, with strongest effects for Heart and Lung followed by Metabolic and Brain systems. The causality- enriched clocks indicated increases in both damaging and adaptive aging, though these effects were weaker compared to SystemsAge scores. OMICmAge indicated changes in multiple clinical biomarkers, including hematologic and hepatic markers that support system-specific aging, as well as novel proteins and metabolites not previously linked to schizophrenia. Most clocks demonstrated age acceleration at the first psychotic episode. Notably, clozapine use was associated with increased Heart and Inflammation aging, which may partially be driven by smoking. Most results survived strict Bonferroni multiple testing correction. Conclusions and relevance: These are the first analyses of novel multidimensional clocks in patients with schizophrenia and provide a nuanced view of aging that identifies multiple organ systems at high risk for disease in schizophrenia-related disorders.

Gait speed is a robust health biomarker in older adults, correlating with the risk of physical and cognitive impairments, including dementia. Myelination plays a crucial role in neurotransmission and consequently affects various functions, yet the connection between myelination and motor functions such as gait speed is not well understood. Understanding this link could offer insights into diagnosing and treating neurodegenerative diseases that impair mobility. This study analyzed 437 longitudinal observations from 138 cognitively unimpaired adults, aged 22 to 94 years, to investigate the relationship between myelin content and changes in gait speed over an average of 6.42 years. Myelin content was quantified using a novel multicomponent magnetic resonance relaxometry method, and both usual and rapid gait speeds (UGS, RGS) were measured following standard protocols. Adjusting for covariates, we found a significant fixed effect of myelin content on UGS and RGS. Longitudinally, lower myelin content was linked to a greater decline in UGS, particularly in brain regions associated with motor planning. These results suggest that changes in UGS may serve as a reliable marker of neurodegeneration, particularly in cognitively unimpaired adults. Interestingly, the relationship between myelin content and changes in RGS was only observed in a limited number of brain regions, although the reason for such local susceptibility remains unknown. These findings enhance our understanding of the critical role of myelination in gait performance in unimpaired adults and provide evidence of the interconnection between myelin content and motor function impairment.

This study investigates the effects of integrated instability resistance training and cognitive training (IRCT) versus isolated instability resistance training (IRT) on balance, gait, muscle strength, and cognitive functions in elderly women.This randomized controlled trial included 36 participants, with 18 in the IRCT group and 18 in the IRT group. The sample size was estimated to achieve a statistical power of 0.95 with a large effect size (0.40; n = 12 each group). The closed-eye single-leg stand test was measured for static balance, the closed-eye stepping test, and the Timed Up and Go Test (TUGT) were measured for dynamic balance. Dual-task balance was assessed by combining the TUGT with cognitive tasks (TUGT-C) and motor tasks (TUGT-M). Gait performance was evaluated using a gait function system. Lower limb muscle strength was measured with the 30-Second Chair Stand Test. Cognitive function was assessed through the Trail Making Test (TMT), Digit Span Test (DST), Stroop Color and Word Test (Stroop), and Digit Symbol Substitution Test (DSST). Results IRCT group showed better improvements in both cognitive (p < 0.001) and motor (p = 0.812 for baseline; p < 0.001 for post-intervention) dual-task abilities, IRCT also experienced better enhancement in certain cognitive functions, particularly in the TMT (p = 0.001) and DSST (p = 0.022) compared to the IRT group. Both groups demonstrated enhancements in walking abilities as shown on selective markers of the gait performance test (p < 0.05) and leg muscle strength via 30-Second Chair (p < 0.001 for time main effect). These results suggest that combining cognitive exercises with physical training more effectively addresses the complex challenges associated with aging in women. The study highlights the potential of comprehensive training approaches in boosting health and quality of life for the elderly, with implications for developing tailored exercise programs focused on reducing fall risks and enhancing quality of life in this population.

Aging profoundly affects the immune system leading to an increased propensity for inflammation. Age-related dysregulation of immune cells is implicated in the development and progression of numerous age-related diseases such as: cardiovascular diseases, neurodegenerative disorders, and metabolic syndromes. Monocytes and monocyte-derived macrophages, being important players in the inflammatory response, significantly influence the aging process and the associated increase in inflammatory disease risk. Ischemic stroke is among age-related diseases where inflammation, particularly monocyte-derived macrophages, plays an important deteriorating role but could also strongly promote post-stroke recovery. Also, biological sex influences the incidence, presentation, and outcomes of ischemic stroke, reflecting both biological differences between men and women. Here, we studied whether human peripheral blood monocyte subtype (classical, intermediate, and non-classical) expression of genes implicated in stroke-related inflammation and post-stroke tissue regeneration depends on age and sex. A flow cytometry analysis of blood samples from 44 healthy volunteers (male and female, aged 28 to 98) showed that in contrast to other immune cells, the proportion of NK-cells increased in females. The proportion of B-cells decreased in both sexes with age. Gene expression analysis by qPCR identified several genes differentially correlating with age and sex within different monocyte subtypes. Interestingly, ANXA1 and CD36 showed a consistent increase with aging in all monocytes, specifically in intermediate (CD36) and intermediate and non-classical (ANXA1) subtypes. Other genes (IL-1β, S100A8, TNFα, CD64, CD33, TGFβ1, TLR8, CD91) were differentially changed in monocyte subtypes with increasing age. Most age-dependent gene changes were differentially expressed in female monocytes. Our data shed light on the nuanced interplay of age and sex in shaping the expression of inflammation- and regeneration-related genes within distinct monocyte subtypes. Understanding these dynamics could pave the way for targeted interventions and personalized approaches in post-stroke care, particularly for the aging population and individuals of different sexes.

Frailty in older adults is influenced by various factors, such as poor nutritional status. Mid-upper arm circumference (MUAC) is a validated, simple, and non-invasive tool for assessing nutritional status. Despite its potential, no study has explored the association between MUAC and physical frailty in older adults. This study aims to investigate this association and assess whether MUAC can be used as a screening tool in community and primary clinical practice.

In this study, we evaluate lipids and select proteins in human lung fibroblasts (hLFs) to interrogate changes occurring due to aging and senescence. To study single cell populations, a comparison of cells adhered onto slides using poly-d-lysine versus centrifugal force deposition was first analyzed to determine whether specific alterations were observed between preparations. The poly-d-lysine approach was then utilized to interrogate the lipidome of the cell populations and further evaluate potential applications of the MALDI-immunohistochemistry (IHC) platform for single-cell-level analyses. Two protein markers of senescence, vimentin and p21, were both observed within the fibroblast populations and quantified. Lipidomic analysis of the fibroblasts found 12 lipids significantly altered because of replicative senescence, including fatty acids, such as stearic acid, and ceramide phosphoethanolamine species (CerPE). Similar to previous reports, alterations were detected in putative fatty acid building blocks, ceramides, among other lipid species. Altogether, our results reveal the ability to detect lipids implicated in senescence and show alterations to protein expression between normal and senescent fibroblast populations, including differences between young and aged cells. This report is the first time that the MALDI-IHC system has been utilized at a single-cell level to analyze both protein expression and lipid profiles in cultured cells, with a particular focus on changes associated with aging and senescence.

Single-cell RNA sequencing has enabled the study of aging at a molecular scale. While substantial progress has been made in measuring age-related gene expression, the underlying patterns and mechanisms of aging transcriptomes remain poorly understood. To address this gap, we propose a physics-inspired, data-analysis approach to extract additional insights from single-cell RNA sequencing data. By considering the genome as a many-body interacting system, we leverage central idea of the Renormalization Group to construct an approach to hierarchically describe aging across a spectrum of scales for the gene expresion. This framework provides a quantitative language to study the multiscale patterns of aging transcriptomes. Overall, our study demonstrates the value of leveraging theoretical physics concepts like the Renormalization Group to gain new biological insights from complex high-dimensional single-cell data.

Dogs exhibit striking within-species variability in lifespan, with smaller breeds often living more than twice as long as larger breeds. This longevity discrepancy also extends to health and aging-larger dogs show higher rates of age-related diseases. Despite this well-established phenomenon, we still know little about the biomarkers and molecular mechanisms that might underlie breed differences in aging and survival. To address this gap, we generated an epigenetic clock using DNA methylation from over 3 million CpG sites in a deeply phenotyped cohort of 864 companion dogs from the Dog Aging Project, including some dogs sampled annually for 2-3 years. We found that the largest breed size tends to have epigenomes that are, on average, 0.37 years older per chronological year compared to the smallest breed size. We also found that higher residual epigenetic age was significantly associated with increased mortality risk, with dogs experiencing a 34% higher risk of death for each year increase in residual epigenetic age. These findings not only broaden our understanding of how aging manifests within a diverse species but also highlight the significant role that demographic factors play in modulating the biological mechanisms underlying aging. Additionally, they highlight the utility of DNA methylation as both a biomarker for healthspan-extending interventions, a mortality predictor, and a mechanism for understanding inter-individual variation in aging in dogs.

Vertebrate spermatogonial stem cells maintain sperm production over the lifetime of an animal, but fertility declines with age. Although morphological studies have informed our understanding of typical spermatogenesis, the molecular and cellular mechanisms underlying the maintenance and decline of spermatogenesis are not yet understood. We used single-cell RNA sequencing to generate a developmental atlas of the aging zebrafish testis. All testes contained spermatogonia, but we observed a progressive decline in spermatogenesis that correlated with age. Testes from some older males only contained spermatogonia and a reduced population of spermatocytes. Spermatogonia in older males were transcriptionally distinct from spermatogonia in testes capable of robust spermatogenesis. Immune cells including macrophages and lymphocytes drastically increased in abundance in testes that could not complete spermatogenesis. Our developmental atlas reveals the cellular changes as the testis ages and defines a molecular roadmap for the regulation of spermatogenesis.

Impaired proteostasis can induce protein aggregation which is toxic to neuronal cells, contributing to neurodegeneration and other signs of aging. In this study, we delineate an early-onset progressive neuropathy evoking Giant Axonal Neuropathy 1. The causative gene IVNS1ABP encodes a E3-ubiquitin ligase adaptor which is a close gigaxonin paralogue. Patient-derived fibroblasts, iPSCs, and neural progenitors exhibited hallmarks of protein accumulation and lysosomal dysfunction. Ubiquitome analysis revealed overlapping targets with gigaxonin, including Vimentin and MAP1B. The biallelic correction to the isogenic wildtype state in disease- relevant motor neurons partly rescued cellular vulnerabilities. A newly generated ivns1abpa/b knockout zebrafish model partially recapitulated the human peripheral neuropathy, exhibiting aberrant primary motor neuron axon pathfinding, leading to impaired locomotion. Our findings indicate that IVNS1ABP functions in the same pathway as gigaxonin, ensuring appropriate cellular turnover of critical protein substrates, whose accumulation leads to accelerated aging in discrete cellular lineages.

Microglia, the primary immune cells of the central nervous system, play a crucial role in maintaining brain homeostasis through phagocytosis of various substrates, including amyloid-{beta} (A{beta}) fibrils, a hallmark of Alzheimer disease (AD) pathology. However, the molecular mechanisms regulating microglial A{beta} uptake remain poorly understood. Here, we identified GPR34, a Gi/o-coupled receptor highly expressed in microglia, as a novel regulator of fibrillar A{beta} phagocytosis. Treatment with a selective GPR34 agonist, M1, specifically enhanced uptake of A{beta} fibrils, but not its monomer or oligomer, in both mouse and human microglia. Mechanistically, M1 reduced intracellular cAMP levels, which inversely correlated with A{beta} uptake activity. Importantly, a single intrahippocampal injection of M1 in an AD mouse model significantly increased microglial A{beta} uptake in vivo. Furthermore, single-nucleus RNA-sequencing analysis of Japanese AD patient samples revealed a significant reduction of GPR34 expression in microglia from AD patients compared to controls. We also observed an age-dependent decline in microglial GPR34 expression in both human and mouse datasets, suggesting a potential contribution of GPR34 downregulation to age-related A{beta} accumulation and AD risk. Collectively, our findings identify GPR34 as a promising target for modulating microglial A{beta} clearance and highlight the therapeutic potential of GPR34 agonists in AD. Significance statementAlzheimer disease (AD) is characterized by amyloid-{beta} (A{beta}) accumulation in the brain. Microglia, the brains immune cells, play a crucial role in the metabolism of A{beta}. We discovered that activating the microglial receptor GPR34 with a selective agonist enhances the phagocytosis of A{beta} fibrils, a key pathogenic form of A{beta}. Importantly, GPR34 expression decreases with aging and AD progression, potentially contributing to impaired A{beta} clearance. Our findings highlight GPR34 as a promising therapeutic target for AD, as boosting its activity could promote A{beta} clearance and slow disease progression. This study provides valuable insights into microglial function in AD and offers a novel strategy for developing disease-modifying therapies.

The iron-sulfur domain (CISD) proteins of CDGSH are classified into three classes: CISD1, CISD2, and CISD3. During premature ageing, mutations that affect these proteins, namely their binding sites, could result in reduced protein production and an inability to preserve cellular integrity. Consequently, this leads to the development of conditions such as diabetes. Notably, CISD3 plays a crucial role in the management of age-related disorders such as Wolfram syndrome, which is often referred to as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). Computational analyses have predicted that CISD3 regulates the redox state, safeguards the endoplasmic reticulum and mitochondria, and maintains intracellular calcium levels. CISD3, a member of a recently discovered gene family associated with the CDGSH iron protein apoptotic compensatory response, fulfils a crucial function in mitigating the effects of accelerated ageing. The compound "(-)-(2S)-7,4'-Dihydroxyflavanone" has been discovered by computational drug design as a possible activator of CISD3. It shows potential therapeutic benefits in ameliorating metabolic dysfunction and enhancing glucose regulation. The ligand binds to the binding pocket of the CISD3 protein, increasing the stability of the protein and enhancing its functionality. The current research investigates the binding processes of the molecule in various structures and its anticipated effects on these tissues, therefore providing valuable insights into the mitigation of age-related diabetes and metabolic dysfunction. The projected tripling of the worldwide population of individuals aged 50 and above by 2050 necessitates the urgent development of immunoinformatics-based approaches, including pharmaceutical therapies that target CISD3, to prevent age-related pathologies. The stimulation of CISD3, namely by compounds such as "(-)-(2S)-7,4'-Dihydroxyflavanone", has the potential to counteract telomere shortening and improve metabolic pathways.

Among the numerous changes that occur in skeletal muscle during aging, the reduced regeneration potential after an injury is largely due to the impaired ability of satellite cells to proliferate and differentiate. Herein, using the freeze-fracture electron microscopy technique, we analyzed both the incidence and size of dihydropyridine receptors (DHPRs) tetrads (4 particles) in cultured myotubes from a young subject (28 years) after 9 days of differentiation and from an old subject (71 years) after 9 and 12 days of differentiation. Compared to young myotubes, at 9 days of differentiation old myotubes exhibited: i) a lower incidence and a smaller size of DHPR clusters and ii) a lower number of complete tetrads. At 12 days of differentiation values of incidence, size and number of complete tetrads in old myotubes were instead comparable with those of young myotubes at 9 days of differentiation. Collectively, these results indicate that in aged myotubes the synthesis process of the proteins involved in the excitation-contraction coupling mechanism, such as the DHPR, is somehow slowed, supporting previous studies evidence of a decrease in the differentiation potential of myotubes from elderly individuals.

The integumentary system serves as a crucial protective barrier and is subject to complex signaling pathways that regulate its physiological functions. As the body's first line of defense, the skin is continuously exposed to environmental stressors, necessitating a robust network of signaling molecules to maintain homeostasis. Considering the main cellular components to be keratinocytes, melanocytes, fibroblasts, and fibrous components, collagen of various types, this review explores the intricate signaling mechanisms that govern skin integrity, focusing on key pathways involved in impacts of ageing and environment factors on skin health. The role of growth factors, cytokines, hormones and other molecular mediators in these processes is examined. Specially for women, decrease of estrogen is determinant to alter signaling and to compromise skin structure, especially the dermis. Environmental factors, such as ultraviolet rays and pollution alongside the impact of ageing on signaling pathways, especially TGF-β and proteases (metalloproteinases and cathepsins). Furthermore, with advancing age, the skin's capacity to shelter microbiome challenges diminishes, leading to alterations in signal transduction and subsequent functional decline. Understanding these age-related changes is essential for developing targeted therapies aimed at enhancing skin health and resilience, but also offers a promising avenue for the treatment of skin disorders and the promotion of healthy ageing.

Motor learning is a lifelong process, from infancy through old age. Acquiring new motor skills through repetitive practice requires adjusting motor output in response to sensory input and integrating them to facilitate learning. For this to occur, the central nervous system must flexibly predict and adapt to the dynamic interplay between sensory inputs and motor outputs. Although overall brain function changes with age, it remains unclear how neural flexibility evolves and influences motor learning ability with aging. To address this, we designed a motor learning paradigm involving both younger and older adults and quantitatively assessed neural flexibility from the perspective of functional brain networks, leveraging multichannel electroencephalography (EEG) in humans. Here we found age-related differences in motor learning properties, brain network flexibility, and their neural relationships. In younger adults, motor learning retention was associated with brain network flexibility during the preparatory period of the task. However, this association was not observed in older adults. Together, our findings establish that brain network flexibility plays a crucial role in acquiring and maintaining new motor skills in younger adults, but this relationship becomes less effective with age.

Finding interventions to break the trade-off between reproduction and lifespan can provide insight into physiological limitations of animals. Effects of dietary protein quality on the trade-off are currently unclear, but clarity could lead to better designed diets that match animal needs. Dietary amino acid blends matching yolk proteins support reproduction and extend lifespan in fruit flies. To test if this is conserved across species, we matched dietary amino acids to vitellogenin to test reproduction and lifespan in adult females of the lubber grasshopper. Specifically, we compared varying degrees of protein quality by manipulating dietary essential amino acids. We identified a high-quality protein diet (amino acids matched to vitellogenin, or reproductive needs) that increased reproduction and matched lifespan in comparison to diets that differed only in the ratios of essential amino acids (i.e., were isocaloric and isonitrogenous). All these diets had longer lifespan but lower reproductive output than fully fed controls. In a separate experiment, full reproduction was possible on the high-quality artificial diet when offered at a 78% higher protein quantity and with a larger lettuce supplement (~ 17% of ad libitum). Additionally, we observed that as dietary protein quality was decreased (i.e., diets were less matched to vitellogenin), reproduction was reduced, and lifespan was extended in the more extreme scenarios. Taken together, these results indicate that the balance of dietary essential amino acids plays an important role in the lifespan and reproduction trade-off, while more work needs to be conducted to find the optimal diet mix for this species.

Substantial evidence indicates that measuring leukocyte telomere length (LTL) is a useful tool that may be considered as a valuable biomarker of individual biological age, correlating with numerous chronic disorders. However, to date, there has been a lack of in-depth understanding regarding the current landscape and forthcoming developments in the LTL field. Therefore, this study aimed to utilize bibliometric methods to summarize the knowledge structure, current focus, and emerging directions in this field.

Regulator of G-protein signaling 10 (RGS10), a key homeostatic regulator of immune cells, has been implicated in multiple diseases associated with aging and chronic inflammation including Parkinson's Disease (PD). Interestingly, subjects with idiopathic PD display reduced levels of RGS10 in subsets of peripheral immune cells. Additionally, individuals with PD have been shown to have increased activated peripheral immune cells in cerebral spinal fluid (CSF) compared to age-matched healthy controls. However, it is unknown whether CSF-resident peripheral immune cells in individuals with PD also exhibit decreased levels of RGS10. Therefore, we performed an analysis of RGS10 levels in the proteomic database of the CSF from the Michael J. Fox Foundation Parkinson's Progression Markers Initiative (PPMI) study. We found that RGS10 levels are decreased in the CSF of individuals with PD compared to healthy controls and prodromal individuals. Moreover, we find that RGS10 levels decrease with age but not PD progression and that males have less RGS10 than females in PD. Importantly, studies have established an association between chronic systemic inflammation (CSI) and neurodegenerative diseases, such as PD, and known sources of CSI have been identified as risk factors for developing PD; however, the role of peripheral immune cell dysregulation in this process has been underexplored. As RGS10 levels are decreased in the CSF and circulating peripheral immune cells of individuals with PD, we hypothesized that RGS10 regulates peripheral immune cell responses to CSI prior to the onset of neurodegeneration. To test this, we induced CSI for 6 weeks in C57BL6/J mice and RGS10 KO mice to assess circulating and CNS-associated peripheral immune cell responses. We found that RGS10 deficiency synergizes with CSI to induce a bias for inflammatory and cytotoxic cell populations, a reduction in antigen presentation in peripheral blood immune cells, as well as in and around the brain that is most notable in males. These results highlight RGS10 as an important regulator of the systemic immune response to CSI and implicate RGS10 as a potential contributor to the development of immune dysregulation in PD.

This article is a summary of the first AGS Symposium entitled "Update on Vaccination Strategies for Older Adults: Matching the Approach to the Individual and the Care Setting." Given declines in host defenses and immune function with aging, vaccinations play a pivotal role in fortifying older adults against preventable infections, resulting diseases, disability, and death. Current guidelines generally list recommendations applicable for an average older adult of a given chronological age. However, growing evidence indicates that heterogeneity in terms of factors as varied as biological sex, frailty, functional status, and multimorbidity may impact vaccine responses and clinical outcomes. As a result, clinicians will increasingly need to take these additional factors into consideration as they seek to improve outcomes through improved targeting of such aging-related heterogeneity. Moreover, efforts at protecting older citizens through vaccination must also include strategies to overcome barriers to the adoption of vaccine recommendations in varied settings including long-term care. This 2023 AGS Plenary Symposium sought to commence a broader dialogue across AGS and beyond on optimizing vaccinations for older adults, ensuring not only extended lifespans but also healthier and more active lives. This report is not a systematic review, and thus should not be considered comprehensive.

Age-related loss of muscle mass and function is underpinned by changes at the myocellular level. However, our understanding of the aged muscle phenotype might be confounded by factors secondary to ageing per se, such as inactivity and adiposity. Here, using healthy, lean, recreationally active, older men, we investigated the impact of ageing on myocellular properties in skeletal muscle. Muscle biopsies were obtained from young men (22 ± 3 years, n = 10) and older men (69 ± 3 years, n = 11) matched for health status, activity level and body mass index. Immunofluorescence was used to assess myofibre composition, morphology (size and shape), capillarization, the content of satellite cells and myonuclei, the spatial relationship between satellite cells and capillaries, denervation and myofibre grouping. Compared with young muscle, aged muscle contained 53% more type I myofibres, in addition to smaller (-32%) and misshapen (3%) type II myofibres (P < 0.05). Aged muscle manifested fewer capillaries (-29%) and satellite cells (-38%) surrounding type II myofibres (P < 0.05); however, the spatial relationship between these two remained intact. The proportion of denervated myofibres was ∼2.6-fold higher in old than young muscle (P < 0.05). Aged muscle had more grouped type I myofibres (∼18-fold), primarily driven by increased size of existing groups rather than increased group frequency (P < 0.05). Aged muscle displayed selective deterioration of type II myofibres alongside increased denervation and myofibre grouping. These data are key to understanding the cellular basis of age-related muscle decline and reveal a pressing need to fine-tune strategies to preserve type II myofibres and innervation status in ageing populations.

Chemokine receptors belong to the G-protein-coupled receptors family and multiple lines of emerging evidence suggest that several chemokines are elevated in aging associated with central nervous system disorders. Increased level of CXCL10 in central nervous system is reported in several neurodegenerative diseases, including Multiple sclerosis, Alzheimers disease, and Virus-associated dementia. We also observed significantly increased expression of CXCL10 and CXCR3 in the prefrontal cortex and hippocampus of aged C57BL/6J mice (12- and 18-month-old mice). This leads us to hypothesize that CXCL10, being a component of SASPs, may aggravate/perpetuate the brain aging process and, finally, neurodegenerative diseases. To test this hypothesis, we administered CXCL10 (intracerebroventricular: ICV, 0.5 pg/ hrs, 28 days) in 8-month-old C57BL/6J mice. We observed increased expression of senescent marker proteins p16INK4a, p21Cip1, p53 and decreased expression of pRB in the prefrontal cortex, which was blocked by CXCR3-specific antagonist AMG487. Furthermore, chronic infusion of CXCL10 induced learning and memory deficits in Y-maze, social recognition, contextual freeze tests and c-FOS expression in the prefrontal cortex. To further determine the specificity of CXCL10/CXCR3 signaling, we treated the primary cortical neuron (Days in vitro: DIV 7-8) with CXCL10 and found increased senescence in CXCR3 dependent fashion. Using RFP-EGFP-LC3-tagged transgenic mice, we also showed CXCL10/CXCR3 signaling attenuates autophagic flux in primary cortical neurons. Lastly, using a c-FOS-iRFP reporter, we observed that increased CXCL10/CXCR3 signaling impairs glutamatergic signaling in primary cortical neurons. These results support the hypothesis that increased CXCL10/CXCR3 facilitates brain aging and could be targeted for the management of aging-associated CNS disorders.

Exposure to early life adversity is linked to detrimental fitness outcomes across taxa. Owing to the challenges of collecting longitudinal data, direct evidence for long-term fitness effects of early life adversity from long-lived species remains relatively scarce. Here, we test the effects of early life adversity on male and female longevity in a free-ranging population of rhesus macaques (

The role of sociality in the demography of animals has become an intense focus of research in recent decades. However, efforts to understand the sociality-demography nexus have hitherto focused on single species or isolated taxonomic groups. Consequently, we lack generality regarding how sociality associates with demographic traits within the Animal Kingdom. Here, I propose a continuum of sociality, from solitary to tightly social, and test whether this continuum correlates with the key demographic properties of 152 species, from jellyfish to humans. After correction for body mass and phylogenetic relationships, I show that the sociality continuum is associated with key life history traits: more social species live longer, postpone maturity, have longer generation time and greater probability of achieving reproduction than solitary, gregarious, communal or colonial species. Contrary to the social buffering hypothesis, sociality does not result in more buffered populations. While more social species have a lower ability to benefit from disturbances, they display greater resistance than more solitary species. Finally, I also show that sociality does not shape reproductive or actuarial senescence rates. This cross-taxonomic examination of sociality across the demography of 13 taxonomic classes highlights key ways in which individual interactions shape most aspects of animal demography.This article is part of the discussion meeting issue 'Understanding age and society using natural populations'.

Diabetic nephropathy (DN) is a frequent and costly complication of diabetes with limited understandings of mechanisms and therapies. Emerging evidence points to the important roles of interleukin-33 (IL-33) in acute kidney injury, yet its contribution to DN is still unclear. We here found a ubiquitous increase of IL-33 and its receptor (ST2) in murine models and patients with DN. Surprisingly, both IL-33 and ST2 knockdown aggravated renal lesions in DN, while overexpression of IL-33 also exacerbated the condition. Further population-based analyses revealed a positive correlation of IL-33 expression with renal dysfunction in DN patients. Individuals with high IL-33 expression-related polygenic risk score had a higher DN risk. These findings confirmed the harmful effects of IL-33 on DN. Conversely, endogenous and exogenous partial reduction of IL-33 signaling conferred renoprotective effects in vivo and in vitro. Mechanistically, IL-33 induced senescence by regulating cell cycle factors in HK-2 cells, and accordingly senescence led to renal cell damage through the secretion of senescence-related secretory phenotype (SASP) including IL-33 and prostaglandins. Together, elevated IL-33 accelerates cellular senescence to drive DN possibly by SASP production, while a partial blockage improves renal injury and senescence. Our findings pinpoint a possible and new avenue for DN interventions.

Approximately half of mammalian genomes are occupied by retrotransposons, highly repetitive interspersed genetic elements expanded through the mechanism of reverse transcription. The evolution of this "retrobiome" involved a series of explosive amplifications, presumably associated with high mutation rates, interspersed with periods of silencing. A by-product of retrotransposon activity is the formation of processed pseudogenes (PPGs)-intron-less, promoter-less DNA copies of messenger RNA (mRNA). We examined the proportion of PPGs with varying degrees of deviation from their ancestor mRNAs as an indicator of the intensity of retrotranspositions at different times in the past. Our analysis revealed a high proportion of "young'' (recently acquired) PPGs in the DNA of mice and rats, indicating significant retrobiome activity during the recent evolution of these species. The ongoing process of new PPG entries in mouse germ line DNA was confirmed by identifying diversity in PPG content within the single strain of mice, C57BL/6. In contrast, the highly abundant PPGs of the naked mole rat (NMR) exhibited substantial deviation from their mRNAs, with a near-complete lack of PPGs without mutations, indicative of the silencing of the retrobiome in the most recent evolutionary past, preceded by a period of high activity. This distinctive feature of the NMR genome was confirmed through the analysis of a broad range of mammalian species. The peculiar evolutionary dynamics of PPGs in the NMR, an organism with exceptional longevity and resistance to cancer, may reflect the role played by the retrobiome in aging and cancer.

Oligodendrocyte progenitor cells (OPCs) are highly dynamic, widely distributed glial cells of the central nervous system (CNS) that are responsible for generating myelinating oligodendrocytes during development. By also generating new oligodendrocytes in the adult CNS, OPCs allow formation of new myelin sheaths in response to environmental and behavioral changes and play a crucial role in regenerating myelin following demyelination (remyelination). However, the rates of OPC proliferation and differentiation decline dramatically with aging, which may impair homeostasis, remyelination, and adaptive myelination during learning. To determine how aging influences OPCs, we generated a novel transgenic mouse line that expresses membrane-anchored EGFP under the endogenous promoter/enhancer of Matrilin-4 (Matn4-mEGFP) and performed high-throughput single-cell RNA sequencing, providing enhanced resolution of transcriptional changes during key transitions from quiescence to proliferation and differentiation across the lifespan. Comparative analysis of OPCs isolated from mice aged 30 to 720 days, revealed that aging induces distinct inflammatory transcriptomic changes in OPCs in different states, including enhanced activation of HIF-1 and Wnt pathways. Inhibition of these pathways in acutely isolated OPCs from aged animals restored their ability to differentiate, suggesting that this enhanced signaling may contribute to the decreased regenerative potential of OPCs with aging. This Matn4-mEGFP mouse line and single-cell mRNA datasets of cortical OPCs across ages help to define the molecular changes guiding their behavior in various physiological and pathological contexts.

It is increasingly clear that social environments have profound impacts on the life histories of 'non-social' animals. However, it is not yet well known how species with varying degrees of sociality respond to different social contexts and whether such effects are sex-specific. To survey the extent to which social environments specifically affect lifespan and ageing in non-social species, we performed a systematic literature review, focusing on invertebrates but excluding eusocial insects. We found 80 studies in which lifespan or ageing parameters were measured in relation to changes in same-sex or opposite-sex exposure, group size or cues thereof. Most of the studies focused on manipulations of adults, often reporting sex differences in lifespan following exposure to the opposite sex. Some studies highlighted the impacts of developmental environments or social partner age on lifespan. Several studies explored potential underlying mechanisms, emphasizing that studies on insects could provide excellent opportunities to interrogate the basis of social effects on ageing. We discuss what these studies can tell us about the social environment as a stressor, or trade-offs in resources prompted by different social contexts. We suggest fruitful avenues for further research of social effects across a wider and more diverse range of taxa.This article is part of the discussion meeting issue 'Understanding age and society using natural populations'.

The benefits of social living are well established, but sociality also comes with costs, including infectious disease risk. This cost-benefit ratio of sociality is expected to change across individuals' lifespans, which may drive changes in social behaviour with age. To explore this idea, we combine data from a group-living primate for which social ageing has been described with epidemiological models to show that having lower social connectedness when older can protect against the costs of a hypothetical, directly transmitted endemic pathogen. Assuming no age differences in epidemiological characteristics (susceptibility to, severity and duration of infection), older individuals suffered lower infection costs, which was explained largely because they were less connected in their social networks than younger individuals. This benefit of 'social ageing' depended on epidemiological characteristics and was greatest when infection severity increased with age. When infection duration increased with age, social ageing was beneficial only when pathogen transmissibility was low. Older individuals benefited most from having a lower frequency of interactions (strength) and network embeddedness (closeness) and benefited less from having fewer social partners (degree). Our study provides a first examination of the epidemiology of social ageing, demonstrating the potential for pathogens to influence the evolutionary dynamics of social ageing in natural populations.This article is part of the discussion meeting issue 'Understanding age and society using natural populations'.

Ageing affects almost all aspects of life and therefore is an important process across societies, human and non-human animal alike. This article introduces new research exploring the complex interplay between individual-level ageing and demography, and the consequences this interplay holds for the structure and functioning of societies across various natural populations. We discuss how this Special Issue provides a foundation for integrating perspectives from evolutionary biology, behavioural ecology and demography to provide new insights into how ageing shapes individuals' social behaviour and social associations, and how this in turn impacts social networks, social processes (such as disease or information transfer) and fitness. Through examining these topics across taxa, from invertebrates to birds and mammals, we outline how contemporary studies are using natural populations to advance our understanding of the relationship between age and society in innovative ways. We highlight key emerging research themes from this Special Issue, such as how sociality affects lifespan and health, the genetic and ecological underpinnings of social ageing and the adaptive strategies employed by different species. We conclude that this Special Issue underscores the importance of studying social ageing using diverse systems and interdisciplinary approaches for advancing evolutionary and ecological insights into both ageing and sociality more generally.This article is part of the discussion meeting issue 'Understanding age and society using natural populations '.