Longevity Papers

Cellular systems that govern protein folding rely on a delicate balance of functional redundancy and diversification to maintain protein homeostasis (proteostasis). Here, we use Caenorhabditis elegans to demonstrate how both overlapping and divergent activities of two homologous endoplasmic reticulum (ER)-resident HSP70 family chaperones, HSP-3 and HSP-4, orchestrate ER proteostasis and contribute to organismal physiology. We identify tissue-, age-, and stress-specific protein expression patterns and find both redundant and distinct functions for HSP-3 and HSP-4 in ER stress resistance, reproduction, and body size regulation. We show that only HSP-3 overexpression is sufficient to improve longevity and that loss of HSP-3 or HSP-4 during distinct stages of the worm cycle or specific tissues have opposing effects on worm lifespan. Furthermore, we find that loss of HSP-4, but not HSP-3, improves tolerance to protein aggregation induced-stress by activating ER-Phagy through the engagement of IRE-1 and the putative ER-Phagy receptor, C18E9.2. Mechanistically, we show that de-repression of IRE-1 via HSP-4 dissociation allows for direct inhibition of C18E9.2-mediated ER-Phagy and demonstrate that a conserved orthologous mechanism involving the respective human orthologs, BiP, Sec-62, and IRE-1, contributes to ER proteostasis regulation in human cells. Taken as a whole, our study demonstrates that functional diversification of orthologous proteins within a single organelle is an efficient mechanism to maximize stress resilience while also defining a novel link between ER-phagy and proteostasis regulation.

Hematopoietic aging is characterized by chronic inflammation associated with myeloid bias, HSC accumulation, and functional HSC impairment. Yet it remains unclear how inflammation promotes these aging phenotypes. NFkappaB both responds to and directs inflammation, and we present an experimental model of elevated NFkappaB activity (IkappaBminus) to dissect its role in hematopoietic aging phenotypes. We found that while elevated NFkappaB activity is not sufficient for HSC accumulation, HSC-autonomous NFkappaB activity impairs their functionality, leading to reduced bone marrow reconstitution. In contrast, myeloid bias is driven by the IkappaBminus proinflammatory bone marrow milieu as observed functionally, epigenomically, and transcriptomically. A new scRNA-seq HSPC labeling framework enabled comparisons with aged murine and human HSC datasets, documenting an association between HSC-intrinsic NFkappaB activity and quiescence, but not myeloid bias. These findings delineate separate regulatory mechanisms that underlie the three hallmarks of hematopoietic aging, suggesting that they are specifically and independently therapeutically targetable.

Summary-data-based multivariable Mendelian randomization (MVMR) methods, such as MVMR-Egger, MVMR-IVW, MVMR median-based, and MVMR-PRESSO, assess the causal effects of multiple risk factors on disease. However, accounting for variances in summary statistics related to risk factors remains a challenge. We propose a linear mixed model with measurement error correction (LMM-MEC) that accounts for the variance of summary statistics for both disease outcomes and risk factors. In step I, a linear mixed model is applied to account for the variance in disease summary statistics. Specifically, if heterogeneity is present in disease summary statistics, we treat it as a random effect and adopt an iteratively re-weighted least squares algorithm to estimate causal effects. In step II, we treat the variance in the summary statistics of risk factors as multiple measurement errors and apply a regression calibration method for simultaneous multiple measurement error correction. In a simulation study, when using independent genetic variants as instrumental variables (IV), our method showed comparable performance to existing MVMR methods under conditions of no pleiotropy or balanced pleiotropy with the outcome, and it exhibited higher coverage rates and power under directional pleiotropy. Similar findings were observed when using genetic variants with low to moderate linkage disequilibrium (LD) as IVs, although coverage rates reduced for all methods compared to using independent genetic variants as IVs. In the application study, we examined causal associations between correlated cholesterol biomarkers and longevity. By including 739 genetic variants selected from GWAS and allowing for low LD, our method identified that large LDL-c were causally associated with lower likelihood of achieving longevity.

Age is a primary risk factor for chronic conditions, including age-related macular degeneration (AMD). Impairments in autophagy processes are implicated in AMD progression, but the extent of autophagy\'s contribution and its therapeutic potential remain ambiguous. This study investigated age-associated transcriptomic changes in autophagy pathways in the retinal pigment epithelium (RPE) and evaluated the protective effects of topical trehalose, an autophagy-enhancing small molecule, against light-induced outer retinal degeneration in mice. Transcriptomic analysis of human RPE/choroid and mouse RPE revealed consistent downregulation of autophagy pathways with age, alongside variable changes as AMD severity progressed. Given the age- and AMD-associated perturbation of autophagy pathways, we examined trehalose treatment in vitro, which enhanced autophagic flux and restored mitochondrial respiratory function in primary murine RPE cells exposed to oxidative stress. In vivo, topical trehalose improved autophagy-lysosome activity in mouse RPE, demonstrated by elevated LC3B turnover and SQSTM1/p62 degradation. Furthermore, trehalose eyedrops protected mice from light-induced damage to the RPE and photoreceptors, preserving outer nuclear layer thickness, RPE morphology, and junctional F-actin organization. Taken together, the data support that age-related decline and severe dysregulation in autophagy contributed to AMD progression. By restoring autophagic flux, topical trehalose demonstrates therapeutic potential to address early autophagy-related pathological changes in AMD.

Urolithin A is an anti-aging and anti-inflammatory gut bacterial metabolite derived from ellagic acid (EA), a polyphenol abundant in berries and nuts. The conversion of EA to urolithin A involves multiple chemically challenging phenol dehydroxylation steps that produce urolithins with varying bioactivities. Despite their biological and chemical significance, the bacterial enzymes responsible for urolithin production remain unidentified. Here, we use differential gene expression analysis, anaerobic protein expression, and enzyme assays to identify members of two distinct molybdenum enzyme families (the DMSO reductase family and the xanthine oxidase family) capable of regioselective dehydroxylation and urolithin generation. These two enzyme families have distinct substrate requirements, suggesting they employ different catalytic mechanisms for phenol dehydroxylation. Multi-omics analysis of a human cohort uncovers decreased levels of urolithin A and genes encoding urolithin A-producing enzymes in patients with inflammatory bowel disease (IBD), implying reduced health effects of EA consumption in this setting. Together, this study elucidates the molecular basis of urolithin production, expands the known enzymatic repertoire of the human gut microbiome, and suggests a potential link between gut bacterial urolithin production and host inflammation.

In migratory fibroblasts, the front-rear polarity required for cell migration is defined by an anterior centrosome relative to the nucleus. To achieve this polarity, actin cables drive the nucleus backward by coupling to nuclear membrane proteins nesprin-2G and SUN2. Aging disrupts this cell polarity by increasing the protein levels of SUN1, a SUN2 homolog. Here, we investigated the molecular mechanisms behind this disruption and found that the dominant negative effect of SUN1 and progerin, an aging-related lamin A variant, required direct SUN1-lamin A interaction. Microtubule interaction and force transmission through a nesprin, identified as nesprin-2, are crucial for SUN1\'s effect. We further discovered that stable microtubules are both necessary and sufficient to inhibit cell polarity. Using SUN1-SUN2 chimeric proteins, we demonstrated that the SUN domains determine their roles in cell polarization. Our findings reveal how elevated SUN1 disrupts cell polarity through coupling microtubule and nuclear lamina, emphasizing the impact of altered microtubule stability and nuclear mechanotransduction in aging.

Sarcopenia, the pathological age-related loss of muscle mass and strength, contributes to physical decline, frailty, and diminished healthspan. The impact of sarcopenia is expected to rise as the aging population grows, and treatments remain limited. Therefore, novel approaches for enhancing physical function and strength in older adults are desperately needed. Recent evidence suggests that deficits in motor neuron excitability contribute significantly to age-related weakness. Accordingly, we hypothesized that enhancing motor neuron excitability could be a novel strategy for mitigating age-related declines in physical function and strength. To test this hypothesis, we targeted the 5-HT

Curcumin (CU), a bioactive compound of turmeric, has been put forward as a golden molecule due to its anti-inflammatory, antioxidant, hepatoprotective, neuroprotective, and anti-cancer ability, as proven by research conducted over the decade and more. Our laboratory, developed an adult life stage specific (ALSS) Drosophila model of sporadic Parkinson disease (PD), and for first time demonstrated that dopaminergic (DAergic) neuroprotective efficacy of curcumin is limited to health phase viz. adult-young life stage and is absent during transition phase viz. adult senior life stages when PD set in. This observation suggests the limitation of curcumin as a therapeutic agent for late-onset disorders like PD. Further, our laboratory also demonstrated that despite curcumin ability to sequester oxidative stress during both the adult life stages, neuroprotection and brain dopamine replenishment is granted only in health stages but not in a vulnerable transition stage, which prompted to put forward the hypothesis that the molecular target(s) of CU, may be absent or inadequate in the transition stage of aging brain. With this insight, the current study was implemented to analyse the life stage-specific differential regulation of multiple molecular players of neuro-integral pathways in brain of ALSS Drosophila model of PD with curcumin intervention. It is discovered that curcumin-mediated health phase-specific neuroprotection underlies the correction of an altered expression of 1. dFOXO, GADD45, Puc of Bsk-dFOXO stress response pathway, 2. Mfn2 of Mitochondrial dynamics 3. CncC, GCLC, Prx 2540 -1,2, Jafrac1, Prx3 of Phase II antioxidant defense system pathway. Further, it is discovered that significant aging-associated naturally altered expression of certain molecular targets exists, that may contribute to the limitation of curcumin DAergic neuroprotective efficacy during the adult-transition stage. This knowledge will help in developing altered therapeutic strategies for PD as molecular targets of curcumin are conserved among fly, mice and human.

Manganese superoxide dismutase (MnSOD/SOD2) is an essential mitochondrial enzyme that detoxifies superoxide radicals generated during oxidative respiration. MnSOD/SOD2 lysine 68 acetylation (K68-Ac) is an important post-translational modification (PTM) that regulates enzymatic activity, responding to nutrient status or oxidative stress, and elevated levels have been associated with human illness. To determine the in vivo role of MnSOD-K68 in the heart, we used a whole-body non-acetylation mimic mutant (MnSOD

Aging is a complex biological process characterized by increased inflammation and susceptibility to various age-related diseases, including cognitive decline, osteoporosis, and type 2 diabetes. Exercise has been shown to modulate mitochondrial function, immune responses, and inflammatory pathways, thereby attenuating aging through the regulation of exerkines secreted by diverse tissues and organs. These bioactive molecules, which include hepatokines, myokines, adipokines, osteokines, and neurokines, act both locally and systemically to exert protective effects against the detrimental aspects of aging. This review provides a comprehensive summary of different forms of exercise for older adults and the multifaceted role of exercise in anti-aging, focusing on the biological functions and sources of these exerkines. We further explore how exerkines combat aging-related diseases, such as type 2 diabetes and osteoporosis. By stimulating the secretion of these exerkines, exercise supports healthy longevity by promoting tissue homeostasis and metabolic balance. Additionally, the integration of exercise-induced exerkines into therapeutic strategies represents a promising approach to mitigating age-related pathologies at the molecular level. As our understanding deepens, it may pave the way for personalized interventions leveraging physical activity to enhance healthspan and improve quality of life.

The pursuit of healthy aging has long rendered aging and senescence captivating. Age-related ailments, such as cardiovascular diseases, diabetes, and neurodegenerative disorders, pose significant threats to individuals. Recent studies have shed light on the intricate mechanisms encompassing genetics, epigenetics, transcriptomics, and metabolomics in the processes of senescence and aging, as well as the establishment of age-related pathologies. Amidst these underlying mechanisms governing aging and related pathology metabolism assumes a pivotal role that holds promise for intervention and therapeutics. The advancements in metabolomics techniques and analysis methods have significantly propelled the study of senescence and aging, particularly with the aid of multiscale metabolomics which has facilitated the discovery of metabolic markers and therapeutic potentials. This review provides an overview of senescence and aging, emphasizing the crucial role metabolism plays in the aging process as well as age-related diseases.

The association between leisure-time physical activity (LTPA) and a lower risk of mortality is susceptible to bias from multiple sources. We investigated the potential of biological ageing to mediate the association between long-term LTPA and mortality and whether the methods used to account for reverse causality affect the interpretation of this association.

Aging adversely affects the self-renewal and differentiation capabilities of stem cells, which impairs tissue regeneration as well as the homeostasis. Epigenetic mechanisms, specifically DNA methylation, play a key role in the maintenance of pluripotency in stem cells and regulation of pluripotency-related gene expression. Age-related modifications in methylation patterns could influence the expression of genes critical for stem cell potency maintenance, including transcription factors Nanog and Sox2. The following chapter describes a step-by-step bisulfite sequencing protocol for detection of methylation changes in the aging stem cells and provides valuable insights into the stem cells epigenetic profile. Further, the methodology describes the steps of genomic DNA extraction, bisulfite conversion, real-time PCR amplification, and sequencing for an in-depth view of the epigenetic profile derived from aging stem cells.

Decline in mobility is a global issue that must be addressed in rapidly aging societies. We aimed to clarify the association between locomotive syndrome (LS), a condition of decreased mobility and health literacy (HL) in community-dwelling Japanese adults aged ≥ 40 years. A descriptive survey was conducted in Onjuku Town, Japan, between 2019 and 2023. The participants performed LS risk tests, including the two-step test, stand-up tests and 25-question geriatric locomotive function scale, to assess mobility. They completed the 14-item health literacy scale to quantify the total HL and functional, communicative and critical HL subscales. Other participant characteristics, such as chronic diseases, bodily pain and physical activity, were also surveyed. The association between LS and HL was assessed using univariate and multivariate logistic regression analyses, adjusted for participant characteristics. We analyzed 492 participants with a median age of 71 years. The total HL score decreased as the LS stage increased, with 56, 54 and 51 points in stages 0, 1 and ≥ 2, respectively (p = 0.004). In the logistic regression analysis, a high total HL score was significantly associated with reduced odds of stage ≥ 2 LS (adjusted odds ratio, 0.95; p < 0.001). Furthermore, functional HL score had an independent association with stage ≥ 2 LS (adjusted odds ratio, 0.88; p = 0.009). Our results suggest that clinicians should provide HL education in addition to known preventive measures, such as promoting physical activity, as a holistic approach to decreased mobility.

To examine the longitudinal association between estimated pulse wave velocity (ePWV) and cognitive phenotypes in a rural Chinese older population.

Advanced glycation end products (AGEs) accumulate in various tissues, including bone, due to aging and conditions like diabetes mellitus. To investigate the effects of AGEs on bone material quality and biomechanical properties, an

Age-related dependencies of electric and spectral powers in conventional frequency bands were studied by the newly proposed method of detailed spectral analysis. The magnetic encephalograms (MEG) and magnetic resonance images (MRI) of the head were obtained from the open archive Cam-CAN. The spatial distributions of elementary spectral components (MEG-based functional tomograms) were reconstructed from MEG for 501 subjects (248 males and 253 females, ages 18-88 years, mean age 54.8 ±18.4). Physiological noise was eliminated by joint analysis of MEG-based functional tomogram and magnetic resonance image for each subject. Spectral and electric powers were calculated in six conventional frequency bands (1-4 Hz - delta; 4-8 Hz - theta; 8-13 Hz - alpha; 13-21 Hz - beta-1; 21-30 Hz - beta-2; 30-48 Hz - gamma), and age-related changes were examined. It was found that the spectral power of the delta band is significantly decreasing (p-value 0.002) and beta-1 and gamma are significantly increasing (p-values 0.001, 0.003). Electric power in the delta band is significantly decreasing (p-value 0.033), while electric power in the beta-1 band is significantly increasing (p-value 0.001). Also, the summary electric power of theta, alpha, beta-1, beta-2, and gamma bands is significantly increasing (p-value 0.024). Results represent general time dependence of the aging brain's electrical sources. The proposed method of joint MEG and MRI analysis can be used for a detailed study of sources location and connectivity.

The extent to which lifestyle shapes trajectories of normal cognitive aging, and the factors with highest potential for mitigating cognitive decline, remain poorly uncharacterized.

Numerous factors, including age chronic disease, level of education, and depression, affect the health and function of skeletal muscles. However, it is still unclear which factors affect skeletal muscle health in older age groups across age range segments. Decision tree and logistic regression models were employed in this study to examine the factors that influence older adults' likelihood of developing sarcopenia. The database information of the China Health and Retirement Longitudinal Study (CHARLS) in 2015 was selected, and a sample of 2965 people who met the inclusion criteria was screened. Logistic regression research revealed that while height (

Age-associated depletion in nicotinamide adenine dinucleotide (NAD+) concentrations has been implicated in metabolic, cardiovascular, and neurodegenerative disorders. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), offers a potential therapeutic avenue against neurodegenerative pathologies in aging, Alzheimer's disease, and related dementias. A crossover, double-blind, randomized placebo (PBO) controlled trial was conducted to test the safety and efficacy of 8 weeks' active treatment with NR (1 g/day) on cognition and plasma AD biomarkers in older adults with subjective cognitive decline and mild cognitive impairment.

Mitochondrial Rho-GTPase 1 (MIRO1) is an outer mitochondrial membrane protein which regulates mitochondrial transport and mitophagy in mitosis. In present study, we reported the crucial roles of MIRO1 in mammalian oocyte meiosis and its potential relationship with aging. We found that MIRO1 expressed in mouse and porcine oocytes, and its expression decreased in aged mice. MIRO1 deficiency caused the failure of meiotic resumption and polar body extrusion in both mouse and porcine oocytes, which could be rescued by exogenous MIRO1 supplementation. Mass spectrometry data indicated that MIRO1 associated with several cytoskeleton and cell cycle-related proteins, and MIRO1 regulated motor protein Dynein for microtubule-organizing centers (MTOCs) dynamics at germinal vesicle (GV) stage, which determined meiotic resumption. Furthermore, we found that MIRO1 regulated Aurora A and kinesin family member 11 (KIF11) for meiotic spindle assembly in oocytes. Besides, MIRO1 associated with several mitochondria-related proteins dynamic-related protein 1 (DRP1), Parkin and lysosomal-associated membrane protein 2 (LAMP2) for mitochondrial dynamics and mitophagy during oocyte meiosis. Taken together, our results suggested that MIRO1 played pivotal roles in meiotic resumption, spindle assembly and mitochondrial function in mouse and porcine oocytes, and its insufficiency might contribute to the oocyte maturation defects during aging.

Modulating immune function is a critical strategy in cancer and atherosclerosis treatments. For cancer, boosting or maintaining the immune system is crucial to prevent tumor growth. However, in vascular disease, mitigating immune responses can decrease inflammation and slow atherosclerosis progression. Anti-inflammatory therapy, therefore, presents a unique dilemma for cancer survivors: while it may decrease cardiovascular risk, it might also promote cancer growth and metastasis by suppressing the immune response. Senescence presents a potentially targetable solution to this challenge; senescence increases the risk of both cancer therapy resistance and vascular disease. Exercise, notably, shows promise in delaying this premature senescence, potentially improving cancer outcomes and lowering vascular disease risk post-treatment. This review focuses on the long-term impact of cancer therapies on vascular health. We underscore the importance of modulating senescence to balance cancer treatment's effectiveness and its vascular impact, and we emphasize investigating the role of exercise-mediated suppression of senescence in improving cancer survivorship.

Dietary protein is a key regulator of healthy aging in both mice and humans. In mice, reducing dietary levels of the branched-chain amino acids (BCAAs) recapitulates many of the benefits of a low protein diet; BCAA-restricted diets extend lifespan, reduce frailty, and improve metabolic health, while BCAA supplementation shortens lifespan, promotes obesity, and impairs glycemic control. Recently, high protein diets have been shown to promote cellular senescence, a hallmark of aging implicated in many age-related diseases, in the liver of mice. Here, we test the hypothesis that the effects of high protein diets on metabolic health and on cell senescence are mediated by BCAAs. We find that reducing dietary levels of BCAAs protects male and female mice from the negative metabolic consequences of both normal and high protein diets. Further, we identify tissue-specific effects of BCAAs on cellular senescence, with restriction of all three BCAAs - but not individual BCAAs - protecting from hepatic cellular senescence while potentiating cell senescence in white adipose tissue. We find that the effects of BCAAs on hepatic cellular senescence are cell-autonomous, with lower levels of BCAAs protecting cultured cells from antimycin-A induced senescence. Our results demonstrate a direct effect of a specific dietary component on a hallmark of aging and suggest that cellular senescence may be highly susceptible to dietary interventions.

The largest risk factor for dementia is age. Heterochronic blood exchange studies have uncovered age-related blood factors that demonstrate 'pro-aging' or 'pro-youthful' effects on the mouse brain. The clinical relevance and combined effects of these factors for humans is unclear. We examined five previously identified brain rejuvenation factors in cerebrospinal fluid of adults with autosomal dominant forms of frontotemporal dementia and sporadic Alzheimer's disease. Our frontotemporal dementia cohort included 100 observationally followed adults carrying autosomal dominant frontotemporal dementia mutations (M

Cellular senescence contributes to inflammation and organ dysfunction during aging. While this process is generally characterized by irreversible cell cycle arrest, its morphological features and functional impacts vary in different cells from various organs. In this study, we examined the expression of multiple senescent markers in the lungs of young and aged humans and mice, as well as in mouse lung endothelial cells cultured with a senescence inducer, suberoylanilide hydroxamic acid (SAHA), or doxorubicin (DOXO). We detected increased levels of p21, γH2AX, and SA-β-Gal and decreased Ki-67 and Lamin B1 in aged lungs and senescent lung endothelial cells. Importantly, the expression of senescent markers was associated with an inflammatory response in aged mouse lungs characterized by neutrophil infiltration, increased expression of intercellular adhesion molecule 1 (ICAM-1), and decreased protein levels of VE-cadherin and ZO-1. As the latter two are critical constituents of endothelial cell-cell junctions, we hypothesized that their decreased expression could lead to compromised junction barrier integrity. Indeed, senescent endothelial cells (ECs) exhibited impaired barrier properties, as measured by increased permeability to solutes of small size (3-kD) and albumin (70-kD). When co-cultured with neutrophils, senescent ECs and their supernatant promoted neutrophil chemotaxis and trans-endothelial migration. Taken together, our results suggest that lung EC senescence weakens cell-cell junctions, impairs barrier function, and promotes neutrophil adhesion and migration, which may contribute to the development of inflammation and related pathologies in the lungs during aging.

The Mesenchymal Stem Cell (MSC) is a multipotent progenitor cell with known differentiation potential towards various cell lineage, making it an appealing candidate for regenerative medicine. One major contributing factor to age-related MSC dysfunction is cellular senescence, which is the hallmark of relatively irreversible growth arrest and changes in functional properties. GATA4, a zinc-finger transcription factor, emerges as a critical regulator in MSC biology. Originally identified as a key regulator of heart development and specification, GATA4 has since been connected to several aspects of cellular processes, including stem cell proliferation and differentiation. Accumulating evidence suggests that the involvement of GATA4-nuclear signalizing in the process of MSC senescence-related traits may contribute to age-induced alterations in MSC behavior. GATA4 emerged as the central player in MSC senescence, interacting with several signaling pathways. Studies have shown that GATA4 expression is reduced with age in MSCs, which is associated with increased expression levels of senescence markers and impaired regenerative potential. At the mechanistic level, GATA4 regulates the expression of genes involved in cell cycle regulation, DNA repair, and oxidative stress response, thereby influencing the senescence phenotype in MSCs. The findings underscore the critical function of GATA4 in MSC homeostasis and suggest a promising new target to restore stem cell function during aging and disease. A better understanding of the molecular mechanisms that underlie GATA4 mediated modulation of MSC senescence would provide an opportunity to develop new therapies to revitalize old MSCs to increase their regenerative function for therapeutic purposes in regenerative medicine.

Prion disease is a fatal neurodegenerative disease caused by the misfolding of prion protein (PrP) encoded by the PRNP gene. While there is currently no cure for the disease, depleting PrP in the brain is an established strategy to prevent or stall templated misfolding of PrP. Here we developed in vivo cytosine and adenine base strategies delivered by adeno-associated viruses to permanently modify the PRNP locus to achieve PrP knockdown in the mouse brain. Systemic injection of dual-adeno-associated virus PHP.eB encoding BE3.9max and single guide RNA installing PRNP R37X resulted in 37% average installation of the desired edit, 50% reduction of PrP in the mouse brain and 52% extension of lifespan in transgenic human PRNP mice inoculated with pathogenic human prion isolates representing the most common sporadic and genetic subtypes of prion disease. We further engineered base editing systems to achieve improved in vivo potency and reduced base editor expression in nontargeting tissues, resulting in 63% average PrP reduction in the mouse brain from a 6.7-fold lower viral dose, with no detected off-target editing of anticipated clinical significance observed in either human cells or mouse tissues. These findings support the potential of in vivo base editing as one-time treatment for prion disease.

Background: A significant proportion of individuals maintain healthy cognitive function despite having extensive Alzheimer\'s disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals can identify therapeutic targets for AD dementia. This study aims to define molecular and cellular signatures of cognitive resilience, protection and resistance, by integrating genetics, bulk RNA, and single-nucleus RNA sequencing data across multiple brain regions from AD, resilient, and control individuals. Methods: We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk (n=631) and multi-regional single nucleus (n=48) RNA sequencing. Subjects were categorized into AD, resilient, and control based on {beta}-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition distribution. Results: Transcriptomic results, supported by GWAS-derived polygenic risk scores, place cognitive resilience as an intermediate state in the AD continuum. Tissue-level analysis revealed 43 genes enriched in nucleic acid metabolism and signaling that were differentially expressed between AD and resilience. Only GFAP (upregulated) and KLF4 (downregulated) showed differential expression in resilience compared to controls. Cellular resilience involved reorganization of protein folding and degradation pathways, with downregulation of Hsp90 and selective upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. Excitatory neuronal subpopulations in the entorhinal cortex (ATP8B1+ and MEF2Chigh) exhibited unique resilience signaling through neurotrophin (modulated by LINGO1) and angiopoietin (ANGPT2/TEK) pathways. We identified MEF2C, ATP8B1, and RELN as key markers of resilient excitatory neuronal populations, characterized by selective vulnerability in AD. Protective rare variant enrichment highlighted vulnerable populations, including somatostatin (SST) inhibitory interneurons, validated through immunofluorescence showing co-expression of rare variant associated RBFOX1 and KIF26B in SST+ neurons in the dorsolateral prefrontal cortex. The maintenance of excitatory-inhibitory balance emerges as a key characteristic of resilience. Conclusions: We identified molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preservation of neuronal function, maintenance of excitatory/inhibitory balance, and activation of protective signaling pathways. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable SST interneurons likely provide compensation against AD-associated dysregulation. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD.

Due to the increased burden of non-AIDS-related comorbidities in people living with HIV (PLHIV), identifying biomarkers and mechanisms underlying premature aging and the risk of developing age-related comorbidities is a priority. Evidence suggests that the plasma proteome is an accurate source for measuring biological age and predicting age-related clinical outcomes. To investigate whether PLHIV on antiretroviral therapy (ART) exhibit a premature aging phenotype, we profiled the plasma proteome of two independent cohorts of virally suppressed PLHIV (200HIV and 2000HIV) and one cohort of people without HIV (200FG) using O-link technology. Next, we built a biological age-prediction model and correlated age advancement (the deviation of the predicted age from the chronological age) with HIV-related factors, comorbidities, and cytokines secreted by immune cells. We identified a common signature of 77 proteins associated with chronological age across all cohorts, most of which were involved in inflammatory and senescence-related processes. PLHIV showed increased age advancement compared to people without HIV. In addition, age advancement in the 2000HIV cohort was positively associated with prior hepatitis C and cytomegalovirus (CMV) infections, non-AIDS-related comorbidities, ART duration, cumulative exposure to the protease inhibitor Ritonavir, as well as higher production of monocyte-derived proinflammatory cytokines and chemokines and lower secretion of T-cell derived cytokines. Our proteome-based predictive model is a promising approach for calculating the age advancement in PLHIV. This will potentially allow for further characterization of the pathophysiological mechanisms linked to accelerated aging and enable monitoring the effectiveness of novel therapies aimed at reducing age-related diseases in PLHIV.

Induction of senescence by chemotherapeutic agents arrests cancer cells and activates immune surveillance responses to contribute to therapy outcomes. In this investigation, we searched for ways to enhance the NK-mediated elimination of senescent cells. We used a staggered screen approach, first identifying siRNAs potentiating the secretion of immunomodulatory cytokines to later test for their ability to enhance NK-mediated killing of senescent cells. We identified that genetic or pharmacological inhibition of SMARCA4 enhanced senescent cell elimination by NK cells. SMARCA4 expression is elevated during senescence and its inhibition derepresses repetitive elements, inducing the SASP via activation of cGAS/STING and MAVS/MDA5 pathways. Moreover, a PROTAC targeting SMARCA4 synergized with cisplatin to increase the infiltration of CD8 T cells and mature, activated NK cells in an immunocompetent model of ovarian cancer. Our results indicate that SMARCA4 inhibitors enhance NK-mediated surveillance of senescent cells and may represent senotherapeutic interventions for ovarian cancer.

Cellular senescence (CS) is recognized as a critical driver of aging and age-related disorders. Recent studies have emphasized the roles of ion channels as key mediators of CS. Nonetheless, the roles and regulatory mechanisms of chloride intracellular channels (CLICs) during CS remain largely unexplored. In this study, we conducted RNA sequencing on bleomycin-induced senescent lung tissues from mice and identified Clic3 as the most significantly upregulated CLIC member. Furthermore, our findings revealed that the knockdown of CLIC3 mitigated intracellular chloride ion lose, mitochondrial dysfunction, nuclear enlargement, DNA damage, CS progression, and expression of senescence-associated secretory phenotype (SASP) triggered by bleomycin. Mechanistically, CLIC3 controls CS by translocating to the membrane where it interacts with extracellular signal-regulated kinase 7 (ERK7). Overall, our work demonstrates that the chloride intracellular channel CLIC3 modulates CS by repressing ERK7 activity and provides novel insights into the role of chloride channels.

Chronological age is not an accurate predictor of morbidity and mortality risk, as individuals' aging processes are diverse. Phenotypic age acceleration (PhenoAgeAccel) is a validated biological age measure incorporating chronological age and biomarkers from blood samples commonly used in clinical practice that can better reflect aging-related morbidity and mortality risk. The heterogeneity of age-related decline is not random, as environmental exposures can promote or impede healthy aging. Social Vulnerability Index (SVI) is a composite index accounting for different facets of the social, economic, and demographic environment grouped into four themes: socioeconomic status, household composition and disability, minority status and language, and housing and transportation. We aim to assess the concurrent and combined associations of the four SVI themes on PhenoAgeAccel and the differential effects on disadvantaged groups. We use electronic health records data from 31,913 patients from the Mount Sinai Health System (116,952 person-years) and calculate PhenoAge for years with available laboratory results (2011-2022). PhenoAge is calculated as a weighted linear combination of lab results, and PhenoAgeAccel is the differential between PhenoAge and chronological age. A decile increase in the mixture of SVI dimensions was associated with an increase of 0.23 years (95% CI 0.21, 0.25) in PhenoAgeAccel. The socioeconomic status dimension was the main driver of the association, accounting for 61% of the weight. Interaction models revealed a more substantial detrimental association for women and racial and ethnic minorities with differences in leading SVI themes. These findings suggest that neighborhood-level social vulnerability increases the biological age of its residents, increasing morbidity and mortality risks. Socioeconomic status has the larger detrimental role among the different facets of social environment.

Advanced Glycation End Products (AGEs) are the end result of the irreversible, non-enzymatic glycation of proteins by reducing sugars. These chemical modifications accumulate with age and have been associated with various age-related and diabetic complications. AGEs predominantly accumulate on proteins with slow turnover rates, of which collagen is a prime example. Glycation has been associated with tissue stiffening and reduced collagen fibril remodelling. In this study, we investigate the effects of glycation on the stability of type I collagen, its molecular-level mechanics and its ability to perform its physiological role of self-assembly. Collagen AGEing is induced in vitro by incubation with ribose. We confirm and assess glycation using fluorescence measurements and changes in collagen's electrophoretic mobility. Susceptibility to trypsin digestion and circular dichroism (CD) spectroscopy are used to probe changes in collagen's triple helical stability, revealing decreased stability due to glycation. Atomic Force Microscopy (AFM) imaging is used to quantify how AGEing affects collagen flexibility, where we find molecular-scale stiffening. Finally we use microscopy to show that glycated collagen molecules are unable to self-assemble into fibrils. These findings shed light on the molecular mechanisms underlying AGE-induced tissue changes, offering insight into how glycation modifies protein structure and stability.

Neurons and glia work together to dynamically regulate neural circuit assembly and maintenance. In this study, we show Drosophila exhibit large-scale synapse formation and elimination as part of normal CNS circuit maturation, and that glia use conserved molecules to regulate these processes. Using a high throughput ELISA-based in vivo screening assay, we identify new glial genes that regulate synapse numbers in Drosophila in vivo, including the scavenger receptor ortholog Croquemort (Crq). Crq acts as an essential regulator of glial-dependent synapse elimination during development, with glial Crq loss leading to excess CNS synapses and progressive seizure susceptibility in adults. Loss of Crq in glia also prevents age-related synaptic loss in the adult brain. This work provides new insights into the cellular and molecular mechanisms that underlie synapse development and maintenance across the lifespan, and identifies glial Crq as a key regulator of these processes.

Aging affects the 12-lead electrocardiogram (ECG) and correlates with cardiovascular disease (CVD). AI-ECG models estimate aging effects as a novel biomarker but have only been evaluated on single ECGs-without utilizing longitudinal data. We validated an AI-ECG model, originally trained on Brazilian data, using a German cohort with over 20 years of follow-up, demonstrating similar performance (r

Cutaneous photoaging, induced by chronic exposure to ultraviolet (UV) radiation, typically manifests as alterations in both the physical appearance and functional properties of the skin and may predispose individuals to cancer development. Recent studies have demonstrated the reparative potential of exosomes derived from mesenchymal stem cells in addressing skin damage, while specific reports highlight their efficacy in ameliorating skin photoaging. However, the precise role of exosomes derived from human hair follicle mesenchymal stem cells (HFMSC-Exos) in the context of cutaneous photoaging remains largely unexplored. We successfully isolated HFMSC-Exos using the ultracentrifugation technique. In cellular experiments, we assessed the migration of human dermal fibroblasts (HDFs) through scratch and transwell assays, evaluated the angiogenesis of human umbilical vein endothelial cells through angiogenesis assays, and examined the expression levels of collagen and matrix metalloproteinase 1 (MMP-1) using Western blotting and quantitative reverse transcription polymerase chain reaction. Furthermore, we established a nude mouse model of photoaging to observe wrinkle formation on the dorsal surface of the animals, as well as to assess dermal thickness and collagen fiber generation through histological staining. Ultimately, we performed RNA sequencing on skin tissues from mice before and after treatment to elucidate the relevant underlying mechanisms. Our findings revealed that HFMSC-Exos effectively enhanced the migration and proliferation of HDFs and upregulated the expressions of transforming growth factor-β1 (TGF-β1), p-Smad2/p-Smad3, collagen type 1, and collagen type 3 while concurrently down-regulating MMP-1 levels in HDFs. Additionally, mice in the HFMSC-Exo group showed quicker wrinkle healing and increased collagen production. HFMSC-Exos miR-125b-5p was demonstrated to reduce skin photoaging by increasing profibrotic levels via TGF-β1 expression. UV-irradiated HDFs and photoaged nude mouse skin showed low TGF-β1 expressions, whereas overexpression of TGF-β1 in HDFs increased collagen type 1, collagen type 3, and p-Smad2/p-Smad3 expressions while decreasing MMP-1 expression. HDFs overexpressing TGF-β1 produced more collagen and altered the Smad pathway. This study demonstrated, both in vitro and in vivo, that HFMSC-Exos increased collagen formation, promoted HDF cell proliferation and migration, and reversed the senescence of UV-irradiated HDFs. TGF-β1 was identified as a target of HFMSC-Exos miR-125b-5p, which controls photoaging via regulating the Smad pathway. The antiphotoaging capabilities of HFMSC-Exos may occur via the miR-125b-5p/TGF-β1/Smad axis, suggesting a promising therapeutic approach for treating skin photoaging.

Presbycusis, also referred to as age-related hearing loss, poses a substantial burden on both individuals and society. The hallmark of presbycusis is a progressive decrease in auditory sensitivity. Irreversible hearing loss occurs due to the limited regenerative capacity of spiral neurons and peripheral cochlear hair cells (HCs). Although hearing aids and cochlear implantations (CIs) are established approaches for alleviating symptoms of presbycusis, there are currently no preventive or curative measures available. This article provides a comprehensive discussion on the research progress pertaining to the classification, molecular mechanism, genetic susceptibility, as well as the applications and prospects of diverse therapeutic interventions of presbycusis. Building upon these discussions, promising interventions like gene therapy and stem cell (SC) therapy are proposed for their potential value in restoring cochlear function; thus aiming to pave new avenues for prevention and cure of presbycusis.

Nutrition plays a central role in healthy living, however, extensive variability in individual responses to dietary interventions complicates our understanding of its effects. Here we present a comprehensive study utilizing the Drosophila Genetic Reference Panel (DGRP), investigating how genetic variation influences responses to diet and aging. Quantitative genetic analyses of the impact of dietary restriction on lifespan, locomotor activity, dry weight, and heat knockdown time were performed. Locomotor activity, dry weight and heat knockdown time were measured on the same individual flies. We found significant genotype-by-diet interaction (GDI) and genotype-by-age interaction (GAI) for all traits. Therefore, environmental factors play a crucial role in shaping trait variation at different ages and diets, and/or distinct genetic variation influences these traits at different ages and diets. Our genome wide association study also identified a quantitative trait locus for age-dependent dietary response. The observed GDI and GAI indicates that susceptibility to environmental influences changes as organisms age, which could have significant implications for dietary recommendations and interventions aimed at promoting healthy aging in humans. The identification of associations between DNA sequence variation and age-dependent dietary responses opens new avenues for research into the genetic mechanisms underlying these interactions.

The hypothalamus integrates peripheral signals and modulates food intake and energy expenditure by regulating the metabolic function of peripheral tissues, including the liver and adipose tissue. In a previous study, we demonstrated that s-resistin, an intracellular resistin isoform highly expressed in the hypothalamus and upregulated during aging, is important in the central control of energy homeostasis, affecting mainly the peripheral response to insulin by still unknown mechanisms. Herein, using an intracerebroventricular injection of a specific lentiviral RNAi against s-resistin, we assessed, in the Wistar rat, the effects of central s-resistin downregulation on the expression and phosphorylation levels of intermediates involved in insulin signaling and the inflammatory response in epididymal white adipose tissue (eWAT) and liver. Additionally, we studied the imbalance of eWAT hypertrophy/hyperplasia remodeling. Our results indicate that central downregulation of s-resistin regulates insulin signaling cascade in a tissue-specific manner, reduces the inflammatory status both in the liver and eWAT, and prevents eWAT hypertrophy. Taken together, our results highlight the pivotal role of central s-resistin in maintaining metabolic homeostasis in AT and the liver. This suggests a direct association between its function and the modulation of the inflammatory response in these tissues.

The growing population of older adults emphasizes the need to develop interventions that prevent or delay some of the cognitive decline that accompanies aging. In particular, as memory impairment is the foremost cognitive deficit affecting older adults, it is vital to develop interventions that improve memory function. This study addressed the problem of false memories in aging by training older adults to use details of past events during memory retrieval to distinguish targets from related lures. We examined the neural basis of a retrieval-based monitoring strategy by assessing changes in univariate BOLD activity and discriminability of targets and lures pre and post training. Results showed training-related decreases in false memory rates with no alterations to hit rates. Both training and practice were associated with altered recruitment of a frontoparietal monitoring network as well as benefits to neural discriminability within network regions. Participants with lower baseline neural discriminability between target and lure items exhibited the largest changes in neural discriminability. Collectively, our results highlight the benefits of training for reductions of false memories in aging. They also provide an understanding of the neural mechanisms that support these reductions.

The aging population represents a formidable global challenge, with China experiencing an accelerated demographic shift. While previous research has established a directional link between mental health literacy, social participation, and active aging, the moderating effect of socioeconomic status (SES) on these associations remains underexplored. This study sought to address this gap by employing moderated network analysis, in contrast to the total score approaches commonly used in prior literature.

Subjective wellbeing (SWB) is a crucial measure of life quality in older adults. Understanding its relationship with frailty may inform strategies to promote healthy aging.

Aging is a complex process that affects individuals at the molecular, cellular, tissue, and systemic levels, arising from the cumulative effects of damage and reduced repair mechanisms. This process leads to the onset of age-related diseases, including cancer, which exhibits increased incidence with age. Telomeres, the protective caps at chromosome ends, play a crucial role in genome stability and are closely connected with aging and age-related disorders. Both excessively short and long telomere lengths may contribute to cancer development when their balance is disrupted. Fragile telomeres, characterized by abnormalities and replication stress, may provide novel insights into the connection between aging and cancer. The accumulation of fragile telomeres, possibly due to intense replicative stress, may represent a key factor. Given the dynamic nature of telomeres, large longitudinal studies are essential for understanding their role in aging and cancer susceptibility, which is crucial for developing effective strategies to promote healthy aging and mitigate cancer risk.

Idiopathic pulmonary fibrosis (IPF) is a condition predominantly affecting the elderly and leading to a decline in lung function. Our study investigates the aging-related mechanisms in IPF using artificial intelligence (AI) approaches. We developed a pathway-aware proteomic aging clock using UK Biobank data and applied it alongside a specialized version of Precious3GPT (ipf-P3GPT) to demonstrate an AI-driven mode of IPF research. The aging clock shows great performance in cross-validation (R2=0.84) and its utility is validated in an independent dataset to show that severe cases of COVID-19 are associated with an increased aging rate. Computational analysis using ipf-P3GPT revealed distinct but overlapping molecular signatures between aging and IPF, suggesting that IPF represents a dysregulation rather than mere acceleration of normal aging processes. Our findings establish novel connections between aging biology and IPF pathogenesis while demonstrating the potential of AI-guided approaches in therapeutic development for age-related diseases.

Senescent bone tissue displays a pathological imbalance characterized by decreased angiogenesis, disrupted bioelectric signaling, ion dysregulation, and reduced stem cell differentiation. Once bone defects occur, this pathological imbalance makes them difficult to repair. An innovative synergistic therapeutic strategy is utilized to reverse these pathological imbalances via a conductive hydrogel doped with magnesium ion (Mg

In pediatric hematopoietic cell transplantation (HCT) recipients, transplanted donor cells may need to function far beyond normal human lifespan. Here, we investigated the risk of clonal hematopoiesis (CH) in 144 pediatric long-term HCT survivors and 258 non-transplanted controls. CH was detected in 16% of HCT recipients and 8% of controls, at variant allele frequencies (VAFs) of 0.01-0.31. Mutations were predominantly in DNMT3A (80%) and TET2 (20%). Older hematopoietic age (odds ratio: 1.07, p<0.001) and the HCT procedure (odds ratio: 2.53, p=0.02) independently increased the risk of CH, indicating both aging- and transplantation-induced effects. Large clones (VAF >0.10) were found exclusively in HCT recipients. Notably, CH was also detected within 15 years after a cord blood HCT. Inflammatory processes around graft infusion were associated with CH presence. Future studies are required to track the evolution of post-transplant CH and its impact on future cardiovascular disease, second malignancies and overall survival.

Rejuvenation of elementary immune system components has emerged as a promising strategy to deal with increased susceptibility to infections, cancers, autoimmune disorders, and low efficacy to vaccines, frequently accompanying aging. In this context, the thymus has gained significant attention. A recent study by Santamaria et al. reveals that the receptor activator of nuclear factor-κB (RANK)-RANK ligand (RANKL) axis is altered during age related thymic involution, compromising immune responses. Based on their findings, authors propose exogenous RANKL administration as a therapeutic strategy to reinvigorate thymic function and improve T-cell immunity during aging.

A combination of intermittent fasting and administering Wnt3a proteins to a bone injury can rejuvenate bone repair in aged mice.

Aging is a complex process characterized by biological decline and a wide range of molecular alterations to cells, including changes to DNA methylation. In this study, we used a male-specific epigenetic marker of aging to build an epigenetic predictor that measures long-term androgen exposure in sheep and mice (median absolute error of 4.3 and 1.4 mo, respectively). We term this predictor the androgen clock and show its "tick" is mediated by the androgen receptor and can be accelerated beyond that in normal male mice by supplementing females with dihydrotestosterone. Conversely, the removal of androgens by castration in sheep completely halted the androgen clock. In addition to potential applications in medicine and agriculture, we predict the androgen clock will prove a useful model to understand the mechanisms and processes of age-associated DNA methylation change because it can be precisely enhanced and halted using small molecule manipulation with few additional effects on the cell.

Age-related muscle wasting, sarcopenia is an extensive loss of muscle mass and strength with age and a major cause of disability and accidents in the elderly. Mechanisms purported to be involved in muscle ageing and sarcopenia are numerous but poorly understood, necessitating deeper study. Hence, we employed high-throughput RNA sequencing to survey the global changes in protein-coding gene expression occurring in skeletal muscle with age. Caloric restriction (CR) is a known prophylactic intervention against sarcopenia. Therefore, total RNA was isolated from the muscle tissue of both rats fed ad libitum and CR rats. RNA-seq data were subjected to Gene Ontology, pathway, co-expression, and interaction network analyses. This revealed the functional pathways most activated by both ageing and CR, as well as the key "hub" proteins involved in their activation.RNA-seq revealed 442 protein-coding genes to be upregulated and 377 to be downregulated in aged muscle, compared to young muscle. Upregulated genes were commonly involved in protein folding and immune responses; meanwhile, downregulated genes were often related to developmental biology. CR was found to suppress 69.7% and rescue 57.8% of the genes found to be upregulated and downregulated in aged muscle, respectively. In addition, CR uniquely upregulated 291 and downregulated 304 protein-coding genes. Hub genes implicated in both ageing and CR included Gc, Plg, Irf7, Ifit3, Usp18, Rsad2, Blm and RT1-A2, whilst those exclusively implicated in CR responses included Alb, Apoa1, Ambp, F2, Apoh, Orm1, Mx1, Oasl2 and Rtp4. Hub genes involved in ageing but unaffected by CR included Fgg, Fga, Fgb and Serpinc1. In conclusion, this comprehensive RNA sequencing study highlights gene expression patterns, hub genes and signalling pathways most affected by ageing in skeletal muscle. This data may provide the initial evidence for several targets for potential future therapeutic interventions against sarcopenia.

Masticatory dysfunction due to tooth loss is a potentially modifiable risk for mortality, but the pathway behind that remains to be investigated. This prospective study aimed to examine the role of diet and ageing in the associations between chewing capacity and long-term mortality.

Cellular senescence is a complex biological response to sublethal damage. The RNA-binding protein HNRNPK was previously found to decrease prominently during senescence in human diploid fibroblasts. Here, analysis of the mechanisms leading to reduced HNRNPK abundance revealed that in cells undergoing senescence,

With the exacerbation of global population aging, sarcopenia has become an increasingly recognized public health issue. Sarcopenia, characterized by a progressive decline in skeletal muscle mass, strength, and function, significantly impacts the quality of life in the elderly. Herein, we explore the role of chroniclow-gradeinflammation in the development of sarcopenia and its underlying molecular mechanisms, including chronic inflammation-associated signaling pathways, immunosenescence, obesity and lipid infiltration, gut microbiota dysbiosis and intestinal barrier disruption, and the decline of satellite cells. The interplay and interaction of these molecular mechanisms provide new perspectives on the complexity of the pathogenesis of sarcopenia and offer a theoretical foundation for the development of future therapeutic strategies.