Longevity Papers

This study investigates the association between dietary methyl donor nutrients intake and phenotypic aging. This cross-sectional study comprised 27,211 adult participants from the NHANES 2005-2018. The methyl-donor nutritional quality index (MNQI) was calculated by assessing the intake of the seven methyl donor nutrients: protein, folate, choline, riboflavin, vitamin B6, vitamin B12, and zinc. Phenotypic age acceleration (PhenoAge.Accel) was calculated using biochemical markers to assess biological aging. Weighted generalized linear regression models were utilized to assess the associations between MNQI and PhenoAge.Accel, and the impact of different demographic and health characteristics was evaluated through interaction effect tests. After adjusting for various potential confounding factors, a significant negative association was found between MNQI and PhenoAge.Accel (β = - 0.66; 95% CI - 0.91, - 0.40; P < 0.0001), indicating that an increase in MNQI is associated with a slowdown in PhenoAge.Accel. Furthermore, subgroup analysis indicated stronger negatively association between MNQI and PhenoAge.Accel in males (β = - 0.94; 95% CI - 1.36, - 0.52) with significant interactions (P

Age-related diseases imposed heavy burdens to the healthcare systems globally, while cell senescence served as one fundamental molecular/cellular basis for these diseases. How to tackle the senescence-relevant problems is a hotspot for biomedical research. In this review article, the hallmarks and molecular pathways of cell senescence were firstly discussed, followed by the introduction of the current anti-senescence strategies, including senolytics and senomorphics. With suitable physical or chemical properties, multiple types of nanomaterials were used successfully in senescence therapeutics, as well as senescence detection. Based on the accumulating knowledges for senescence, the rules of how to use these nanoplatforms more efficiently against senescence were also summarized, including but not limited to surface modification, material-cargo interactions, factor responsiveness etc. The comparison of these "senescence-selective" nanoplatforms to other treatment options (prodrugs, ADCs, PROTACs, CART etc.) was also given. Learning from the past, nanotechnology can add more choice for treating age-related diseases, and provide more (diagnostic) information to further our understanding of senescence process.

Epigenetic modifications play a critical role in regulating gene expression under various physiological and pathological conditions. Epigenetic modifications reprogramming is a recognized hallmark of aging and a key component of the aging clock used to differentiate between chronological and biological age. The potential for prospective diagnosis and regulatory capabilities position epigenetic modifications as an emerging drug target to extend longevity and alleviate age-related organ dysfunctions. In the past few decades, numerous preclinical studies have demonstrated the therapeutic potential of natural products in various human diseases, including aging, with some advancing to clinical trials and clinical application. This review highlights the discovery and recent advancements in the aging clock, as well as the potential use of natural products as anti-aging therapeutics by correcting disordered epigenetic reprogramming. Specifically, the focus is on the imbalance of histone modifications, alterations in DNA methylation patterns, disrupted ATP-dependent chromatin remodeling, and changes in RNA modifications. By exploring these areas, new insights can be gained into aging prediction and anti-aging interventions.

Aging-related liver and brain damage caused by oxidative stress and inflammation significantly impacts health and quality of life. Natural bioactive compounds, such as 6'-O-caffeoylarbutin (CA), which is primarily distributed in Vaccinium species, have been studied for their antioxidant and anti-inflammatory properties. This study aims to investigate the protective effect on liver and brain damage induced by D-galactose (D-gal) in mice and to explore its potential molecular mechanisms.

Sarcopenia, defined as the progressive loss of skeletal muscle mass and function associated with ageing, has devastating effects in terms of reducing the quality of life of older people. Muscle ageing is characterised by muscle atrophy and decreased capacity for muscle repair, including a reduction in the muscle stem cell pool that impedes recovery after injury. Histone deacetylase 11 (HDAC11) is the newest member of the HDAC family and it is highly expressed in skeletal muscle. Our group recently showed that genetic deficiency in HDAC11 increases skeletal muscle regeneration, mitochondrial function and globally improves muscle performance in young mice. Here, we explore for the first time the functional consequences of HDAC11 deficiency in old mice, in homeostasis and during muscle regeneration. Aged mice lacking HDAC11 show attenuated muscle atrophy and postsynaptic fragmentation of the neuromuscular junction, but no significant differences in the number or diameter of myelinated axons of peripheral nerves. Maintenance of the muscle stem cell reservoir and advanced skeletal muscle regeneration after injury are also observed. HDAC11 depletion enhances mitochondrial fatty acid oxidation and attenuates age-associated alterations in skeletal muscle fatty acid composition, reducing drastically the omega-6/omega-3 fatty acid ratio and improving significantly the omega-3 index, providing an explanation for improved muscle strength and fatigue resistance and decreased mortality. Taken together, our results point to HDAC11 as a new target for the treatment of sarcopenia. Importantly, selective HDAC11 inhibitors have recently been developed that could offer a new therapeutic approach to slow the ageing process.

Gut microbiota alteration during the aging process serves as a causative factor for aging-related cognitive decline, which is characterized by the early hallmark, hippocampal synaptic loss. However, the impact and mechanistic role of gut microbiota in hippocampal synapse loss during aging remains unclear. Here, we observed that the fecal microbiota of naturally aged mice successfully transferred cognitive impairment and hippocampal synapse loss to young recipients. Multi-omics analysis revealed that aged gut microbiota was characterized with obvious change in Bifidobacterium pseudolongum (B.p) and metabolite of tryptophan, indoleacetic acid (IAA) in the periphery and brain. These features were also reproduced in young recipients that were transplanted with aged gut microbiota. Fecal B.p abundance was reduced in patients with cognitive impairment compared to healthy subjects and showed a positive correlation with cognitive scores. Microbiota transplantation from patients who had fewer B.p abundances yielded worse cognitive behavior in mice than those with higher B.p abundances. Meanwhile, supplementation of B.p was capable of producing IAA and enhancing peripheral and brain IAA bioavailability, as well as improving cognitive behaviors and microglia-mediated synapse loss in 5 × FAD transgenic mice. IAA produced from B.p was shown to prevent microglia engulfment of synapses in an aryl hydrocarbon receptor-dependent manner. This study reveals that aged gut microbiota -induced cognitive decline and microglia-mediated synapse loss that is, at least partially, due to the deficiency in B.p and its metabolite, IAA. It provides a proof-of-concept strategy for preventing neurodegenerative diseases by modulating gut probionts and their tryptophan metabolites.

Silicosis, an age-related disease, is still a heavy burden on global occupational health. Emerging evidence has revealed that targeting senescent cells may be a promising therapeutic strategy for silicosis. This study was designed to investigate the novel function of Bazibushen (BZBS), a known anti-aging drug, in improving silica-induced lung fibrosis. We first confirmed the accumulation of senescent fibroblasts in the fibrotic regions of silicotic lungs. In both young (6-8 weeks) and aged (12 months) silicotic mice, BZBS exhibited anti-fibrosis and anti-senescence effects. Results of in vitro experiments showed the ability of BZBS to block the expression of p21, fibrotic markers, and senescence-associated secretory phenotype factors. Furthermore, BZBS was observed to attenuate mitochondrial dysfunction in senescent fibroblasts through FOXO1/PINK1/Parkin signaling. Collectively, these results indicated BZBS as a potential anti-fibrosis agent, which exerted its role through maintaining mitochondrial homeostasis in senescent fibroblasts.

This study examines the effects of continuous versus interrupted lifelong exercise on lipid metabolism in naturally aging male BALB/c mice. Five-week-old male BALB/c mice were randomly assigned to five groups: young control group (YC), natural ageing control group (AC), exercise cessation group (DE), middle-aged commencing exercise group (ME), and lifelong exercise group (LE). Moderate Intensity Continuous Training exercise sessions were conducted three times per week, with each session lasting 50 min; after exercise interventions until 72 weeks of age, the following parameters were measured: body morphology, exercise capacity, blood lipid, liver fat content, liver function, expression of liver lipid metabolism-related genes and endoplasmic reticulum stress-related genes, and activities of liver metabolism enzymes. The results suggest that advancing age leads to disrupted lipid processing, reduced hepatic performance, and increased endoplasmic reticular tension. Compared with the AC group, the ME and LE cohorts showed reduced serum lipids, whereas the LE group exhibited elevated high-density lipoprotein cholesterol (HDL-C) levels (P < 0.05). Post-exercise reductions were observed in hepatic total cholesterol and free fatty acid (FFA). Moreover, the exercises mitigated age-related hepatic impairments and diminished susceptibility towards cirrhosis despite higher aspartate aminotransferase (AST) and lower albumin (ALB) levels being evident within the DE cohort (P < 0.05). Exercise demonstrates the potential to mitigate age-related abnormalities in lipid metabolism. Middle-aged commencing and lifelong exercise interventions are more effective in alleviating lipid abnormalities than exercise cessation in middle age. This disparity in efficacy can be attributed to differences in regulating endoplasmic reticulum stress, enhancing liver lipid oxidation capacity, and reducing lipid synthesis ability. Notably, middle-aged individuals commencing exercise yield similar outcomes in regulating aging-associated abnormal lipid metabolism compared to the lifelong exercise group. This highlights the importance of initiating exercise in middle age, as it remains beneficial even if lifelong commitment is unfeasible, so exercise initiation in midlife is still beneficial. However, to prevent liver lipid metabolism disorders later in life, the earlier exercise initiation, the better.

Biological ageing is a time-dependent process that has implications for health and disease. Cellular senescence is a key driver in ageing and age-related diseases. Senotherapeutic agents have been shown to slow biological ageing by eliminating senescent mammalian cells. Given the increasing awareness of the gut microbiome in regulating human health, this study aimed to investigate the effects of senotherapeutic agents as pharmacological interventions on the human gut microbiota. In this study, the bidirectional effects of four senotherapeutic agents, quercetin, fisetin, dasatinib, and sirolimus, with the gut microbiota sourced from healthy human donors were investigated. The results revealed that quercetin was completely biotransformed by the gut microbiota within six hours, while dasatinib was the most stable of the four compounds. Additionally, metagenomic analysis confirmed that all four compounds increased the abundance of bacterial species associated with healthy ageing (e.g., Bacteroides fragilis, Bifidobacterium longum, and Veillonella parvula), and decreased the abundance of pathogenic bacteria primarily associated with age-related diseases (e.g., Enterococcus faecalis and Streptococcus spp.). The findings from this study provide a comprehensive understanding of the pharmacobiomics of senotherapeutic interventions, highlighting the potential of microbiome-targeted senolytics in promoting healthy ageing.

Male infertility and age-related reproductive decline remain major unmet medical challenges, with limited understanding of the underlying mechanisms. Here, we identify a stress granule-driven necroptosis pathway involving ZBP1 and RIPK3 as a central driver of non-obstructive azoospermia (NOA), a severe form of male infertility marked by loss of spermatogenesis. We show that heat stress or environmental insults activate eIF2 kinases, inducing stress granules that recruit ZBP1 and RIPK3 to form a signaling complex. This leads to RIPK3 activation, MLKL phosphorylation, and necroptotic death of spermatogonia and Sertoli cells. Genetic ablation of Zbp1 or Ripk3 protects mice from heat-induced testicular atrophy, highlighting their essential role in testicular cell death. Notably, this same necroptosis pathway is also activated in aged human testes, suggesting a shared mechanism driving both male infertility and age-related testicular degeneration.

Previous studies found that frailty has a significant impact on the prognosis of hypertensive patients. However, most of the previous studies only focused on baseline frailty status. The association of changes in frailty with mortality in hypertensive patients is little known. Therefore, we aimed to investigate the association of frailty transitions with all-cause mortality and cardiovascular death in older adults with hypertension. A total of 1827 older hypertensive participants age ≥ 65 years from the Chinese Longitudinal Healthy Longevity Study were included. Frailty status was assessed by a 35-item frailty index (FI). Changes in frailty were evaluated by frailty at baseline (wave 2011) and the second survey (wave 2014), and four types of changes in frailty were identified: remaining non-frail, frail to non-frail, non-frail to frail, and remaining frail. The accelerated failure time model was used to evaluate the association of changes in frailty status with all-cause mortality and cardiovascular death. The dose-response relationship between annual changes in FI and mortality was analyzed using restricted cubic splines (RCS). During 6128.9 person-years of follow-up, a total of 623 all-cause mortality and 131 cardiovascular deaths were recorded. Compared to the remaining non-frail group, the fully adjusted time ratios (TRs) of all-cause mortality were 0.75 (95% CI 0.59-0.96, p = 0.025), 0.48 (95% CI 0.41-0.57, p < 0.001), and 0.45 (95% CI 0.37-0.55, p < 0.001) in the frail to non-frail group, non-frail to frail group, and remaining frail group, respectively. After adjusting for potential confounding variables, the adjusted TRs of cardiovascular death were 0.63 (95% CI 0.36-1.11, p = 0.108), 0.34 (95% CI 0.23-0.48, p < 0.001), and 0.34 (95% CI 0.22-0.53, p < 0.001) in the frail to non-frail group, non-frail to frail group, and remaining frail group, respectively. RCS analysis revealed a non-linear relationship between annual changes in FI and all-cause mortality and cardiovascular death (both p for non-linearity < 0.05). Stratified and sensitivity analysis showed similar results. Frailty is a dynamic process, and worsening in frailty status accelerated all-cause mortality and cardiovascular death in older adults with hypertension. In contrast, improvement in frailty status prolonged the survival time of patients.

Diseases related to oxidative ageing are becoming increasingly evident in younger individuals. In this study, we investigated the mechanisms underlying the actions of mogroside V when used to treat anti-oxidative ageing.

Cellular senescence in renal resident cells plays a pivotal role in the progression of acute kidney injury (AKI), necessitating the expansion of effective drug targets. Traditional Chinese medicine (TCM) formulations, characterized by their multi-target effects, offer a promising perspective for advancing research on AKI. Wuling San (WLS), a well-established compound used in treating urological disorders, has yet to elucidate its potential pharmacological targets and mechanisms in ameliorating AKI and delaying cellular senescence.

This study investigates how miR-146a-5p, found in adipose tissue-derived small extracellular vesicles (sEV), influences mitochondrial autophagy and its impact on delaying skeletal muscle aging through the targeting of Fbx32. The findings highlight miR-146a-5p as crucial in skeletal muscle development and aging, influencing autophagy, apoptosis, differentiation, and proliferation, collectively impacting muscle atrophy. In C2C12 cells, miR-146a-5p mimics decreased apoptosis, autophagy, and reactive oxygen species (ROS) levels, while enhancing ATP production; conversely, miR-146a-5p inhibitors had the opposite effects. Furthermore, miR-146a-5p-enriched sEV from adipose tissue alleviated skeletal muscle atrophy in aged mice and promoted muscle fiber growth and repair by regulating mitochondrial autophagy and apoptosis. Mechanistically, miR-146a-5p modulated mitochondrial autophagy in myoblasts by targeting Fbx32 and impacting the FoxO3 signaling pathway. This led to a notable decrease in apoptosis-related gene expression, reduced ROS production, and elevated ATP levels. In conclusion, miR-146a-5p derived from WAT-sEV modulates myoblast autophagy, apoptosis, ROS, and differentiation through the Fbx32/FoxO3 signaling axis. This work presents a novel molecular target and theoretical framework for delaying skeletal muscle aging and developing therapies for skeletal muscle-related disorders.

Skin tissue, which consists of epidermal, dermal, and hypodermal cells, plays an important role in biological defense and physical appearance. External and internal stresses occurring with aging disrupt skin homeostasis, promoting the development of phenotypes associated with aging. Although many studies of skin aging focus on the dermis, potential epidermal changes have largely remained uncharacterized. In this study, we demonstrate that epidermal cells do not exhibit cellular senescence phenotypes with aging but instead show age-related decreases in mitochondrial number. We also found that mice lacking TFAM in epidermal cells exhibit delayed hair regrowth and impaired wound healing by middle age, resembling changes seen in skin of aged mice. Furthermore, middle-aged epidermis-specific TFAM-deficient mice exhibited obesity, suggesting that impaired fatty acid metabolism in epidermal cells resulting from mitochondrial decline may lead to obesity. These findings overall suggest that mitochondrial decline occurs as a primary event in epidermal aging and that antiaging strategies to enhance activity or number of epidermal mitochondria could antagonize both skin-aging phenotypes and age-related metabolic disease.

The mitochondrial bioenergetics hypothesis postulates a critical role of mitochondrial activity in aging, which leads to the development of age-related diseases if disturbed. NAD+ and NADH generate a powerful oxidoreductive system driving ATP production in mitochondria, therefore, the maintenance of the NAD+/NADH ratio is crucial for the metabolic homeostasis in cells. The activation of nicotinamide phosphoribosyl transferase (NAMPT) is a superior approach to increase cellular levels of NAD+ since it is a rate-limiting enzyme of NAD+ salvage pathway producing NAD+ precursor nicotinamide mononucleotide. NAMPT inhibitors are, however, also desired by pharmaceutical applications due to their potency in limiting the growth of cancer cells. The present work demonstrates an in-silico approach for screening NAMPT activity modulators using compound libraries from traditional African, Chinese, and Russian medicinal plants. The compounds predicted to pass the blood-brain barrier, with low predicted toxicity and desirable pharmacokinetic and drug-likeness characteristics, were subjected to further selection by molecular docking using CB-Dock2. A panel of 21 compounds, including known NAMPT activators, inhibitors, negative controls, and randomly chosen compounds, was used to validate the docking method. The selection yielded 17 compounds with increased docking scores when tested against 6 co-crystallized structures of NAMPT. Their 2D protein-ligand interactions were critically evaluated and correlated with known interactions of the NAMPT activators and inhibitors with the active and allosteric sites of the enzyme. The selected compounds are suitable for the experimental pharmaceutical developments of drugs for aging, neurological diseases, and cancer treatments.

Endothelial aging is an independent risk factor of cardiovascular diseases, and this study aims to explore the mechanism of endothelial aging. We first applied two animal aging models and two cellular aging models to observe the characteristics of senescent endothelium at the morphological, functional, and molecular levels. It was confirmed that the aging of endothelial cells was accompanied by activation of Nod like receptor protein 3 (NLRP3) inflammasome pathway, reduced levels of hydrogen sulfide (H

Telomere length regulation is essential for genome stability as short telomeres can trigger cellular senescence and apoptosis constituting an integral aspect of biological aging. Telomere biology disorders (TBDs) such as dyskeratosis congenita (DC) are rare, inherited diseases with known mutations in at least 16 different genes encoding components of the telomere maintenance complexes. The precise role of TEN1, part of the CST complex (CTC1, STN1, and TEN1), and the consequences of its loss of function in vivo are not yet known. We investigated the first viable murine model of

The LRRK2 G2019S mutation is known to have a high penetrance rate associated with Parkinson's disease (PD), prevalent across both familial and sporadic PD cases and implicated in neurodegenerative mechanisms. This mutation disrupts several key cellular processes, particularly affecting the endoplasmic reticulum and mitochondrial functions in neural stem cells (NSCs), which are crucial for protein homeostasis and energy metabolism. Although aging is a major risk factor for PD, the complex interplay between LRRK2 G2019S and aging-related cellular dysfunction in NSCs remains poorly understood. In this study, we performed a comprehensive transcriptomic analysis to characterize the temporal transcriptional changes in LRRK2 G2019S-carrying NSCs across sequential passages, resembling cellular aging. BAC DNA-mediated correction of the LRRK2 mutation significantly restored dysregulated cellular processes, including endoplasmic reticulum-associated protein processing, mitochondrial function, and vesicular trafficking pathways, thereby restoring cellular homeostasis in NSCs. Notably, aged NSCs harboring the LRRK2 G2019S mutation exhibited pronounced alterations in epithelial-mesenchymal transition or TGF-β signaling, exacerbating declines in NSC function. Our findings elucidate the molecular mechanisms underlying LRRK2 G2019S-mediated pathogenesis in aging NSCs and highlight the therapeutic potential of genetic correction strategies for PD treatment.

While midlife obesity is consistently associated with cognitive decline in later life, there is limited understanding of how weight variations from early life to midlife affect cognitive decline. We investigated the association between early- to midlife weight trajectories and mid- to late-life cognitive decline.

Obesity is a global health issue which has been widely accepted as an aging related pathogenesis. α-Klotho is a protein involved in aging process, mineral metabolism, insulin sensitivity, and the pathogenesis of various age-related diseases. Adiposity correlates with lower soluble α-Klotho, but the role of fat distribution and inflammation remains unclear. The body roundness index (BRI) refines central adiposity assessment beyond BMI. Herein, We aimed to investigate the relationship of BRI, inflammation and serum level of soluble α-Klotho.

The gradual increase in ultraviolet B (UVB) health hazards to human skin, coupled with the irritation associated with existing sunscreen products, underscores the critical need for the development of natural sunscreens to combat UVB-induced photoaging. Chuanxiong oil (CXO) and hyaluronic acid (HA) possess excellent antioxidant and anti-apoptotic properties, which are closely linked to the mechanisms of photoaging. In this study, a composite nano-system (HA-CXO-Lip) comprising chuanxiong oil (CXO) and hyaluronic acid (HA) was initially fabricated. Subsequently, both in vitro HaCaT cell models and in vivo murine photoaging models were established to systematically evaluate the therapeutic efficacy and mechanistic actions of HA-CXO-Lip against photoaging under controlled experimental conditions. The investigation encompassed comprehensive assessments of its pharmacological effects and underlying molecular mechanisms through multimodal experimental approaches. Vitro experiments showed HA-CXO-Lip significantly reduced intracellular reactive oxygen species (ROS) levels and senescence-associated β-galactosidase (SA-β-Gal) activity. Furthermore, HA-CXO-Lip restored the levels of antioxidant enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and hydroxyproline (HYP), while also decreasing the levels of lipid metabolites such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). These findings indicate that HA-CXO-Lip effectively inhibits excessive oxidative stress. Additionally, HA-CXO-Lip inhibited apoptosis by reducing Bax levels and enhancing Bcl-2 expression in HaCaT cells. In vivo studies demonstrated that HA-CXO-Lip significantly reduced UVB irradiation-induced erythema and epidermal thickening in the backs of mice. It restored the orderly arrangement of collagen fibers and inhibited the activation of the core senescence pathway, AKT/mTOR, along with the downstream expression of matrix metalloproteinase 9 (MMP9), resulting in a decrease in collagen I disassembly. Additionally, HA-CXO-Lip was shown to significantly decrease the number of apoptotic cells, as indicated by the expression of the apoptosis marker cleaved cysteine aspartic protease-3 (C-Caspase-3) and the surface type I transmembrane glycoprotein (CD44), thereby further inhibiting apoptosis. The findings of this study suggest that HA-CXO-Lip can exert anti-photoaging effects through its antioxidant and anti-apoptotic properties, highlighting the synergistic efficacy of CXO and HA, which holds promise for the prevention and treatment of photoaging.

This study examines the association between sports social capital and cognitive health in middle-aged and elderly individuals in China. Using data from the China Health and Retirement Longitudinal Study (CHARLS) and deep learning methods, we analyze interactions between sports social capital, cognitive function, and various health behaviors across multiple time points. Findings reveal that baseline cognitive scores and education are key predictors of cognitive health, consistent with cognitive reserve theory. Importantly, education amplifies the benefits of sports social capital, suggesting a synergistic effect that supports cognitive function. Results further show that sports social capital exerts a cumulative effect on cognition, with its influence increasing over time. Unlike general physical activity, sports social capital-formed through social engagement in sports-plays a unique role in sustaining cognitive function. Additionally, it is associated with a reduction in the cognitive risks of smoking and other behaviors, highlighting its potential role as a buffer against health risks. This research extends social capital theory in health contexts and suggests that promoting group sports activities that foster social support networks could serve as an effective intervention. Such policies, particularly among lower-education groups, may help preserve cognitive health within aging populations.

The self-renewal capacity of intestinal stem cells (ISCs) declines with aging, leading to a loss of homeostasis and an increased susceptibility to intestinal diseases. Despite the established significance of lipid metabolism and epigenetic regulation in ISC function, the molecular mechanisms that connect these processes to aging-related ISC dysfunction remain elusive. Here, we demonstrate that Histone 3 lysine 36 trimethylation (H3K36me3) caused by SETD2 is critical for ISC stemness. We found that H3K36me3 deficiency results in reduced ISC proliferation and differentiation, disrupts fatty acid oxidation (FAO) metabolism, and induces ISC senescence. Mechanistically, the loss of H3K36me3 triggers the activity of the SWI/SNF chromatin remodeling complex and leads to increased chromatin accessibility and enhancer activation, which alters FAO- and senescence-related gene expression. Importantly, we discover that metabolic intervention can prevent the senescence of ISC due to H3K36me3 deficiency. Our findings reveal a crucial role for H3K36me3 in maintaining the epigenetic landscape that orchestrates FAO metabolism and determines intestinal stem cell functions, emphasizing the role of FAO as a key modulator between H3K36me3 and ISC aging, suggesting that metabolic intervention may help mitigate age-related ISC dysfunction.

Autophagy is a crucial cellular process that facilitates the degradation of damaged organelles and protein aggregates, and the recycling of cellular components for the energy production and macromolecule synthesis. It plays an indispensable role in maintaining cellular homeostasis. Over recent decades, research has increasingly focused on the role of autophagy in regulating adult stem cells (SCs). Studies suggest that autophagy modulates various cellular processes and states of adult SCs, including quiescence, proliferation, self-renewal, and differentiation. The primary role of autophagy in these contexts is to sustain homeostasis, withstand stressors, and supply energy. Notably, the dysfunction of adult SCs during aging is correlated with a decline in autophagic activity, suggesting that autophagy is also involved in SC- and aging-associated disorders. Given the diverse cellular processes mediated by autophagy and the intricate mechanisms governing adult SCs, further research is essential to elucidate both universal and cell type-specific regulatory pathways of autophagy. This review discusses the role of autophagy in regulating adult SCs during quiescence, proliferation, self-renewal, and differentiation. Additionally, it summarizes the relationship between SC aging and autophagy, providing therapeutical insights into treating and ameliorating aging-associated diseases and cancers, and ultimately promoting longevity.

Bone fractures and related complications are a significant concern for older adults, particularly with the growing aging population. Therapeutic interventions that promote bone tissue regeneration are attractive for geriatric fracture repair. Extracellular adenosine plays a key role in bone homeostasis and regeneration. Herein, we examined the changes in extracellular adenosine with aging and the potential of local delivery of adenosine to promote fracture healing using aged mice. Extracellular adenosine level was found to be significantly lower in aged bone tissue compared to young mice. Concomitantly, the ecto-5'-nucleotidase CD73 expression was also lower in aged bone. Local delivery of adenosine using injectable, in situ curing microgel delivery units yielded a pro-regenerative environment and promoted fracture healing in aged mice. This study offers new insights into age-related physiological changes in adenosine levels and demonstrates the therapeutic potential of adenosine supplementation to circumvent the compromised healing of geriatric fractures.

While traditionally regarded as \"noise\", blood-oxygenation-level-dependent (BOLD) fMRI fluctuations coupled to systemic physiology--such as heart rate and respiratory changes--also hold valuable information about brain vascular properties and autonomic function. In this study, we leverage these physiological BOLD signals to characterize age-related changes in brain physiology. Using a large dataset from the Lifespan Human Connectome Project Aging study, we investigated how the spatiotemporal BOLD-fMRI signatures of autonomic physiology, specifically heart rate and respiratory variation, change with advancing age. Our findings reveal that aging is associated with globally slower respiratory fMRI responses, alongside faster cardiac fMRI responses and enhanced brain-cardiac signal coupling. Moreover, we show that the impact of age on physiological fMRI signals exhibits a notable turning point after age 60, suggesting a critical role of declining vascular health and autonomic function in aging. The potential impact of age-related changes in brain structure, tissue perfusion, and in-scan arousal states on the identified physiological fMRI patterns is also tested and discussed. Altogether, our results underscore significant age effects in the fMRI signatures of systemic physiology, emphasizing the pivotal role of altered vascular properties and autonomic function in aging. Methodologically, this study also demonstrates the utility of resting-state fMRI for extracting multi-parametric information about brain physiology, offering new biomarker opportunities that complement established functional connectivity metrics.

Insufficiency in nutrient availability, oxidative stress and autophagy failure are fundamental factors for the decline of bone mass and strength with aging. Accumulating evidence indicates that these factors affect normal autophagosomal or lysosomal activities which are the major force in clearance of aggregated or damaged proteins. Cathepsin D (CtsD), the principal lysosomal aspartate protease and a main endopeptidase, exists in the skeleton during development or homeostasis. However, the molecular and cellular mechanisms of CtsD mediated autophagosome or lysosome function in the skeletal homeostasis remain unclear. In the present study, we showed that deletion of CtsD dramatically decreased bone mass in the 3-week old mutant mice compared with their control littermates as indicated by decreased bone volume (BV), bone volume / total volume (BV/TV), bone surface (BS), trabecular number, trabecular thickness and increase trabecular separation in the microCT analysis. Histomorphometry analysis revealed that the phenotype was characterized by decreased osteoblast numbers, osteoblast surface/bone surface and mineral apposition rate, increased osteoclast numbers, osteoclast surface/bone surface and erosion surface/bone surface. At molecular level, siRNA medicated inactivation of CtsD in MC3T3E1 cells attenuated osteoblastic differentiation and downregulated LC3B expression, which was accompanied by decreased levels of P62, p-Akt and p-GSK3beta in osteoblasts. Intriguingly, inactivation of CtsD in RAW264.7 cells increased osteoclast differentiation with decreased LC3B expression but upregulated P62 level. This was accompanied by alterations in the formation of autophagosome and differential transcription profiles associated with the autophagy pathway during the differentiation of osteoblasts and osteoclasts. The results suggest that CtsD mediated autophagy pathway plays important roles in regulation of bone mass and homeostasis through distinct mode of actions in osteoblasts and osteoclasts, and CtsD may serve as a potential therapeutic target for the maintenance of bone mass.

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly, with dysfunction of the retinal pigment epithelium (RPE) central to disease pathogenesis. Using our uniquely developed MLST8 (MTOR associated protein, LST8 homolog) knock-in animal model with RPE-specific overexpression, which drives MTOR (mechanistic target of rapamycin kinase) upregulation, we demonstrate that increased MTOR complexes 1 and 2 in the RPE disrupts macroautophagy/autophagy by suppressing autophagosome formation genes and impairing MAP1LC3/LC3 processing. This leads to autophagosome accumulation and defective autolysosome formation, driving RPE dysfunction and AMD-like pathology, including subretinal debris build up and photoreceptor degeneration. Notably, MTOR inhibition with torin1 treatment or CRYBA1 overexpression rescues these defects, restoring autophagy and RPE integrity. Our findings reveal that autophagy disruption mediated by both MTORC1 and MTORC2 drives AMD-like pathology in our mouse model, establishing autophagy regulation as a promising avenue for therapeutic intervention in this vision-threatening disease.

This study investigates the effectiveness of quercetin (QUE) in preventing sarcopenia via the PI3K/AKT signaling pathway. Thirty SD rats were categorized into three groups: a young control group (Y), an old control group (O), and an old QUE-supplemented group (O + QUE). Body weight and grip strength were monitored weekly during the experiment. Soleus and gastrocnemius muscle weights, gastrocnemius tissue pathological examination, cell apoptosis, and mitochondrial damage were evaluated using HE, TUNEL staining, electron microscopy, and JC-1 staining. Biochemical assays and molecular biology techniques (qPCR and Western blot) were used to assess oxidative stress markers and the expression of sarcopenia-related genes and proteins. QUE supplementation increased muscle weight and improved grip strength in aged rats. Furthermore, QUE supplementation alleviated tissue damage, apoptosis, enhanced antioxidant capacity, and decreased damage to oxidative stress and mitochondria in the gastrocnemius of old rats. Molecular assessments revealed downregulation of muscle degradation markers (MuRF1, Atrogen-1, Bnip3) and upregulation of PI3K/AKT pathway proteins, suggesting a mechanistic pathway through which QUE mitigates sarcopenia. QUE maybe modulate the PI3K/AKT pathway to alleviate oxidative stress, mitochondrial damage, and muscle degradation due to aging, highlighting its potential as a therapeutic agent against sarcopenia.

Chaperone-mediated autophagy (CMA) is a selective autophagic pathway that targets specific proteins for lysosomal degradation, playing a crucial role in maintaining cellular homeostasis. Recent research has highlighted the involvement of CMA in aging and age-related diseases, yet its regulation remains complex. The study by Khawaja et al. provides novel insights into the sex-specific and cell-type-specific regulation of CMA during aging. This commentary discusses the key findings of this study, their implications for autophagy and aging research, and potential future directions. Understanding these regulatory mechanisms is essential for developing targeted therapies to combat age-related diseases and promote healthy aging.

Biological aging was found to be associated with the higher prevalence of several diseases, but it is unclear in the prevalence of chronic kidney disease (CKD). This study investigated the effect of aging phenotypes, characterized by PhenoAge (PA), Klemera-Doubal Method (KDM), allostatic load (AL), homeostatic dysregulation (HD), and telomere length (TL) on CKD from the perspective of both clinical relevance and genetic susceptibility.

Oral Langerhans cells (LCs) are well recognized for their immunological roles, but their involvement in other physiological processes remains poorly understood. This study identifies a novel function of oral LCs in regulating tongue epithelial innervation. Postnatal LC development coincides with the establishment of local innervation, and LC depletion impairs innervation and alters nociceptive responses, underscoring their neuroimmune function. This function is driven by LC-derived IL-1{beta}, which stimulates basal epithelial cells to produce nerve growth factor (NGF), thereby promoting sensory nerve growth. Transcriptomic analyses revealed neuronal-related pathways enriched in LCs. Aging reduces LC frequency, NGF expression, and epithelial innervation, linking neuroimmune regulation to epithelial aging. While LC frequencies in the tongue remain unaffected in germ-free mice, the microbiota is essential for optimal LC function and NGF production. These findings expand our understanding of oral LCs, revealing their pivotal role in epithelial innervation beyond immune surveillance.

Androgenetic alopecia is a common type of hair loss disease. As the most promising seeder for cell-based therapy, dermal papilla cells are prone to undergo premature senescence during passaging in vitro. Our previous studies revealed high expression of lncRNA H19 in early-passage dermal papilla cells and the maintenance of hair follicle-inducing ability upon prolonged culture. However, the exact mechanism of H19 regulating Wnt signaling pathway related to hair follicle regeneration has not been fully elucidated. Here, a cell senescence model was constructed by continuous cultivation in vitro to investigate the molecular mechanism of H19 in human dermal papilla cells. Animal hair follicle inductivity, cell proliferation and molecular experiments were performed to evaluate the cell inductivity, proliferation, senescence, expression of Wnt signaling key factors in early- and late-passage dermal papilla cells. Ectopic expression and silencing experiments were conducted to estimate effects of H19 on the proliferation and senescence of dermal papilla cells and the possible mechanism. Hair follicles from frontal baldness-prone and occipital non-balding areas of patients with androgenetic alopecia were exploited to detect the expression of H19 and relevant factors. Results showed late-passage DP8 cells exhibited lost hair follicle inductive properties, attenuated cell proliferation, elevated senescent marker and key Wnt factor levels, decreased inducing marker levels. Furthermore, overexpression of H19 inhibited senescence marker expression by binding to SAHH to upregulate miR-29, thus activating the Wnt signaling pathway to maintain inducing ability of DP cells. Knockdown of H19 showed opposite experimental results. Consistently, H19 together with miR-29a levels were lower and the expression levels of miR-29a target genes (DKK1, SFRP2) increased in the dermal papilla cells from frontal baldness-prone and occipital non-balding areas. Conclusively, our data provide a novel insight into the regulation and mechanism of H19 in inhibiting dermal papilla cell senescence, suggesting a potential therapy strategy for androgenetic alopecia.

Spermidine is a naturally occurring polyamine present in all cells and is necessary for viability in eukaryotic cells. The cellular levels of spermidine decline as an organism ages, and its supplementation has been found to extend lifespan in yeast, worms, flies, mice, and human cultured cells. The lifespan extending effect of spermidine is thought to be due to its ability to induce autophagy, a turnover of cellular components. Mitochondrial dysfunction is believed to be a major driver of the aging process. We asked whether spermidine could rescue mitochondrial dysfunction using the yeast Saccharomyces cerevisiae lacking mtDNA (ρ

The selective eradication of senescent cells using senolytic compounds represents a promising strategy to treat senescence-associated diseases like aging and cancer. However, many senolytics may cause systemic toxicity. Magkouta et al., writing in Nature Aging, introduced mGL392, an advanced senolytic platform utilizing a lipofuscin-binding domain scaffold conjugated with a senolytic drug (e.g., dasatinib). mGL392 effectively eliminates senescent cells in vitro and in vivo, reducing tumor size in melanoma models while minimizing systemic toxicity. Compared to existing senolytics, it offers improved specificity, reducing off-target effects. This innovation presents a safer and more effective approach for treating senescence-related diseases.

The influence of gut microbes on aging has been reported in several studies, but the mediating pathways of gut microbiota, whether there is a causal relationship between the two, and biomarker screening and validation have not been fully discussed. In this study, Mendelian Randomization (MR) and Linkage Disequilibrium Score Regression (LDSC) are used to systematically investigate the associations between gut microbiota, three aging indicators, and 14 age-related diseases. Additionally, this study integrates machine learning algorithms to explore the potential of MR and LDSC methods for biomarker screening. Gut microbiota is found to be a potential risk factor for 14 age-related diseases. The causal effects of gut microbiota on chronic kidney disease, cirrhosis, and heart failure are partially mediated by aging indicators. Additionally, gut microbiota identified through MR and LDSC methods exhibit biomarker properties for disease prediction (average AUC = 0.731). These methods can serve as auxiliary tools for conventional biomarker screening, effectively enhancing the performance of disease models (average AUC increased from 0.808 to 0.832). This study provides evidence that supports the association between the gut microbiota and aging and highlights the potential of genetic correlation and causal relationship analysis in biomarker discovery. These findings may help to develop new approaches for healthy aging detection and intervention.

Longevity research aims to extend the healthspan while minimizing the duration of disability and morbidity, known as the sickspan. Most longevity interventions in model organisms extend healthspan, but it is not known whether they compress sickspan relative to the lifespan. Here, we present a theory that predicts which interventions compress relative sickspan, based on the shape of the survival curve. Interventions such as caloric restriction that extend mean lifespan while preserving the shape of the survival curve, are predicted to extend the sickspan proportionally, without compressing it. Conversely, a subset of interventions that extend lifespan and steepen the shape of the survival curve are predicted to compress the relative sickspan. We explain this based on the saturating-removal mathematical model of aging, and present evidence from longitudinal health data in mice, Caenorhabditis elegans and Drosophila melanogaster. We apply this theory to identify potential interventions for compressing the sickspan in mice, and to combinations of longevity interventions. This approach offers potential strategies for compressing morbidity and extending healthspan.

Parkinsons disease (PD) affects millions worldwide, with no efficient therapy currently available. A major cause of the initiation and progression of this degenerative disease is the dysfunctional cellular protein quality control system (PQC), leading to the accumulation of toxic protein aggregates in neurons. We previously reported azadiradione (AZD), a small molecule (MW 451 Da), as a potent inducer of heat shock factor 1 (HSF1) activity, which could alleviate cellular toxicity induced by misfolded proteins by upregulating the levels of inducible molecular chaperones and proteasome activity. Here, we show the multifaceted effect of AZD in enhancing the capacity of PQC machinery in cells, fruit flies, and a PD mouse model. AZD activated HSF1 by promoting its phosphorylation at S326 through MEK. In parallel, AZD boosted protein degradation through increased chymotrypsin-like proteasome activity, upregulation of the ubiquitin ligase CHIP. AZD induced autophagy, marked by elevated levels of Beclin 1, ATG7, and ULK1 phosphorylation at S555, along with mTORC1 inhibition via AMPK activation. Surprisingly, the calorie restriction pathway was also upregulated upon AZD treatment, as demonstrated by the enhanced phosphorylation of FOXO3 and FOXO1, along with increased activity of their target enzymes SOD and catalase. Notably, AKT activity was also suppressed in AZD-treated cells. In vivo, AZD improved motor function, dopaminergic neuron survival, and tyrosine hydroxylase activity in an MPTP-induced mouse model of PD, and extended lifespan in Drosophila without compromising fertility or mobility. These findings highlight AZD as a promising therapeutic candidate for restoring PQC and mitigating PD pathology.

NAD+ is an important cofactor involved in regulating many biochemical processes in cells. An imbalance in NAD+/NADH ratio is linked to many diseases. NAD+ is depleted in diabetes, cardiovascular and neurodegenerative diseases, and in aging, and is increased in tumor cells. NAD+ is generated in cells via the de novo, Preiss-Handler, and salvage pathways. Most of the cellular NAD+ is generated through Nampt activation, a key rate-limiting enzyme that is involved in the salvage pathway. Restoration of NAD+/NADH balance offers therapeutic advantages for improving tissue homeostasis and function. NAD+ is known to benefit and restore the body's physiological mechanisms, including DNA replication, chromatin and epigenetic modifications, and gene expression. Recent studies elucidate the role of NAD+ in cells utilizing transgenic mouse models. Translational new therapeutics are positioned to utilize the NAD+ restoration strategies for overcoming the drawbacks that exist in the pharmacological toolkit. The present review highlights the significance of Nampt-NAD+ axis as a major player in energy metabolism and provides an overview with insights into future strategies, providing pharmacological advantages to address current and future medical needs.

Purpose: The glymphatic system facilitates brain waste clearance via cerebrospinal fluid (CSF) flow, and its dysfunction has been linked to aging and neurodegeneration. However, clinically accessible methods to quantify glymphatic function in humans remain limited. This study aimed to examine the potential of dynamic 18F-FDG PET for measuring ventricular CSF clearance - as a surrogate marker of glymphatic function. Specifically, we evaluated its association with age, its test-retest reliability, and the feasibility of reduced scan durations for clinical applicability. Methods: We analyzed 72 baseline 18F-FDG PET scans from participants enrolled in a prior depression trial. Time-activity curves (TACs) were extracted from the lateral ventricles and fitted with a {gamma}-variate model to estimate influx (_in) and clearance (_out) parameters. Associations with age and clinical factors were examined using correlation and multiple linear regression. Test-retest reliability was assessed in 11 placebo-treated participants who underwent repeat scans eight weeks apart. A feasibility analysis tested whether shorter scan windows could yield comparable clearance estimates. Results: _out showed a strong negative correlation with age (r = -0.680, p < 0.001), while _in was not significantly age-related. Age remained a significant predictor of _out after adjusting for sex, ventricle size, and depression severity. A positive association between _out and depression severity was observed after covariate adjustment. Test-retest analysis yielded an intraclass correlation coefficient of 0.702 for _out, indicating moderate-to-good reproducibility. A shortened 30-minute scan window (starting 30 minutes post injection) preserved strong correlations with both _out and age, supporting the potential for abbreviated imaging protocols. Conclusion: Dynamic 18F-FDG PET provides a reliable and noninvasive method to quantify ventricular CSF clearance, revealing age-related decline indicative of glymphatic impairment. The method demonstrates reproducibility over time and retains key clearance metrics even with shortened scan durations. These findings establish a clinically feasible 18F-FDG PET-based approach for studying brain clearance and glymphatic function in aging and disease.

Chronic inflammation is a pervasive feature of aging and may be associated with testosterone in middle-aged and older men. Systemic immune-inflammation index (SII) is a novel inflammatory biomarker. We aimed to assess the association between SII and serum testosterone and free testosterone (FT) in middle-aged and older men.

To date, various epigenetic clocks have been constructed to estimate biological age, most commonly using DNA methylation (DNAm). These include "first-generation" clocks such as DNAmAgeHorvath and "second-generation" clocks such as DNAmPhenoAge and DNAmGrimAge. The divergence of one's predicted DNAm age from chronological age, termed DNAmAge acceleration (AA), has been linked to mortality and various aging-related conditions, albeit with varying findings. In metabolic syndrome (MetS) and type 2 diabetes (T2D), it remains inconclusive which DNAm-based predictor(s) is/are closely related to these two metabolic conditions. Therefore, we examined the cross-sectional associations between seven DNAm-based predictors and prevalent metabolic conditions in participants with methylation data from the KORA study. We also analyzed the longitudinal association with time-to-incident T2D and the relative prognostic value compared to clinical predictors from the Framingham 8-year T2D risk function in predicting incident disease over eight years.

Neurodegenerative diseases, including Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis, are increasingly prevalent among aging populations. Oxidative stress contributes to these diseases, leading to cellular damage and neuronal death. Natural antioxidants are being explored as preventive measures. This study aims to assess the effectiveness of natural antioxidants in delaying the onset or progression of neurodegenerative diseases by identifying their specific mechanisms of action. A comprehensive review of existing literature was conducted, focusing on studies that examine the role of natural antioxidants in neuroprotection. Key natural antioxidants, including flavonoids, polyphenls, vitamins C and E, and omega-3 fatty acids, were reviewed and analyzed for their bioavailability, mechanisms of action, and outcomes in both in vitro and in vivo studies. Additionally, clinical trials involving human subjects were considered to provide insights into the translational implications of antioxidant consumption. The findings suggest that several natural antioxidants exhibit neuroprotective properties by modulating oxidative stress, reducing inflammation, and promoting neuronal survival. For instance, flavonoids such as quercetin and resveratrol have shown promise in enhancing cognitive function and mitigating the pathophysiological alterations associated with neurodegeneration. In clinical studies, higher intakes of dietary antioxidants were correlated with a reduced risk of developing neurodegenerative disorders. Natural antioxidants offer potential for preventing neurodegenerative diseases by counteracting oxidative stress and maintaining cellular integrity. Overall, our report recommends that further research is needed to optimize dosages and understand their long-term benefits.

Dietary restriction (DR) is a well-established method for extending lifespan across various species, including C. elegans. Among the different DR regimens, axenic dietary restriction (ADR), in which worms are grown in a nutrient-rich sterile liquid medium, yields the most powerful lifespan extension. However, the molecular mechanisms underlying this longevity phenotype remain largely unexplored. Through a pilot screen of candidate genes, we identified the proprotein convertase BLI-4 as a crucial factor in neurons for modulating lifespan under ADR conditions. BLI-4's role appears to be specific to ADR, as it does not significantly impact longevity under other DR regimens. We further explored the involvement of different bli-4 isoforms and found that isoforms b, f, i and j redundantly contribute to the ADR-mediated lifespan extension, while the bli-4d isoform is mainly involved in development. Proteomics analysis revealed that the loss of BLI-4 function under ADR conditions specifically downregulates GOLG-2, involved in Golgi complex organization. This gene also partially mediates the longevity effects of BLI-4 under ADR conditions. Our findings highlight the importance of neuronal BLI-4 and its downstream targets in regulating lifespan extension induced by ADR in C. elegans.

Age-related cognitive impairment (ARCI) is linked to β-amyloid (Aβ) accumulation and disrupted blood-brain barrier (BBB) transport via receptors for advanced glycation end products (RAGE) and low-density lipoprotein receptor-related protein 1 (LRP1). This study examines electroacupuncture (EA) effects on cognition, hippocampal pathology, neurotransmitters, and the RAGE/LRP1 system in senescence-accelerated mouse prone 8 (SAMP8) mice. EA at Zusanli (ST36) and Baihui (GV20) improved cognitive performance, reduced hippocampal neuronal degeneration, elevated cerebrospinal fluid dopamine, norepinephrine, serotonin, and 5-hydroxyindoleacetic acid, and decreased Aβ42 levels. EA downregulated hippocampal RAGE, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1), upregulated LRP1 and apolipoprotein E (ApoE), promoting Aβ clearance. NF-κB expression remained unchanged, suggesting alternative anti-inflammatory pathways. Thus, EA offers a promising non-pharmacological treatment for ARCI.

Clonal dominance characterizes hematopoiesis during aging and increases susceptibility to blood cancers and common nonmalignant disorders. VEXAS syndrome is a recently discovered, adult-onset, autoinflammatory disease burdened by a high mortality rate and caused by dominant hematopoietic clones bearing somatic mutations in the UBA1 gene. However, pathogenic mechanisms driving clonal dominance are unknown. Moreover, the lack of disease models hampers the development of disease-modifying therapies. In the present study, we performed immunophenotype characterization of hematopoiesis and single-cell transcriptomics in a cohort of nine male patients with VEXAS syndrome, revealing pervasive inflammation across all lineages. Hematopoietic stem and progenitor cells (HSPCs) in patients are skewed toward myelopoiesis and acquire senescence-like programs. Humanized models of VEXAS syndrome, generated by inserting the causative mutation in healthy HSPCs through base editing, recapitulated proteostatic defects, cytological alterations and senescence signatures of patients' cells, as well as hematological and inflammatory disease hallmarks. Competitive transplantations of human UBA1-mutant and wild-type HSPCs showed that, although mutant cells are more resilient to the inflammatory milieu, probably through the acquisition of the senescence-like state, wild-type ones are progressively exhausted and overwhelmed by VEXAS clones, overall impairing functional hematopoiesis and leading to bone marrow failure. Our study unveils the mechanism of clonal dominance and provides models for preclinical studies and preliminary insights that could inform therapeutic strategies.

A global obesity pandemic, coupled with an increasingly ageing population, is exacerbating the burden of cardiovascular disease. Indeed, clinical and experimental evidence underscores a potential connection between obesity and ageing in the pathogenesis of various cardiovascular disorders. This is further supported by the notion that weight reduction not only effectively reduces major cardiovascular events in elderly individuals but is also considered the gold standard for lifespan extension, in obese and non-obese model organisms. This review evaluates the intricate interplay between obesity and ageing from molecular mechanisms to whole organ function within the cardiovascular system. By comparatively analysing their characteristic features, shared molecular and cell biological signatures between obesity and ageing are unveiled, with the intent to shed light on how obesity accelerates cardiovascular ageing. This review also elaborates on how emerging metabolic interventions targeting obesity might protect from cardiovascular diseases largely through antagonizing key molecular mechanisms of the ageing process itself. In sum, this review aims to provide valuable insight into how understanding these interconnected processes could guide the development of novel and effective cardiovascular therapeutics for a growing aged population with a concerning obesity problem.

Sarcopenia could be linked to abdominal obesity through various mechanisms. The aim of the current study was to evaluate the association between sarcopenia and abdominal obesity among community-dwelling aged population.

This study aimed to investigate the molecular mechanisms underlying the improvement of aged skeletal muscle atrophy by high-intensity interval training (HIIT) combined with glycine supplementation.

The African turquoise killifish, Nothobranchius furzeri, is an emerging model for functional genomics research. Interest in N. furzeri stems from its extremely short lifespan, and the breadth of research on this fish is rapidly expanding. All currently available whole-genome assemblies for N. furzeri are based on the GRZ strain. However, N. furzeri shows substantial phenotypic differences among populations. Here, we present a whole-genome assembly of the MZM-0403 strain of N. furzeri, which differs from the GRZ strain with respect to lifespan and male coloration patterns. We used PacBio HiFi sequencing to sequence the genome of an MZM-0403 male to approximately 48X coverage. The PacBio reads were de novo assembled and then scaffolded against an existing N. furzeri genome assembly. This strategy resulted in a chromosome-level assembly. Our MZM-0403 assembly differs from previous N. furzeri assemblies in that it is closer to the expected genome size based on independent estimates (∼1.5 Gb) and it has substantially fewer gaps, particularly in the vicinity of genes and within introns. A repeat analysis shows that about two-thirds of the genome is composed of repetitive elements. In addition, our assembly approach allowed us to recover phased fragments of the X- and Y-chromosomes. Analysis of these regions identify 20 genes that are likely in the non-recombining region of the sex chromosomes. Overall, this novel genome assembly will be useful for future functional and comparative genomics studies of fishes in the genus Nothobranchius.

Aging is an inevitable biological process, driven in part by increased oxidative stress, which accelerates cellular damage and contributes to immune system dysfunction. Therefore, targeting oxidative stress has emerged as a potential strategy. Pyrroloquinoline quinone (PQQ), a potent antioxidant, has demonstrated significant efficacy in reducing oxidative stress and modulating immune responses, making it a promising therapeutic candidate. In this study, we investigated the effects of aging on the hematopoietic immune system (HIS) through single-cell RNA sequencing (scRNA-seq) of spleen and bone marrow cells in murine models. Our results revealed widespread age-related inflammation and oxidative stress within immune cell populations. Notably, long-term PQQ supplementation improved physiological parameters and reduced blood inflammatory factors levels in aged mice. Subsequent scRNA-seq analysis demonstrated that PQQ supplementation effectively reduced oxidative stress levels across various HIS cell types and reversed aging-related phenotypes, such as inflammatory responses and immunosenescence. Additionally, PQQ reversed aging-induced disrupted signaling and restored immune homeostasis, particularly in B cells and hematopoietic stem cells (HSCs). Importantly, we identified critical molecular targets, including ASPP1, which mediates PQQ's anti-apoptotic effects in B cells, and Yy1 and CD62L, which were upregulated by PQQ to restore HSCs self-renewal and differentiation potential. Furthermore, the machine learning program and experimental validation demonstrated the senolytic and senomorphic effects of PQQ in vivo and vitro. These findings underscore PQQ's potential not only in mitigating oxidative stress but also in restoring immune homeostasis and promoting cellular regeneration, highlighting its therapeutic potential in addressing immune aging and improving physiological function.

Reprogramming of aged donor tissue cells into induced pluripotent stem cells (A-iPSC) preserved the epigenetic memory of aged-donor tissue, defined as genomic instability and poor tissue differentiation in our previous study. The unbalanced expression of RNA exosome subunits affects the RNA degradation complex function and is associated with geriatric diseases including premature aging and cancer progression. We hypothesized that the age-dependent progressive subtle dysregulation of EXOSC2 (exosome component 2) causes the aging traits (abnormal cell cycle and poor tissue differentiation). We used embryonic stem cells as a tool to study EXOSC2 function as the aging trait epigenetic memory determined in A-iPSC because these aging traits could not be studied in senesced aged cells or immortalized cancer cells. We found that the regulatory subunit of PP2A phosphatase, PPP2R5E, is a key target of EXOSC2 and this regulation is preserved in stem cells and cancer.

Neurodegenerative diseases including Alzheimer's and Parkinson's disease are age-related disorders which severely impact quality of life and impose significant societal burdens. Cellular senescence is a critical factor in these disorders, contributing to their onset and progression by promoting permanent cell cycle arrest and reducing cellular function, affecting various types of cells in brain. Recent advancements in regenerative medicine have highlighted "R3" strategies-rejuvenation, regeneration, and replacement-as promising therapeutic approaches for neurodegeneration. This review aims to critically analyze the role of cellular senescence in neurodegenerative diseases and organizes therapeutic approaches within the R3 regenerative medicine paradigm. Specifically, we examine stem cell therapy, direct lineage reprogramming, and partial reprogramming in the context of R3, emphasizing how these interventions mitigate cellular senescence and counteracting aging-related neurodegeneration. Ultimately, this review seeks to provide insights into the complex interplay between cellular senescence and neurodegeneration while highlighting the promise of cell-based regenerative strategies to address these debilitating conditions.

The development of age-related neurodegenerative diseases is associated with the accumulation of damaged and misfolded proteins. Such proteins are eliminated from cells by proteolytic systems, mainly by 20S proteasomes, whose activity declines with age. Its stimulation has been recognized as a promising approach to delay the onset or ameliorate the symptoms of neurodegenerative disorders. Here we present peptidomimetics that are very effective in stimulating the proteasome in biochemical assays and in cell culture. They are stable in human plasma and capable of penetrating the cell membranes. The activators demonstrated the ability to enhance h20S degradation of α-synuclein and tau, whose aggregates are involved in the development of Parkinson's and Alzheimer's diseases, respectively. The peptidomimetics did not show cytotoxicity to HEK293T and primary hippocampal cells. Additionally, these compounds were highly effective in reducing the amount of phosphorylated α-synuclein aggregates in hippocampal neurons in a mouse embryonic cell model.

Recent studies have established a reciprocal causal link between aging and the activation of transposable elements, characterized in particular by a de-repression of LINE-1 retrotransposons. These LINE-1 elements represent 21% of the human genome, but only a minority of these sequences retain the coding potential essential for their mobility. LINE-1 encoded proteins can induce cell toxicity implicated in aging and neurodegenerative diseases. However, our knowledge of the expression and localization of LINE-1-encoded proteins in the central nervous system is limited. Using a novel approach combining atlas-based brain mapping with deep-learning algorithms on large-scale pyramidal brain images, we unveil a heterogeneous, neuron-predominant and widespread ORF1p expression throughout the murine brain at steady-state. In aged mice, ORF1p expression increases significantly which is corroborated in human post-mortem dopaminergic neurons by an increase in young LINE-1 elements including those with open reading frames. Mass spectrometry analysis of endogenous mouse ORF1p revealed novel, neuron-specific protein interactors. These findings contribute to a comprehensive description of the dynamics of LINE-1 and ORF1p expression in the brain at steady-state and in aging and provide insights on ORF1p protein interactions in the brain.

Aging is associated with declines in muscle strength and physical function, and sleep plays a crucial role in maintaining musculoskeletal health. This cohort study, based on the China Health and Retirement Longitudinal Study (CHARLS), aims to explore the relationship between sleep characteristics and physical performance in middle-aged and elderly individuals.

Essential Tremor (ET) is a common movement disorder characterized by action tremors, primarily affecting the hands and head. lthough previous studies have suggested potential links between ET and aging-related diseases, its relationship with longevity remains unclear, with conflicting evidence in the literature. To investigate this association, we analyzed data from 1,493 individuals across 145 families, encompassing both ET-positive (ET+) and ET-negative (ET-) participants. Using comprehensive statistical methods, including survival function estimation and regression modeling, we examined the potential influence of ET on lifespan. The median age of our participants was 67 years (IQR 54-77). Among deceased individuals, those with ET had a higher median age at death (80 years, IQR 70-86) compared to their ET- counterparts (70 years, IQR 59-77). Living ET+ participants also demonstrated slightly higher median ages (63 years, IQR 53-74) than living ET- individuals (60 years, IQR 49-71). Survival analysis revealed a significantly prolonged lifespan for ET+ individuals compared to ET- individuals (log-rank p =  1.11 ×  10 ⁻23). Furthermore, hazard ratio (HR) calculations indicated a reduced risk of mortality for the ET+ group (HR =  0.44, CI95% =  0.37-0.52), particularly among males. These findings suggest that ET may be associated with increased longevity, though the underlying biological mechanisms remain unclear. Further research is essential to elucidate the processes contributing to this relationship and to explore its implications for understanding aging and neurodegenerative disorders.

Interoception refers to the body's perception and regulation of internal physiological states and involves complex neural mechanisms and sensory systems. The current definition of interoception falls short of capturing the breadth of related research; here, we propose an updated definition. Homeostasis, a foundational principle of integrated physiology, is the process by which organisms dynamically maintain optimal balance across all conditions through neural, endocrine, and behavioral functions. This review examines the role of interoception in body homeostasis. Aging is a complex process influenced by multiple factors and involving multiple levels, including physical, psychological, and cognitive. However, interoceptive and aging interoceptive interactions are lacking. A new perspective on interoception and aging holds significant implications for understanding how aging regulates interoception and how interoception affects the aging process. Finally, we summarize that arachidonic acid metabolites show promise as biomarkers of interoception-aging. The aim of this study is to comprehensively analyze interoceptive-aging interactions, understand the aging mechanism from a novel perspective, and provide a theoretical basis for exploring anti-aging strategies.

Aging is a lifelong process that initiates at birth and is associated with age-related diseases and death. Night shift work has drawn increasing attention due to its negative health effects. This study aims to explore the association between night shift work, biological aging, and life expectancy using data from the UK Biobank.

Vascular aging is characterized by a tandem increase in pulse pressure and large elastic artery stiffness. Greater stiffness of the large arteries leads to elevated pulse pressure transmitted into the cerebral circulation, causing dysfunction. However, little is known in females about age-related stiffening of the arteries and the impacts of high pulse pressure on the cerebral vasculature. To examine the effects of sex and age on the cerebral artery response to pulse pressure, we studied cerebral arteries collected from young and old female and male C57BL/6 mice. Isolated cerebral arteries were exposed ex vivo to static pressure, low pulse pressure, and high pulse pressure. Exposure to high pulse pressure impaired endothelium-dependent dilation in cerebral arteries from young female and male mice, with impairments also occurring in young female cerebral arteries after exposure to low pulse pressure. In contrast, exposure to low or high pulse pressure did not impact cerebral artery endothelium-dependent dilation for old male or female mice. During exposure to high pulse pressure, young females had higher cerebral artery compliance compared with young males and old females. Old mice also had higher cerebral artery passive stiffness and aortic pulse wave velocity compared with young mice. We also found age and sex differences in arterial wall thickness, collagen and elastin content, and matrix metalloproteinase 9 expression. Taken together, young female mice have more compliant cerebral arteries, which are more susceptible to endothelial dysfunction caused by pulse pressure.