Longevity Papers

An in-depth understanding of the molecular processes composing aging is crucial to develop therapeutic approaches that decrease aging as a key risk factor for cognitive decline. Herein, we present a spatio-temporal brain atlas (15 different regions) of microRNA (miRNA) expression across the mouse lifespan (7 time points) and two aging interventions composed of 1009 samples. MiRNAs are promising therapeutic targets, as they silence genes by complementary base-pair binding of messenger RNAs and are known to mediate aging speed. We first established sex- and brain-region-specific miRNA expression patterns in young adult samples. Then we focused on sex-dependent and independent brain-region-specific miRNA expression changes during aging. The corpus callosum in males and the choroid plexus in females exhibited strong sex-specific age-related signatures. In this work, we identified three sex-independent brain aging miRNAs (miR-146a-5p, miR-155-5p and miR-5100). We showed for miR-155-5p that these expression changes are driven by aging microglia. MiR-155-5p targets mTOR signaling pathway components and other cellular communication pathways and is hence a promising therapeutic target.

Background: Cyclin A2 (CCNA2), the master regulatory gene of the cell cycle is commonly silenced in postnatal mammalian cardiomyocytes. We have previously demonstrated that it can induce significant cardiac repair in both small and large animals when delivered to the heart via a viral vector. To date, whether CCNA2 gene delivery can induce cytokinesis in isolated cardiomyocytes from adult human hearts has not been investigated. Here we report that CCNA2 delivery can induce cytokinesis in cardiomyocytes isolated from adult human hearts. Methods: We designed a human gene therapy vector featuring a replication-deficient, E1/E3-deleted human adenovirus five encoding human CCNA2 driven by the cardiac Troponin T promoter to enable the expression of CCNA2 in freshly isolated human cardiomyocytes. We utilized time-lapse microscopy with live imaging to study cultured adult human cardiomyocytes isolated from a 21-year-old male, a 41-year-old female, and a 55-year-old male. To elucidate the mechanistic underpinnings of CCNA2-dependent gene regulation in governing cardiomyocyte cytokinesis, we conducted single nucleus transcriptomics (snRNA-seq, 10X Genomics) analysis of hearts isolated from adult transgenic mice that constitutively express CCNA2 in cardiomyocytes (CCNA2-Tg) and non-transgenic mice (nTg). Results: We now report that human adult cardiomyocytes can be induced to undergo complete cytokinesis in response to CCNA2 gene delivery with preservation of sarcomere integrity in the resulting daughter cells and maintaining active calcium mobilization in redifferentiated cardiomyocytes. Remarkably, snRNA-seq analysis revealed a subpopulation of cardiomyocytes enriched with cytokinesis, proliferative and reprogramming genes in hearts obtained from CCNA2-Tg mice as compared to hearts obtained from nTg mice. Additionally, bulk RNA sequencing of human adult and fetal hearts identified key reprogramming genes relevant for understanding the mechanisms of CCNA2-induced effects observed in our experimental models. Conclusion: These results provide a compelling path forward for the clinical development of cardiac regenerative therapy based on strategic manipulation of CCNA2 in cardiomyocytes.

The aging of the population is a global concern. In the post-COVID-19 pandemic era, there are no effective methods to identify aging acceleration due to infection. In this study, we conducted whole-transcriptome sequencing on peripheral blood samples from 35 healthy individuals (22-88 years old). By analysing the changes in mRNA, lncRNA, and miRNA expression, we investigated the characteristics of transcriptome alterations during the aging process. ceRNA networks were constructed, and ten genes (CD248, PHGDH, SFXN2, MXRA8, NOG, TTC24, PHYKPL, CACHD1, BPGM, and TWF1) were identified as potential aging markers and used to construct an aging clock. Moreover, our aging clock categorized individuals into slow-, average-, and quick-aging groups, highlighting a link between accelerated aging and infection-related clinical parameters. Pseudotime analysis further revealed two distinct aging trajectories, corroborating the variations in the aging rate identified by the aging clock. Furthermore, we validated the results using the OEP001041 dataset (277 healthy individuals aged 17-75), and datasets comprising patients with infectious diseases (n = 1558). Our study revealed that infection accelerates aging via increased inflammation and oxidative stress in infectious disease patients. Besides, the aging clock exhibited alterations after infection, highlighting its potential for assessing the aging rate after patient recovery. In conclusion, our study introduces a novel aging clock to assess the aging rate in healthy individuals and those with infections, revealing a strong link between accelerated aging and infections through inflammation and oxidative stress. These findings offer valuable insights into aging mechanisms and potential strategies for healthy aging.

The water exchange between brain parenchyma and cerebrospinal fluid (CSF) is considered to be responsible for glymphatic clearance of solutes and metabolic wastes from the brain, including amyloid-β, a biomarker in neurodegeneration. Despite the potential significance, no noninvasive technique for in vivo measurement of parenchyma-CSF water exchange has been demonstrated in humans, capable of investigating age-related changes in glymphatic clearance.

Geroscience has helped to usher in a new and exciting era of aging drug development and evaluation of novel and repurposed agents, as well as natural compounds purported to target one or more aging hallmarks. Among the latter, curcumin has long been pursued as a promising strategy but has failed to provide convincing evidence in human trials. Oral intake is the typical route of administration tested for the vast majority of gerotherapeutic candidates, including curcumin, but efficacy is dependent upon good oral bioavailability and pharmacokinetics. However, unlike FDA-approved oral medications, many natural compounds, such as curcumin, have poor oral bioavailability, which may explain their limited success in translation. To overcome these inherent limitations, we tested a novel solvent-based formulation of concentrated curcumin (VASCEPTOR®), developed for effective skin penetration and delivery of high amounts of bioactive curcuminoids directly to the circulation on aging and age-related conditions. We demonstrate that short-term topical treatment (7.5 mg per dose) with VASCEPTOR® twice per week can improve both vascular health in a rat model of hypertension, while a late-life intervention in aged mice improves multiple indices of health span, including improved exercise tolerance, motor coordination, diastolic function (p < 0.05), a reduction in frailty status (p < 0.05) and expression of some age-related markers in tissues, particular heart and kidney. Thus, these data suggest that the therapeutic potential of curcumin can potentially be dramatically enhanced by topical delivery and, along with other promising candidates, should be prioritized for further development, testing and deployment to potentially target some manifestations of aging in humans.

Unhealthy lifestyle behaviors are a doorway to downstream health consequences characterized by the following: 1) poor quality of life and diminished mobility; 2) increased likelihood of chronic disease risk factors and diagnoses; and, ultimately, 3) a shorter lifespan and healthspan. The aim of the current study is to assess if an ecological framework can predict U.S. lifespan via the use of artificial intelligence. The current study utilized several U.S. county-level datasets representing the predictive variables of the ecologic framework. A non-linear artificial intelligence statistical approach was used to assess the ability of these variables to predict life expectancy, death rate, and years of life lost. The R² values demonstrated that the performance of Extra trees models was different across the three outcomes, however, death rate always exhibited the highest R² for each feature number, indicating superior model accuracy for this outcome. Generally, an increase in the number of features led to improved model performance. Variables from all factors included in the proposed ecological framework were retained in the final predictive models. There is a need to understand why individuals/families/community, connected by shared cultural beliefs, decide to make one lifestyle behavior decision over another.

Europe is experiencing a significant demographic shift, with aging populations posing economic and social challenges due to increased healthcare costs and a higher prevalence of age-related diseases. Hungary, in particular, faces these challenges acutely due to higher morbidity and mortality rates from a range of chronic age-related diseases and behavioral risk factors. Addressing these issues requires innovative approaches to promote healthy aging. Semmelweis University, the largest healthcare provider and leading health sciences university in the region, is developing a comprehensive healthy aging program. A critical pillar of this program is the Semmelweis-EUniWell Workplace Health Promotion Model Program, a pioneering initiative aimed at tackling unhealthy aging within Hungary's workforce by leveraging the workplace as a platform for health promotion. Central to this program's goal of combating sedentary lifestyles-a significant contributor to age-related health issues-is the innovative use of micro-gyms and motivational interviewing. Micro-gyms, with their compact size and accessibility, provide convenient exercise opportunities, while motivational interviewing fosters intrinsic motivation and personalized counseling to encourage sustained physical activity. Through concerted efforts and innovative approaches, including the implementation of micro-gyms, the Semmelweis-EUniWell Workplace Health Promotion Model Program aims to set a benchmark for workplace health promotion, fostering a healthier and more resilient aging population in Hungary. This program not only enhances the well-being of employees at Semmelweis University and its EUniWell partner institutions but also catalyzes broader transformations in workplace health promotion and healthy aging nationwide.

Aging is inevitable processes which play a significant role in the development of various diseases, including cardiovascular diseases, neurodegenerative disorders, and cancers. The extension of lifespan and the improvement of age-related diseases can potentially be achieved by targeting evolutionarily conserved pathways and mechanisms through pharmacological interventions. Chrysophanol (Chr), a naturally occurring anthraquinone compound primarily derived from rhubarb of the Polygonaceae family, exhibits a wide range of pharmacological activities, including anti-cancer, anti-inflammatory, and anti-bacterial effects. However, its role in regulating aging remains unclear. In this study, we discovered that Chr extends both lifespan and healthspan in Caenorhabditis elegans by activating the DAF-2/DAF-16 insulin signaling pathway. Furthermore, we observed that Chr promoted longevity in natural aging mice, doxorubicin-induced aging mice, and transgenic mice through the conserved Insulin/IGF-1 signaling pathway. Additionally, Chr also influenced senescence-associated secretory phenotypes (SASPs) and enhanced the expression of antioxidant genes, contributing to delayed aging. These findings highlight that Chr exerts anti-aging effects from C. elegans to mammals via the evolutionarily conserved Insulin/IGF-1 signaling pathway, positioning Chr as a promising candidate for the prevention and treatment of aging and age-related diseases.

The coordination of protein homeostasis from the brain to periphery is essential for the health and survival of all animals. In C. elegans, glia serve a central role in coordinating organismal protein homeostasis and longevity via the unfolded protein response of the endoplasmic reticulum (UPRER). However, the full extent of the cell non-autonomous response and the identity of the signaling molecules required remained unknown. Here, we show that glial UPRER activation induces robust transcriptomic changes in specific tissue types across the animal, particularly in pathways related to neuropeptide signaling. We performed neuropeptidomics and loss and gain-of-function genetic screens and identified a single neuropeptide, FLP-17, that is sufficient but not necessary to induce cell non-autonomous activation of the UPRER. FLP-17 is sufficient to protect against chronic ER stress and age-dependent protein aggregation. We determined that FLP-17 acts through the receptor, EGL-6, to activate cell non-autonomous UPRER. This work reveals a complex peptidergic signaling network initiated by glial activation of the UPRER to regulate organismal protein homeostasis.

Mangiferin (MGN), a flavonoid known for its anti-inflammatory and antioxidant properties, was evaluated in this study for its effects on porcine oocyte maturation in vitro, as well as its potential to modulate the mechanisms associated with aging oocytes. The inclusion of 0.1 μM MGN in the IVM culture medium significantly enhanced blastocyst development following parthenogenetic activation, while also notably upregulating the expression of key embryonic development genes, including SOX2, PCNA, POU5F1, and DNMT3A. MGN treatment improved the oocytes' antioxidant capacity and mitochondrial functionality, concurrently reducing cathepsin B activity and lowering LC3B protein expression (1.06 ± 0.09 vs. 0.55 ± 0.12). To investigate the underlying mechanisms, NRF2 expression was assessed, revealing a marked increase in NRF2 fluorescence and a significant elevation in both NRF2 mRNA and protein levels (1.00 ± 0.05 vs. 1.25 ± 0.09) following MGN treatment compared to the control group. Additionally, MGN treatment enhanced the early developmental potential of aged oocytes, elevating GSH levels and mitochondrial membrane potential and reducing ROS accumulation. Furthermore, MGN treatment upregulated antioxidant genes (SOD1, SOD2). Collectively, these findings suggest that MGN improves porcine oocyte maturation in vitro and enhances subsequent developmental potential through the activation of NRF2 signaling. Moreover, MGN may also delay postovulatory oocyte aging by boosting antioxidant defense and mitochondrial function in aged oocytes.

Background: We present EpImAge, an explainable deep learning tool that integrates epigenetic and immunological markers to create a highly accurate, disease-sensitive biological age predictor. This novel approach bridges two key hallmarks of aging - epigenetic alterations and immunosenescence. Methods: First, epigenetic and immunologic data from the same participants was used for AI models predicting levels of 24 cytokines from blood DNA methylation. Second, open-source epigenetic data (25 thousand samples) was used for generating synthetic immunological biomarkers and training an age estimation model. Results: Using state-of-the-art deep neural networks optimized for tabular data analysis, EpImAge achieves competitive performance metrics against 33 epigenetic clock models, including an overall mean absolute error of 7 years and a Pearson correlation of 0.85 in healthy controls, while demonstrating robust sensitivity across multiple disease categories. Explainable AI revealed the contribution of each immunological feature to the age prediction. Conclusions: The sensitivity to multiple diseases due to combining immunologic and epigenetic profiles is promising for both research and clinical applications. EpImAge is released as an easy-to-use web tool that generates the age estimates and levels of immunological parameters for methylation data, with the detailed report on the contribution of input variables to the model output for each sample.

Age-related alterations in GABAergic function, including depletion of cortical GABA concentrations, is likely associated with declining cognitive performance in normative aging. However, the extent to which GABAergic function is perturbed in the highest-functioning stratum of the oldest-old (85+) population is unknown. For the first time, we report the stability of cortical GABA in this population. We extend our previously-reported Individual Participant Data Meta-Analysis of GABA levels across the lifespan, integrating four large cross-sectional datasets sampling cognitively-intact oldest-old adults. Within our lifespan model, the slope of age-related GABA differences in cognitively-intact oldest-old adults flattens after roughly age 80; within oldest-old adults only, inclusion of age does not improve the fit of models predicting GABA. We interpret these findings as an effect of survivorship: inclusion in the study required intact cognition, and too great a reduction of GABA levels may not be compatible with neurophysiological function needed for intact cognition. This work contributes to a growing body of evidence suggesting that successful cognitive aging may require intact GABAergic function, as well as further characterizing successful aging amongst oldest-old adults and emphasizing GABA as a potential target for interventions to prolong cognitive health in aging.

As the major pollutants of industrial wastewater, lead (Pb) and cadmium (Cd) contaminate the environment and lead to bone aging when combined. To elucidate the potential mechanism by which Pb and Cd accelerate bone aging and to screen effective protective agents, we determined the optimum concentrations of Pb and Cd to establish the aging models in vitro and in vivo. The successful establishment of aging models was confirmed through β-galactosidase (β-gal) staining, the detection of aging markers, and the evaluation of biomechanical parameters. Subsequently, the polysaccharides were extracted separately from seven plants and Atractylodes macrocephala polysaccharide (AMP) was confirmed to have the strongest effect on osteoblast proliferation. Therefore, we purified AMP to obtain a small molecular fragment called AMP1-1 and investigated its effect. It has been revealed that AMP1-1 could resist oxidative stress and promote the proliferation and differentiation of osteoblasts, thereby slowing apoptosis and alleviating cell senescence through the results of the β-gal staining and the analyses of the osteoblastic, antioxidant, apoptotic, and senescence indexes. The results in vivo suggested that AMP1-1 exerted a protective role in bone aging by inhibiting the above pathways. Consequently, AMP1-1 has theoretical significance for further development of biological protective agents against heavy metal pollution.

Clonal hematopoiesis (CH), characterized by the expansion of hematopoietic stem and progenitor cells harboring somatic mutations, has emerged as a significant age-related phenomenon with profound implications for human health. While initially recognized in the 1960s, recent technological advances have revealed its complex nature and widespread prevalence, affecting up to 84% of individuals aged ≥ 70 years. The clinical significance of CH extends beyond its well-established role as a precursor to hematological malignancies, encompassing its association with cardiovascular diseases, chronic kidney disease, and other non-malignant disorders. This comprehensive review synthesizes the current understanding of CH, focusing on recent advances in genetic and molecular mechanisms, particularly the roles of commonly mutated genes such as DNMT3A, TET2, and ASXL1. We address the emerging distinction between myeloid and lymphoid CH, their differential impacts on disease progression, and the complex interplay between CH and inflammation. Special attention is given to newly identified genetic determinants of clonal expansion rates and their implications for disease progression. The review also examines the revolutionary concept of passenger-approximated clonal expansion rate and its utility in understanding CH dynamics. Furthermore, we discuss therapeutic strategies targeting inflammatory pathways and their potential in mitigating CH-associated complications. By integrating recent findings from genetic, molecular, and clinical studies, this review provides a framework for understanding CH as a systemic condition and highlights promising directions for therapeutic interventions.

Age-related changes in human dermal fibroblasts (HDFs) contribute to impaired wound healing and skin aging. While these changes result in altered mechanotransduction, the epigenetic basis of rejuvenating aging cells remains a significant challenge. This study investigates the effects of compressive forces on nuclear mechanotransduction and epigenetic rejuvenation in aged HDFs. Using a compressive force application model, the activation of HDFs through alpha-smooth muscle actin (ɑ-SMA) is demonstrated. Sustained compressive forces induce significant epigenetic modifications, including chromatin remodeling and altered histone methylation patterns. These epigenetic changes correlate with enhanced cellular migration and rejuvenation. Small-scale drug screening identifies the extracellular signal-regulated kinase (ERK) signaling pathway as a key mediator of compression-induced epigenetic activation. Furthermore, implanting aged cell spheroids into an aged skin model and subjecting the tissue to compressive forces resulted in increased collagen I protein levels. Collectively, these findings demonstrate that applying compressive force to aged fibroblasts activates global epigenetic changes through the ERK signaling pathway, ultimately rejuvenating cellular functions with potential applications for wound healing and skin tissue regeneration.

The lymphatic vasculature plays essential roles in fluid balance, immunity, and lipid transport. Chronic, low-grade inflammation in peripheral tissues develops when lymphatic structure or function is impaired, as observed during aging. While aging has been associated with a broad range of heart pathophysiology, its effect on cardiac lymphatic vasculature has not been characterized. Here, we analyzed cardiac lymphatics in aged 20-month-old mice versus young 2-month-old mice. Aged hearts showed reduced lymphatic vascular density, more dilated vessels, and increased inflammation and fibrosis in peri-lymphatic zones. As exercise has shown benefits in several different models of age-related heart disease, we further investigated the effects of aerobic training on cardiac lymphatics. Eight weeks of voluntary wheel running attenuated age-associated adverse remodeling of the cardiac lymphatics, including reversing their dilation, increasing lymph vessel density and branching, and reducing perilymphatic inflammation and fibrosis. Intravital lymphangiography demonstrated improved cardiac lymphatic flow after exercise training. Our findings illustrate that aging leads to cardiac lymphatic dysfunction, and that exercise can improve lymphatic health in aged animals.

Mitochondrial dysfunction, resulting from a diminished oxidative damage repair capacity of mitochondrial DNA (mtDNA) in peripheral lens epithelial cells (LECs), is a key pathogenic mechanism in age-related cortical cataract (ARCC). This study aims to investigate the potential role of the E3 ligase HUWE1 and its ubiquitination substrate, the oxidative damage repair gene ATM, in the pathogenesis of ARCC. Our findings reveal that ATM protein expression is downregulated in human peripheral lens epithelial cells and the turbid cortex, correlating with increased expression of HUWE1. Overexpression of ATM is shown to repair damaged mtDNA, protect mitochondria in LECs from oxidative damage, inhibit mitochondrial fission, enhance mitochondrial biogenesis and mitophagy, and prevent LECs apoptosis. Conversely, overexpression of HUWE1 may negate the protective effects of ATM via the ubiquitination pathway, promote oxidative stress-induced mitochondrial damage, increase the expression of mitochondrial fission proteins Drp1/Fis1, lead to mitochondrial network fragmentation and LECs apoptosis. In a SD rat lens model ex vitro, the ATM inhibitor AZD0156 exacerbated lens opacity, whereas the mitochondrial fission inhibitor Mdivi-1 restored lens transparency. These results suggest that modulating key molecules involved in oxidative damage repair and mitochondrial fission pathways could enhance mitochondrial quality control, paving the way for the development of targeted molecular therapies for the prevention and treatment of ARCC.

Senescent cells (SnCs) accumulate because of aging and external cellular stress throughout the body. They adopt a senescence-associated secretory phenotype (SASP) and release inflammatory and degenerative factors that actively contribute to age-related diseases, such as low back pain (LBP). The senolytics,

Sleep disturbances and cognitive decline are intricately connected, and both are prevalent in aging populations and individuals with neurodegenerative disorders such as Alzheimer's disease (AD) and other dementias. Sleep is vital for cognitive functions including memory consolidation, executive function, and attention. Disruption in these processes is associated with cognitive decline, although causal evidence is mixed. This review delves into the bidirectional relationship between alterations in sleep and cognitive impairment, exploring key mechanisms such as amyloid-β accumulation, tau pathology, synaptic homeostasis, neurotransmitter dysregulation, oxidative stress, and vascular contributions. Evidence from both experimental research and population-based studies underscores the necessity of early interventions targeting sleep to mitigate risks of neurodegenerative diseases. A deeper understanding of the interplay between sleep and cognitive health may pave the way for innovative strategies to prevent or reduce cognitive decline through improved sleep management.

Aging-related decreases in cardiac and skeletal muscle function are strongly associated with various comorbidities. Elamipretide (ELAM), a novel mitochondria-targeted peptide, has demonstrated broad therapeutic efficacy in ameliorating disease conditions associated with mitochondrial dysfunction across both clinical and pre-clinical models. Herein, we investigated the impact of 8-week ELAM treatment on pre- and post-measures of C57BL/6J mice frailty, skeletal muscle, and cardiac muscle function, coupled with post-treatment assessments of biological age and affected molecular pathways. We found that health status, as measured by frailty index, cardiac strain, diastolic function, and skeletal muscle force, is significantly diminished with age, with skeletal muscle force changing in a sex-dependent manner. Conversely, ELAM mitigated frailty accumulation and was able to partially reverse these declines, as evidenced by treatment-induced increases in cardiac strain and muscle fatigue resistance. Despite these improvements, we did not detect statistically significant changes in gene expression or DNA methylation profiles indicative of molecular reorganization or reduced biological age in most ELAM-treated groups. However, pathway analyses revealed that ELAM treatment showed pro-longevity shifts in gene expression, such as upregulation of genes involved in fatty acid metabolism, mitochondrial translation, and oxidative phosphorylation, and downregulation of inflammation. Together, these results indicate that ELAM treatment is effective at mitigating signs of sarcopenia and cardiac dysfunction in an aging mouse model, but that these functional improvements occur independently of detectable changes in epigenetic and transcriptomic age. Thus, some age-related changes in function may be uncoupled from changes in molecular biological age.

Background The pathophysiological mechanisms that may differentially impact brain health and cognitive aging outcomes among Latino compared with non-Latino White (NLW) adults in the U.S remain incompletely understood. Recent evidence suggests that neurofilament light (NfL) levels, a biomarker of neuronal injury predictive of dementia risk, is associated with cardiovascular risk factors in both Latino and NLW populations. The current study examines whether associations between plasma NfL levels and markers for cardiovascular health differ among U.S. Mexican American (MA) and NLW adults enrolled in the Health and Aging Brain Study: Health Disparities (HABS-HD). Methods Data from 1317 participants (648 MA and 669 NLW) were analyzed, including phenotypic, neuroimaging, and plasma NfL data. Cardiovascular health factors included total volume of white matter hyperintensities (WMH), and diagnoses of hypertension, diabetes, and CVD. Results We found that NfL burden levels among MA and NLW participants differed as a function of diabetes and CVD diagnosis, with steeper differences observed in the MA group. Additionally, the association between WMH volume and NfL varied between the two groups, with a steeper association observed in the MA group. Conclusions These findings highlight the potential utility of NfL as a prognostic biomarker for CVD and neurodegeneration, particularly among MA adults. Further research is needed to clarify the mechanisms underlying these associations and to develop targeted neurodegenerative prevention strategies that address disparities in brain aging.

Cordycepin (3'-deoxyadenosine) is a bioactive compound known for its numerous beneficial properties, including antioxidant, anti-aging and antitumor effects. Despite its promising therapeutic potential, the in vivo transport mechanisms of cordycepin remain inadequately understood. Previous studies have highlighted its biological activity, but there is limited information regarding its transport and distribution, as well as how it interacts with biological systems to exert these effects. The present study explored the transport mechanisms of cordycepin, specifically its interaction with bovine serum albumin (BSA) transporters and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes, and assessed its anti-aging effects through cellular experiments.

Recent studies have shown that Akkermansia muciniphila may play a role in regulating lipid metabolism and immune response in diet-induced obese mice. However, in contrast to diet-induced obesity, aging-related obesity is characterized by a gradual increase in body fat proportion over time. This type of obesity is thought to be caused by a combination of factors, including slow metabolism, unhealthy lifestyle choices, and chronic inflammation. Unlike diet-induced obesity, which can occur relatively quickly, aging-related obesity is a long-term and slow process. In this study, we administered Akkermansia muciniphila to aged mice and collected fecal samples to analyze the targeted metabolism of short chain fatty acids (SCFAs). The mice were then euthanized and their abdominal fat was weighed. hematoxylin-eosin (H&E) staining was performed to examine tissue samples. quantitative polymerase chain reaction (qPCR) was used to detect the expression of IL-6 and TNF-α. Flow cytometry was used to examine the proportion of lymphocytes. Enzyme-linked immunosorbent assays (ELISAs) kits were used to measure the levels of inflammatory factors and aging-related indicators. The results indicate that following intragastric administration, the body weight of the aged mice decreased, along with a decrease in abdominal fat and a reduction in the size of fat cells. Additionally, there was a decrease in the mRNA level of inflammatory factors, a decrease in the total number of immune cells in abdominal fat, and a decrease in the proportion of CD8

We introduce a novel approach for the control of oligonucleotides through enzymatic activation with β-galactosidase (β-gal). We use the well-known enzymatic capability of β-gal to hydrolyze the β-galactosidic bond combined with a self-immolative linker and present three ways of sterical or topological blocking of a DNA oligonucleotide. Through a series of in vitro experiments utilizing β-gal variants (recombinant or from human cell lysates), we systematically investigate stability, transitory perturbation and enzymatic activation. Our approach holds significant promise for applications related to senescence-associated β-gal, including targeted gene expression modulation and programmable molecular interventions. The combination of enzymatic activation applied to oligonucleotides represents a significant advance for targeted release into affected cells without the need for external triggering.

The orexinergic system is anatomically and functionally conserved in almost all vertebrates, and the role in healthy ageing and age-associated diseases has been studied in mammals. Here, we review the main findings on the age-related regulation of orexinergic system in mammals, including human patients and highlights how the fish Nothobranchius furzeri serves as an exceptional model to spearhead research and unravel the intricate mechanisms underlying orexinergic regulation during ageing. The ageing brain of this teleost is characterized by the presence of neurodegenerative processes similar to those associated with human pathologies rather than those of healthy ageing. We present an in-depth summary and discussion on the groundbreaking advances in understanding the neuroanatomical organization of the orexinergic system, its pivotal role in mammalian and fish models, and its profound involvement in healthy ageing and age-associated diseases.

Neuroinflammaging is the nervous system version of inflammaging, the low-grade inflammation that develops with advanced age, aside from active disease or infection. Despite neuroinflammaging has been widely investigated, some important issues still need to be resolved such as the analysis of the extremely old subjects and the evaluation of specific brain areas. On this background, we conducted a study to analyze expression of inflammatory and anti-inflammatory genes in Wistar rats of different ages, including the oldest-old, in different brain regions. We found that pro-inflammatory mediators were generally up-regulated with age in cortex, hippocampus, and striatum, especially in the oldest-old group. Specifically, TNF-α showed an increment in expression with age in striatum, IL-1β and IFN-γ in hippocampus, and MCP-1 in cortex, hippocampus and striatum. Conversely, CX3CL1 and NOS2 showed a significant reduction of expression in the cortex of the oldest-old group. A different situation was observed in dura mater where TNF-α, IL-6, IL-1β, CX3CL1, and MCP-1 expression decreased in the older groups in comparison with the younger groups. With age the anti-inflammatory cytokines IL-4 and IL-10 were down-regulated in cortex, and TGF-β1 in dura mater, while IL-4 was up-regulated in the oldest-old group in hippocampus. Finally, we observed that female brains underwent an age-related increase of pro-inflammatory cytokines expression compared to males, except for striatum, and a general down-regulation of anti-inflammatory cytokines within each age group. Protein validation of selected factors by ELISA tests supported the observed changes. These data may represent a basis for future research about the neurobiology of aging, in particular in the neurodegenerative disorder framework.

With the growing elderly population and increasing incidence of various aging-related diseases, the scientific community is faced with an urgent challenge to identify natural anti-aging agents. Traditional Chinese medicine (TCM) polysaccharides have been proven to have good anti-aging activities. This article reviews the literature on the anti-aging pathways of traditional Chinese medicine polysaccharides applied to Caenorhabditis elegans models in the past decade. In our study, we found that 45 TCM polysaccharides from 28 genera and 26 families could delay the aging process of C. elegans. Traditional Chinese medicine polysaccharides delay the aging of C. elegans mainly by anti-oxidative stress, eliminating free radicals, repairing DNA damage, and insulin/insulin-like growth factor signaling pathway (IIS signaling pathway). In addition, an increasing number of traditional Chinese medicine polysaccharides have been found to prolong the lifespan of C. elegans by reducing inflammation, regulating intestinal flora, and affecting immune cell function. In this paper, C. elegans was used as an animal model to clarify the anti-aging pathway of traditional Chinese medicine polysaccharides, so as to provide theoretical guidance for future research and clinical experiments on the anti-aging effect of traditional Chinese medicine polysaccharides.

White-matter diseases like multiple sclerosis begin in young adulthood. Aging, being a risk factor, contributes to the progression of these diseases and makes neurological disabilities worsen. Aging causes white matter alteration due to myelin loss, axonal degeneration, and hyperintensities, resulting in cognitive impairment and neurological disorders. Aging also negatively affects central nervous system resident glial cells and peripheral immune cells, contributing to myelin degeneration and diminished myelin renewal process. Restoration of myelin failure with aging accelerates the progression of cognitive decline. This review will mainly focus on how age-related altered functions of glial and peripheral cells will affect myelin sheath alteration and myelin restoration. This understanding can give us insights into the underlying mechanisms of demyelination and failure of remyelination with aging concerning altered glial and peripheral immune cell function and their crosstalk. Also, we will explain the therapeutic strategies to enhance the remyelination process of an aging brain to improve the cognitive health of an aging person.

Yeast replicative aging is cell autonomous and thus a good model for mechanistic study from a dynamic systems perspective. Utilizing an engineered strain of yeast with a switchable genetic program to arrest daughter cells (without affecting mother cell divisions) and a high throughput microfluidic device, we systematically analyze the dynamic trajectories of thousands of single yeast mother cells throughout their lifespan, using fluorescent reporters that cover a range of biological processes, including some major aging hallmarks. We found that the markers of proteostasis stand out as most predictive of the lifespan of individual cells. In particular, nuclear proteasome concentration at middle age is a good predictor. We found that cell size (measured by area) grows linearly with time, and that nuclear size grows in proportion to maintain isometric scaling in young cells. As the cells become older, their nuclear size increases faster than linear and isometric size scaling breaks down. We observed that proteasome concentration in the nucleus exhibits dynamics very different from that in cytoplasm, with much more rapid decrease during aging; such dynamic behavior can be accounted for by the change of nuclear size in a simple mathematical model of transport. We hypothesize that the gradual increase of cell size and the associated nuclear size increase lead to the dilution of important nuclear factors (such as proteasome) that drives aging. We also show that perturbing proteasome changes mitochondria morphology and function, but not vice versa, potentially placing the change of proteosome upstream of the change of mitochondrial phenotypes. Our study produced large scale single cell dynamic data that can serve as a valuable resource for the aging research community to analyze the dynamics of other markers and potential causal relations between them. It is also a useful resource for building and testing physics/AI based models that identify early dynamics events predictive of lifespan and can be targets for longevity interventions.

A passive consequence of macromolecular condensation is the establishment of an ion concentration gradient between the dilute and dense phases, which in turn governs distinct electrochemical properties of condensates. However, the mechanisms that regulate the electrochemical equilibrium of condensates and their impacts on emergent physicochemical functions remain unknown. Here we demonstrate that the electrochemical environments and the physical and chemical activities of biomolecular condensates, dependent on the electrochemical potential of condensates, are regulated by aging-associated intermolecular interactions and interfacial effects. Our findings reveal that enhanced dense-phase interactions during condensate maturation continuously modulate the ion distribution between the two phases. Moreover, modulating the interfacial regions of condensates can affect the apparent pH within the condensates. To directly probe the interphase and interfacial electric potentials of condensates, we have designed and implemented electrochemical potentiometry and second harmonic generation-based approaches. Our results suggest that the non-equilibrium nature of biomolecular condensates might play a crucial role in modulating the electrochemical activities of living systems.

Aim: Blood flow-induced mechanical forces, particularly wall shear stress (WSS), play a fundamental role in aortic valve remodeling and maturation. Dysregulation of these processes contributes to age-related valve diseases, such as aortic stenosis and regurgitation. While epidermal growth factor receptor (EGFR) signaling has been implicated in valve development, its role in mechanotransduction remains unclear. This study aims to investigate how EGFR regulates WSS-induced signaling in valvular cells and explore its interaction with the mechanosensitive ion channel PIEZO1. Methods and Results: To investigate the role of EGFR in valvular cell mechanotransduction, we used conditional Egfrflox allele to selectively delete Egfr in valvular cells. Histological analysis revealed increased valve leaflet thickness and hyperproliferation of mesenchymal cells when Egfr was deleted both endothelial (Tie2-Cre lineage) and mesenchymal (Sm22 alpha-Cre lineage) cells. This was accompanied by a reduction in maturation-related genes (Egr1, Nos3, Tgf-beta) and extracellular matrix (ECM) components. We previously demonstrated that Egr1 expression is regulated by WSS in valvular endothelial cells, prompting further exploration of Egr1\'s role in valvular cells. In vitro, Egr1 overexpression and shRNA-mediated knockdown confirmed its role in regulating Nos3, Col1a1, and Tgf-beta, key mediators of valve remodeling. Using a pulsatile WSS-mimicking device, we found that WSS induces Erk1/2 phosphorylation and Egr1 expression in valvular cells, both of which were abolished by EGFR inhibition. However, direct EGFR activation via EGF failed to replicate WSS-induced Egr1 expression, suggesting the involvement of additional mechanosensitive pathways. Pharmacological studies further revealed that PIEZO1 inhibition impaired WSS-induced Egr1 expression, while PIEZO1 activation (via YODA) mimicked WSS effects on Erk1/2 phosphorylation and Egr1 expression. These findings suggest a functional interaction between EGFR and PIEZO1 in mechanotransduction, linking mechanical forces to key molecular pathways in valve remodeling. Conclusion: Our findings establish EGFR as a critical mediator of WSS-induced mechanotransduction in valve remodeling, working in synergy with PIEZO1 to regulate flow-sensitive transcription factors such as Egr1. This study provides new insights into the molecular mechanisms governing valve maturation and highlights potential therapeutic targets for age-related valve pathologies linked to abnormal WSS responses.

Aging is a pivotal risk factor for intervertebral disc degeneration (IVDD) and chronic low back pain (LBP). The restoration of aging nucleus pulposus cells (NPCs) to a youthful epigenetic state is crucial for IVDD treatment, but remains a formidable challenge. Here, we proposed a strategy to partially reprogram and reinstate youthful epigenetics of senescent NPCs by delivering a plasmid carrier that expressed pluripotency-associated genes (Oct4, Klf4 and Sox2) in Cavin2-modified exosomes (OKS@M-Exo) for treatment of IVDD and alleviating LBP. The functional OKS@M-Exo efficaciously alleviated senescence markers (p16

Astrocytes are the most abundant glial cell type in the central nervous system (CNS). Astrocytes are born during the early postnatal period in the rodent brain and mature alongside neurons, demonstrating remarkable morphological structural complexity, which is attained in the second postnatal month. Throughout this period of development and across the remainder of the lifespan, astrocytes participate in CNS homeostasis, support neuronal partners, and contribute to nearly all aspects of CNS function. In the present study, we analyzed astrocyte gene expression in the cortex of wild-type male rodents throughout their lifespan (postnatal 7 days to 18 months). A pairwise timepoint comparison of differential gene expression during early development and CNS maturation (7-60 days) revealed four unique astrocyte gene clusters, each with hundreds of genes, which demonstrate unique temporal profiles. These clusters are distinctively related to cell division, cell morphology, cellular communication, and vascular structure and regulation. A similar analysis across adulthood and in the aging brain (3 to 18 months) identified similar patterns of grouped gene expression related to cell metabolism and cell structure. Additionally, our analysis identified that during the aging process astrocytes demonstrate a bias toward shorter transcripts, with loss of longer genes related to synapse development and a significant increase in shorter transcripts related to immune regulation and the response to DNA damage. Our study highlights the critical role that astrocytes play in maintaining CNS function throughout life and reveals molecular shifts that occur during development and aging in the cortex of male mice.

Patients with chronic obstructive pulmonary disease (COPD) often develop complications associated with sarcopenia; however, the underlying mechanisms remain unclear. Through a combination of in vitro and in vivo experiments, as well as bioinformatics analysis, our study identified YAP/TAZ as a key regulator of the aging phenotype in the skeletal muscle of COPD patients. In skeletal muscle affected by cigarette smoke-induced COPD, we observed significant reductions in YAP/TAZ levels, alongside markers indicative of skeletal muscle aging and dysfunction. Notably, overexpression of YAP/TAZ significantly improved these conditions. Our results suggest a novel mechanism whereby the maintenance of YAP/TAZ activity interacts with ACTR2 to preserve nuclear membrane integrity and reduce cytoplasmic dsDNA levels, thereby attenuating STING activation and cellular senescence. Additionally, we found that YAP is involved in the transcriptional regulation of the ACTR2 promoter region. Overall, preserving YAP/TAZ activity may help prevent skeletal muscle aging associated with COPD, representing a new strategy for intervening in COPD-related sarcopenia.

Biological age serves as a common starting point for various age-related diseases and can be associated with a wide range of cardiovascular outcomes. However, associations between cardiovascular biological age (CBA) and various types of cardiovascular disease (CVD) remain unclear.

Epidemiological investigations consistently demonstrate an overrepresentation of the elderly in COVID-19 hospitalizations and fatalities, making the advanced age as a major predictor of disease severity. Despite this, a comprehensive understanding of the cellular and molecular mechanisms explaining how old age represents a major risk factor remain elusive. To investigate this, we compared SARS-CoV-2 infection outcomes in young adults (2 months) and geriatric (15-22 months) mice. Both groups of K18-ACE2 mice were intranasally infected with 500 TCID

With the development of modern society and prolonged education, more women choose to delay their childbearing age, which greatly increases the number of women aged older than 35 years with childbearing needs. However, with increasing age, the quantity and quality of oocytes continue to fall, especially with increasing aneuploidy, which leads to a low in vitro fertilization (IVF) success rate, high abortion rate and high teratogenesis rate in assisted reproduction in women with advanced maternal age. In addition to genetics and epigenetics, follicular metabolism homeostasis is closely related to ovarian aging and oocyte aneuploidy. Glucose, lipid, and amino acid metabolism not only provide energy for follicle genesis but also regulate oocyte development and maturation. This review focuses on the relationships among follicular metabolism, oocyte aneuploidy, and ovarian aging and discusses potential therapeutic metabolites for ovarian aging.

An increasing number of physically active adults are taking the mTOR inhibitor rapamycin off label with the goal of extending healthspan. However, frequent rapamycin dosing disrupts metabolic health during sedentary conditions and abates the anabolic response to exercise. Intermittent once weekly rapamycin dosing minimizes many negative metabolic side effects of frequent rapamycin in sedentary mice. However, it remains unknown how different rapamycin dosing schedules impact metabolic, physical, and skeletal muscle adaptations to voluntary exercise training. Therefore, we tested the hypothesis that intermittent rapamycin (2mg/kg; 1x/week) would avoid detrimental effects on adaptations to 8 weeks of progressive weighted wheel running (PoWeR) in adult female mice (5-month-old) by evading the sustained inhibitory effects on mTOR signaling by more frequent dosing schedules (2mg/kg; 3x/week). Frequent but not intermittent rapamycin suppressed skeletal muscle mTORC1 signaling in PoWeR trained mice. PoWeR improved maximal exercise capacity, absolute grip strength, and myofiber hypertrophy with no differences between vehicle or rapamycin treated mice. Conversely, frequent and intermittent rapamycin treated mice had impaired glucose tolerance and insulin sensitivity compared to vehicle treated mice after PoWeR; however, intermittent rapamycin reduced the impact on glucose intolerance versus frequent rapamycin. Collectively, these data in adult female mice suggest that 1) rapamycin is largely compatible with the physical and skeletal muscle benefits of PoWeR and 2) the detrimental effects of rapamycin on body composition and glucose metabolism in the context of voluntary exercise may be reduced by intermittent dosing.

Viral infections induce symptoms reminiscent of aging, but their impact on the host\'s biological age remains unclear. Using a computational approach, we estimated the biological age of Drosophila melanogaster flies infected with various enteric viruses and demonstrated that enteric viral infections accelerate biological aging. Comparative analysis revealed that more pathogenic viruses induced a faster increase in acceleration of aging.

Telomere dysfunction is a key hallmark of aging linked to numerous age--related diseases including cardiovascular disorders, pulmonary fibrosis, and metabolic syndromes. Despite decades of research yielding strong evidence linking telomere biology to aging processes, the field faces a critical bottleneck: current telomere measurement methods require specialized molecular techniques that prevent large--scale studies and clinical implementation. Here we present TLPath, a novel deep learning framework that extracts normal tissue architecture from routine histopathology (H&E) images to predict bulk--tissue telomere length. Trained on the Genotype--Tissue Expression cohort comprising >7.3 million patch images from >5,000 whole--slide images across 919 individuals, TLPath makes a remarkable discovery: the extracted morphological features spontaneously separate young, middle--aged, and elderly individuals within most tissue types--demonstrating for the first time that aging causes substantial architectural changes in tissues detectable without explicit age supervision. These extracted features can predict bulk--telomere length with significant accuracy (>0.51 in well--represented tissues), outperforming chronological age as a predictor (correlation = 0.20) and identifying age--discordant cases -- detecting both accelerated telomeres shortening in young individuals and preserved telomeres in older individuals. Mechanistic interpretation reveals that TLPath leverages established senescence morphological markers, including nuclear--to--cytoplasmic ratio and nuclear shape variation, for its predictions. We applied TLPath in ~2,800 new GTEx biopsies where concordant with known association, the predicted telomere length is shorter across most tissues from individuals with Type 1/2 diabetes. Overall, we demonstrate that aging substantially alters tissue morphology, which TLPath captures and uses to predict telomere length, enabling large--scale telomere biology studies using existing tissue archives.

Age-related alterations in the skeletal system are linked to decreased bone mass, a reduction in bone strength and density, and an increased risk of fractures and osteoporosis. Therapeutics are desired to stimulate bone regeneration and restore imbalance in the bone remodeling process. Quercetin (Qu), a naturally occurring flavonoid, induces osteogenesis; however, its solubility, stability, and bioavailability limit its therapeutic use. Nanoformulation can improve the physical properties of Qu and enhance its bioactivity and bioavailability. Further, localized delivery of Qu nanoformulations at the site of bone defects could ensure high local concentration, augmenting its osteogenic properties. Thus, this study aims to synthesize selenium nanoparticles-based Qu nanoformulation (Qu-SeNPs) and evaluate their osteogenic stimulation ability along with localized bone regeneration ability. Here, the spontaneously synthesized Qu-SeNPs showed uniform size distribution and rough flower-shaped morphology. The confocal images indicate improved cellular uptake and even cellular distribution of Qu-SeNPs in osteoblasts, resulting in increased osteogenic activity as indicated by enhanced expression of early and late osteoprogenitor differentiation markers. Qu-SeNPs also decreased osteoblasts' RANKL/OPG ratio and inhibited osteoclast formation. Mechanistically, Qu-SeNPs activate critical signaling pathways, including WNT and BMP, and utilize the miR-206/Connexin43 pathway to enhance osteogenesis. In vivo, experiments utilizing a drill-hole bone defect model in mice indicate that hydrogel-mediated localized delivery of Qu-SeNPs significantly accelerates bone defect healing. Thus, well-characterized and mechanistic, detailed synthesized Qu-SeNPs can restore bone remodeling, and Qu-SeNPs embedded in hydrogels may improve Qu cellular uptake and bioavailability in clinical settings, enabling innovative orthopedic and regenerative therapies for bone loss/defects.

Aging decreases the metabolic rate and increases the risk of metabolic diseases, highlighting the need for alternative strategies to improve metabolic health. Heat treatment (HT) has shown various metabolic benefits, but its ability to counteract aging-associated metabolic slowdown remains unclear. This study aimed to investigate the impact of whole-body HT on energy metabolism, explore the potential mechanism involving the heat sensor TRPV1, and examine the modulation of gut microbiota.

Transient receptor potential ankyrin 1 (TRPA1) is a sensory channel expressed in vagal afferent nerves that detect noxious stimuli. Trpa1 knockout accelerates age-related cardiac fibrosis and dysfunction in mice. This study investigated whether TRPA1 activation with its selective agonist, allyl isothiocyanate (AITC), prevents cardiac aging. Male and female 18-month-old C57BL/6 J mice were randomized to receive either a control diet or a diet containing 15 mg of AITC per kilogram of food for 6 months. At 24 months, aged mice on the control diet exhibited increased left ventricular wall thickness but maintained similar left ventricular volume and preserved systolic function compared to 18-month-old middle-aged mice. Additionally, aged mice on a control diet developed restrictive-like cardiomyopathy, characterized by a pathologically elevated E/A ratio. AITC treatment significantly improved diastolic function by normalizing the E/A ratio (P < 0.01) and shortening isovolumetric relaxation time (P < 0.01), without affecting left ventricular wall thickness, volume, or systolic function. Electrocardiographic analysis demonstrated that AITC treatment significantly increased heart rate variability (P < 0.01) and parasympathetic nervous system index (P < 0.05), indicating enhanced vagal activity. Histological analyses revealed decreased cardiac fibrosis and collagen I/III deposition in AITC-treated mice (all P < 0.01). Proteomics analysis demonstrated that differentially expressed proteins in myocardial tissue were mainly enriched in pathways of collagen metabolism, extracellular matrix-receptor interaction, and fatty acid metabolism. These findings suggest that long-term dietary AITC may improve vagal tone, reduce cardiac fibrosis, and enhance diastolic function in aged mice, potentially through TRPA1 activation. TRPA1 could be a promising therapeutic target for age-related diastolic dysfunction.

Aging is a principal driver of cardiomyopathy, characterized by mitochondrial dysfunction, oxidative stress, and progressive telomere shortening in cardiomyocytes. These pathological changes impair cellular bioenergetics and regenerative capacity, accelerating cardiac deterioration. However, targeted interventions to mitigate these effects remain limited. This research investigates the therapeutic potential of CISD1 activation as a novel strategy to counteract aging-associated cardiac decline. Using advanced Immunoinformatic approaches, including molecular docking, protein structure modelling, and molecular dynamics simulations, we assess the role of CISD1 upregulation in enhancing mitochondrial bioenergetics, reducing oxidative stress, and preserving telomere integrity. Our Immunoinformatic findings reveal that CISD1 activation stabilizes mitochondrial function, mitigates oxidative damage, and slows telomere attrition, thereby sustaining cardiomyocyte function and delaying cellular senescence. Our research identifies 4'-Methoxy-3', 5,7-trihydroxy flavanone as a potential small-molecule activator of CISD1, offering a promising pharmacological approach to modulate mitochondrial dynamics in aging cardiomyocytes. By directly addressing the mechanistic link between CISD1, mitochondrial stability, and telomere preservation, this research bridges a critical gap in understanding age-related cardiomyopathy and provides a foundation for targeted therapeutic interventions. Our findings suggest that CISD1 activation could restore cellular homeostasis in aged cardiac tissues, reducing the risk of heart failure and other aging-related cardiovascular diseases. These insights advance age-related disease intervention strategies by targeting fundamental molecular pathways involved in cardiomyocyte aging.

The metazoan lifespan is determined in part by a complex signaling network that regulates energy metabolism and stress responses. Key signaling hubs in this network include insulin/IGF-1, AMPK, mTOR, and sirtuins. The Hippo/Mammalian Ste20-like Kinase1 (MST1) pathway has been reported to maintain lifespan in Caenorhabditis elegans, but its role has not been studied in higher metazoans. In this study, we report that overexpression of Hpo, the MST1 homolog in Drosophila melanogaster, decreased lifespan with concomitant changes in lipid metabolism and aging-associated gene expression, while RNAi Hpo depletion increased lifespan. These effects were mediated primarily by Hpo-induced transcriptional activation of the RNA-binding protein maternal expression at 31B (Me31b)/RCK, resulting in stabilization of mRNA-encoding a lipolytic hormone, Akh. In mouse adipocytes, Hpo/Mst1 mediated adipocyte differentiation, phosphorylation of RNA-binding proteins such as Rck, decapping MRNA 2 (Dcp2), enhancer Of MRNA decapping 3 (Edc3), nucleolin (NCL), and glucagon mRNA stability by interacting with Rck. Decreased lifespan in Hpo-overexpressing Drosophila lines required expression of Me31b, but not DCP2, which was potentially mediated by recovering expression of lipid metabolic genes and formation of lipid droplets. Taken together, our findings suggest that Hpo/Mst1 plays a conserved role in longevity by regulating adipogenesis and fatty acid metabolism.

Chronological age is a particularly well-known indicator of variability in systemic inflammation. Other pertinent aspects of age (or "age proxies") - subjective or epigenetic age - may offer nuanced information about age and inflammation associations. Using the Midlife in the United States Study, we explored how chronological, subjective, and epigenetic age were associated with inflammation. Further, we tested whether chronological age remained a unique predictor of inflammation after accounting for the variance of subjective and epigenetic age. Using an intersectionality framework, we also tested whether associations differed by race and gender.

The Integrator is a metazoan-conserved protein complex with endonuclease activity that functions to cleave various RNA substrates to shape transcriptome homeostasis by coordinating small nuclear RNA biogenesis to premature transcription termination. Depletion of Integrator results in developmental defects across different model systems and has emerged as a causative factor in human neurodevelopmental syndromes. Here, we use the model system Caenorhabditis elegans to enable studying the temporal effects of Integrator depletion on various physiological parameters with the auxin-inducible degron system that permitted depletion of INTS-4 (Integrator subunit) catalytic subunit of the protein complex. We found that Integrator activity is critical and required for C. elegans development within the L1 larval stage, but becomes dispensable for development and lifespan after the animals have reached the L2/L3 stage. Depletion of INTS-4 only shortened lifespan if auxin was introduced at the L1 stage, suggesting that the previously described lifespan reduction by Integrator inhibition is linked to developmental growth defects. We also found that while germline-specific degradation of Integrator results in the accumulation of misprocessed snRNA transcript, it did not impair the development or lifespan but surprisingly increased progeny production. Together, our study illustrates a temporal, and a potential tissue-specific requirement of the Integrator complex function in shaping whole organism development, aging, and reproduction.

Immigrant status and citizenship influence health and well-being, yet their associations with DNA methylation (DNAm)-based biomarkers of aging - key predictors of healthspan and lifespan, also known as epigenetic aging - remain underexplored.

Prematurely aged mice (PAM), characterized by an inadequate stress response, exhibit early immunosenescence and reduced lifespan compared with exceptional non-PAM (E-NPAM) of the same age. Lacticaseibacillus rhamnosus GG (LGG) has been proposed as a beneficial probiotic in healthy aging. This study aimed to evaluate the effects of LGG consumption over 2 and 4 weeks on behavioral parameters, peritoneal leukocyte function, and lifespan in adult female PAM.

Aging is a progressive and irreversible process, serving as the primary risk factor for neurodegenerative disorders. This study aims to identify the molecular mechanisms underlying physiological aging within the substantia nigra, which is primarily affected by Parkinson's disease, and to draw potential conclusions on the earliest events leading to neurodegeneration in this specific brain region. The characterization of essential stages in aging progress can enhance knowledge of the mechanisms that promote the development of Parkinson's disease. To gain a comprehensive overview three study groups are utilized: young individuals (mean age: 28.7 years), middle-aged (mean age: 62.3 years), and elderly individuals (mean age: 83.9 years). Using the proteomic approach, crucial features of physiological aging are able to be identified. These include heightened oxidative stress, enhanced lysosomal degradation, autophagy, remodeling of the cytoskeleton, changes in the structure of the mitochondria, alterations in vesicle transportation, and synaptic plasticity.

Alterations in intercellular communication driven by cellular senescence constitute an important factor in skin aging. Migrasome, a newly discovered vesicular organelle, efficiently participates in intercellular communication; however, the relationship between cellular senescence and migrasomes remains unreported.

Aging is driven by fundamental mechanisms like oxidative stress, telomere shortening and changes in DNA methylation, which together prepare the ground for age-related diseases. Botanical extracts, rich in bioactive phytoconstituents, represent a promising resource for developing therapies that target these mechanisms to promote healthy aging. This study explores the geroprotective potential of Monarda didyma L. extract. In vitro analyses revealed the extract's strong antioxidant activity, ability to reduce telomere shortening, and capacity to protect against DNA damage, thereby decreasing cellular senescence and improving endothelial function. The randomized, double-blind clinical trial demonstrated that daily oral supplementation with the extract significantly improved leukocyte telomere length (LTL) and stabilized DNA methylation age (DNAmAge) in the intervention group, while the placebo group experienced accelerated epigenetic aging and hypermethylation of critical age-related genes (ELOVL2 and FHL2). The intervention group also reported enhanced quality of life, particularly in the physical domain, along with improved movement and quality sleep indices detected by questionnaire and wearable sensors. These compelling findings position Monarda didyma L. extract as a powerful candidate for future geroprotective therapies, with the potential to significantly impact healthy aging.

The accumulation of senescent cells (SEN) with aging produces a chronic inflammatory state that accelerates age-related diseases. Eliminating SEN has been shown to delay, prevent, and in some cases reverse aging in animal disease models and extend lifespan. There is thus an unmet clinical need to identify and target SEN while sparing healthy cells. Here, we show that the lysosomal membrane protein Lysosomal-Associated Membrane Protein 1 (LAMP1) is a membrane-specific biomarker of cellular senescence. We have validated selective LAMP1 upregulation in SEN in human and mouse cells. Lamp1+ cells express high levels of prototypical senescence markers p16, p21, Glb1, and have low Lmnb1 expression as compared to Lamp1- cells. The percentage of Lamp1+ cells is increased in mice with fibrotic lungs due to bleomycin instillation. Finally, we use a dual antibody-drug conjugate (ADC) strategy to eliminate LAMP1+ senescent cells.

Understanding how the brain develops, matures, ages, and declines is one of the fundamental questions facing neuroscience. Recent advances in diffusion MRI microstructure analysis have allowed for detailed descriptions of neuronal change in humans. However, it is essential that findings from these studies are appropriately contextualized to general age-related changes in the brain. This study uses 3-tissue constrained spherical deconvolution (3T-CSD) to examine the relationship between brain diffusion microstructure and chronological age. 3T-CSD is able to quantify signal fraction measurements at the voxel-wise level from three different tissue microenvironments found in the brain: extracellular free water, intracellular isotropic, and intracellular anisotropic. This study applies 3T-CSD analysis to the Nathanial Kline Institute\'s Rockland cohort, a large-scale community sample of brain MRI data across the lifespan. Microstructural measurements were taken in a number of structures throughout the white matter, subcortical gray matter, and lobar cortical regions while additionally evaluating lateral differences in microstructural measurements. The general trajectory of signal fraction measurements was a positive relationship with age and extracellular signal fraction, a negative relationship between age and intracellular isotropic signal fraction, and an inverted U-shaped trajectory for the intracellular anisotropic signal fraction. In individual sub-areas these trends tended to still be present, with some notable exceptions. However there were large differences in 3T-CSD microstructure measurements between individual structures, including significant lateral differences between hemispheres for each of the subcortical gray matter structures and for each of the cortical regions. These results demonstrate that 3T-CSD is able to describe age-related change across the brain and lifespan. By using a healthy population cohort this study can be used as a point of comparison for 3T-CSD analysis of microstructure changes in the presence of pathology. Finally, the detailed analysis of lateralized ROI results can inform diffusion microstructure studies examining cortical and subcortical regions.

Chronic inflammation is a critical mechanism contributing to the aging process; however, research specifically addressing chronic inflammation in skin biology remains limited. This study investigates the protective mechanism of Rosa roxburghii Tratt. (RRT) extract against UVB-induced inflammaging. RRT extract effectively reduces the secretion of IL-6, IL-1α, TNF-α, and PGE2 in keratinocytes. Additionally, it attenuates UVB-induced IL-17 pathway activation by downregulating IL-17RA, c-Fos, and c-Jun protein levels, as well as the gene expression of IL-17RA, TRAF6, HSP90, and IKKγ. Co-culturing human foreskin fibroblasts (HFF) with inflammatory factors secreted by UVB-exposed keratinocytes reveals that these factors significantly reduce mitochondrial membrane potential and mitochondrial reactive oxygen species (ROS), thereby promoting aging in HFF. The anti-inflammaging effects of RRT extract are achieved through the reduction of β-galactosidase activity, targeting of the TGF-β1-Smad2/3 signaling pathway, upregulation of COL1A1 expression, and reduction of senescence-associated secretory phenotype secretion. This study provides a novel perspective and robust scientific foundation for exploring mechanisms of skin aging and potential therapeutic interventions.

Metabolic malnutrition and inflammation-key mechanism links to redox imbalance-are fundamental pathologies that accelerate aging and disease progression, ultimately leading to death. The recently proposed metabolic vulnerability index (MVX) integrates multiple circulatory biomarkers closely linked to both metabolic and inflammatory factors. This study aims to assess MVX's potential to predict mortality in community-based population. In this large community-based prospective study, we included UK Biobank participants who underwent plasma metabolomics analysis. Gender-specific MVX scores were calculated based on six established biomarkers of mortality. Linear and non-linear associations between MVX and mortality were assessed using Cox proportional hazards models and restricted cubic spline models, respectively. Among the 274,092 UKB participants, 24,241 all-cause deaths occurred during a median follow-up period of 13.7 years. A significant, graded positive association was observed between MVX quartiles and all-cause mortality risk (P for trend <0.05), with the highest MVX quartile exhibiting the greatest risk (HR = 1.21 and 95 % CI = 1.16-1.25 after full adjustment). Females had higher MVX score than males (P < 0.05), but males with the same MVX score faced a greater mortality risk. Baseline age and comorbidities interacted (P for interaction <0.05 and synergy index >1) with MVX on mortality risk. Longitudinal analyses showed that females with persistently high MVX score had a significantly increased risk of mortality (HR = 1.39 in fully adjusted model). Collectively, these findings highlight MVX as a novel tool that captures metabolic and potential redox vulnerabilities in community residents, and serves as a valuable resource for identifying high-risk individuals of mortality. Further research is warranted to investigate the underlying mechanisms and establish causal relationships.

Introduction: Aging is associated with a reduction in muscle fascicle length (FL), which contributes to sarcopenia: the age-related loss of muscle mass and function. Studies on rodents have confirmed this reduced FL is driven by a loss of sarcomeres aligned in series (serial sarcomere number; SSN) along a muscle. However, studies on rodents have focused primarily on rat plantar flexor SSN at two aging timepoints, leaving an incomplete view of age-related changes in SSN. Hence, this study investigated SSN as a contributor to the age-related loss of muscle mass in five hindlimb muscles across four aging timepoints in rats. Methods: The soleus, medial gastrocnemius (MG), plantaris, tibialis anterior (TA), and vastus lateralis (VL) were obtained from 5 young (8 months), 5 middle-aged (20 months), 5 old (32 months), and 5 very old (36 months) male F344BN rats. After fixation of muscles in formalin and digestion in nitric acid, fascicles were teased out end-to-end to measure FL. SSN was determined by dividing FL by sarcomere length measured via laser diffraction. Muscle wet weight, anatomical cross-sectional area (ACSA), and physiological cross-sectional area (PCSA) were also determined for insight on age-related losses of whole-muscle mass and in-parallel muscle morphology. Results: Age-related SSN loss was apparent after middle age for all muscles, with the plantaris showing the smallest (8%) and the VL the greatest (21%) loss. The MG and VL appeared to plateau in their SSN loss by 32 months, while the soleus and TA underwent continued loss from 32 to 36 months. In all muscles, SSN loss evidently contributed in part to the loss of muscle mass, alongside losses of contractile tissue in parallel (indicated by ACSA and PCSA). Conclusion: As SSN is closely tied to biomechanical function, these findings present SSN as a distinct target for improving muscle performance in older adults.

Sodium is an essential nutrient, but it can be toxic in excess. In humans, excessive ingestion of dietary sodium is a prevalent cause of high blood pressure, which contributes to age-related diseases including stroke and heart disease. To elucidate how sodium levels influence animal aging, we used C. elegans, a powerful model system to study development and aging. Most experiments on this animal are conducted in standard culture conditions: Nematode Growth Medium (NGM) agar with a lawn of E. coli. Here we present evidence that NaCl in standard NGM accelerates age-related degeneration and decreases lifespan. Standard NGM contains 50 mM supplemental NaCl. For comparison, we prepared NGM with reduced NaCl or excess NaCl. Considering reduced NaCl as a baseline, wild-type worms cultured on standard NaCl displayed a normal rate of development and fertility, indicating young animals are minimally affected, but they displayed decreased lifespan and health span, indicating toxicity in older animals. The long-lived mutants daf-2, age-1, and nuo-6, cultured on NGM with standard NaCl, also displayed decreased lifespan. Thus, the level of NaCl in standard medium accelerates aging in multiple genetic backgrounds. Wild-type worms cultured with excess NaCl displayed delayed development and reduced fertility, indicating toxicity in young animals, and decreased lifespan and health span, indicating toxicity old animals. These results suggest that young animals are relatively resistant to NaCl toxicity, thriving in reduced and standard NaCl levels and only displaying toxicity in excess NaCl. Aging causes progressive sensitivity to NaCl toxicity, so that old animals display toxicity in both standard and excess NaCl. To investigate pathways that respond to NaCl, we examined five stress reporters. Young animals cultured with excess NaCl displayed transcriptional activation of gpdh-1, a specific response to NaCl stress. Old animals cultured with excess NaCl displayed transcriptional activation of gpdh-1 and hsp-6, a reporter for the mitochondrial unfolded protein response. Thus, excess NaCl activates multiple stress response pathways in older animals.

Aging is the group of time-independent changes that occur in an organism and that ultimately end in death. The relationship between aging and neuropsychiatric disorders is complex. Not only does the incidence of several neuropsychiatric disorders rise with age, but also these disorders are linked with premature mortality and are even thought to be syndromes of accelerated biological aging. Oxidative stress, inflammation and telomere length are factors commonly used to assess biological aging. The purpose of this review is to sum up the existing information about the state of those factors in schizophrenia, depression, bipolar disorder and anxiety disorders, and to summarize the effects of treatment on telomere length in patients with those neuropsychiatric disorders. The main focus, however, is on telomere length seeing the highly controversial study results on this biomarker in neuropsychiatric disorders. There is no scientific consensus on the state of those factors in the mentioned neuropsychiatric disorders or on the effects of treatment on telomere length, thus further research is needed where confounding variables are controlled. Regarding telomere length, it is highly important to explore whether short telomeres lead to the development of neuropsychiatric disorders or vice versa, as it carries huge clinical potential.

Substantial heterogeneity in cognitive ageing is well documented. Such heterogeneity has been attributed to individual differences in brain maintenance - i.e., the relative preservation of neural resources in ageing. However, large-scale longitudinal evidence is lacking. We pooled data from three population-based Swedish cohorts (Betula, N = 196; SNAC-K, N = 472; H70, N = 688; aged 60-93 years at baseline, follow-up duration up to 7 years) to assess whether global brain maintenance is associated with better preserved cognition in ageing, and to identify lifestyle predictors of brain maintenance. In each cohort, global brain integrity was indexed by the volume of the lateral ventricles (adjusted for total intracranial volume), and general cognitive function based on a principal component analysis of four age-sensitive cognitive domains. Participants were classified into subgroups of low (i.e., \'aged\') versus high (i.e., \'youth-like\') brain integrity based on ventricular volume estimates available for a younger reference sample in one of the cohorts (Betula, 25-55 years, N = 60). Subgroup differences in cognition at baseline and over the follow-up were assessed with ANCOVAs and linear mixed effects models. Logistic regressions were used to examine lifestyle predictors of brain maintenance. Across cohorts, 881 individuals (64.97%) were classified into the high brain integrity subgroup at baseline and 409 individuals (49.82%) over the follow-up. Maintenance of more youth-like brain integrity was associated with better baseline cognition (p < .001) and less cognitive decline longitudinally (p < .001). Moreover, lower cardiovascular disease (CVD) risk and the absence of diabetes predicted brain maintenance at baseline (CVD risk, OR = 0.80, 95% CI [0.68, 0.93]; diabetes, OR = 0.39, 95% CI [0.26, 0.59]) and over the follow-up (CVD risk, OR = 0.79, 95% CI [0.64, 0.96]; diabetes, OR = 0.53, 95% CI [0.29, 0.94]). These findings underscore brain maintenance as a key determinant of cognitive ageing and highlight the importance of managing cardiovascular and metabolic disease risk factors for promotion of brain and cognitive health in later life.

Aging is a gradual and irreversible process accompanied by the decline in tissue function and a significantly increased risk of various aging-related and geriatric diseases. Especially in the paradoxical context of accelerated global aging and the widespread emergence of pandemics, aging-related and geriatric diseases have become leading causes of individual mortality and disability, drawing increasing attention from researchers and investors alike. Despite the utility of current in vitro systems and in vivo animal models for studying aging, these approaches are limited by insurmountable inherent constraints. In response, microphysiological systems (MPS), leveraging advances in tissue engineering and microfluidics, have emerged as highly promising platforms. MPS are capable of replicating key features of the tissue microenvironment within microfabricated devices, offering biomimetic tissue culture conditions that enhance the in vitro simulation of intact or precise human body structure and function. This capability improves the predictability of clinical trial outcomes while reducing time and cost. In this review, we focus on recent advancements in MPS used to study age-related and geriatric diseases, with particular emphasis on the application of organoids and organ-on-a-chip technologies in understanding cardiovascular diseases, cerebrovascular diseases, neurodegenerative diseases, fibrotic diseases, locomotor and sensory degenerative disorders, and rare diseases. And we aim to provide readers with critical guidelines and an overview of examples for modeling age-related and geriatric diseases using MPS, exploring mechanisms, treatments, drug screening, and other subsequent applications, from a physiopathological perspective, emphasizing the characteristic of age-related and geriatric diseases and their established correlations with the aging process. We also discuss the limitations of current models and propose future directions for MPS in aging research, highlighting the potential of interdisciplinary approaches to address unresolved challenges in the field.

In early postnatal and young adult bone marrow, Leptin receptor-expressing (LepR

The degenerative loss of muscle associated with aging leading to muscular atrophy is called sarcopenia. Currently, practicing regular physical exercise is the only efficient way to delay sarcopenia onset. Identification of therapeutic targets to alleviate the symptoms of aging requires in vivo model organisms of accelerated muscle degeneration and atrophy. The zebrafish undergoes aging, with hallmarks including mitochondrial dysfunction, telomere shortening, and accumulation of senescent cells. However, zebrafish age slowly, and no specific zebrafish models of accelerated muscle atrophy associated with molecular events of aging are currently available. We have developed a new genetic tool to efficiently accelerate muscle-fiber degeneration and muscle-tissue atrophy in zebrafish larvae and adults. We used a gain-of-function strategy with a molecule that has been shown to be necessary and sufficient to induce muscle atrophy and a sarcopenia phenotype in mammals: Atrogin-1 (also named Fbxo32). We report the generation, validation, and characterization of a zebrafish genetic model of accelerated neuromuscular atrophy, the atrofish. We demonstrated that Atrogin-1 expression specifically in skeletal muscle tissue induces a muscle atrophic phenotype associated with locomotion dysfunction in both larvae and adult fish. We identified degradation of the myosin light chain as an event occurring prior to muscle-fiber degeneration. Biological processes associated with muscle aging such as proteolysis, inflammation, stress response, extracellular matrix (ECM) remodeling, and apoptosis are upregulated in the atrofish. Surprisingly, we observed a strong correlation between muscle-fiber degeneration and reduced numbers of neuromuscular junctions in the peripheral nervous system, as well as neuronal cell bodies in the spinal cord, suggesting that muscle atrophy could underly a neurodegenerative phenotype in the central nervous system. Finally, while atrofish larvae can recover locomotive functions, adult atrofish have impaired regenerative capacities, as is observed in mammals during muscle aging. In the future, the atrofish could serve as a platform for testing molecules aimed at treating or alleviating the symptoms of muscle aging, thereby opening new therapeutic avenues in the fight against sarcopenia.

In the context of global ageing, the prevalence of neurodegenerative diseases and dementia, such as Alzheimer's disease (AD), is increasing. However, the current symptomatic and disease-modifying therapies have achieved limited benefits for neurodegenerative diseases in clinical settings. Halting the progress of neurodegeneration and cognitive decline or even improving impaired cognition and function are the clinically meaningful goals of treatments for neurodegenerative diseases. Ageing is the primary risk factor for neurodegenerative diseases and their associated comorbidities, such as vascular pathologies, in elderly individuals. Thus, we aim to elucidate the role of ageing in neurodegenerative diseases from the perspective of a complex system, in which the brain is the core and peripheral organs and tissues form a holistic network to support brain functions. During ageing, the progressive deterioration of the structure and function of the entire body hampers its active and adaptive responses to various stimuli, thereby rendering individuals more vulnerable to neurodegenerative diseases. Consequently, we propose that the prevention and treatment of neurodegenerative diseases should be grounded in holistic antiageing and rejuvenation means complemented by interventions targeting disease-specific pathogenic events. This integrated approach is a promising strategy to effectively prevent, pause or slow down the progression of neurodegenerative diseases.

Epigenetic aging biomarkers are used for evaluating morbidity and mortality, monitoring therapies, and direct-to-consumer testing. However, the influence of environmental exposures on epigenetic age acceleration (EAA), also known as epigenetic age deviation, has not been systematically evaluated. In this systematic review, we synthesized findings from human epidemiologic studies on chemical and climatic environmental exposures, particularly air pollution, chemicals, metals, climate, and cigarette smoke, and EAA. A total of 102 studies analyzing epigenetic data from over 180,000 subjects were evaluated. Overall, studies in each exposure category frequently included adult participants, used a variety of epigenetic clocks, analyzed whole blood samples, and had a low risk of bias. Exposure to air pollution (15/19 of studies; 79%), cigarette smoke (53/66; 80%), and synthetic and occupational chemicals (5/8; 63%) were notably associated with increased EAA. Results for essential and non-essential metal exposure were more equivocal: 7/13 studies (54%) reported increased EAA. One study reported increased EAA with greater temperature exposure. In summary, we identified environmental exposures, such as air pollution and cigarette smoke, that were strongly associated with increased EAA. Further research is needed with larger and more diverse samples and high-quality exposure assessment.

Photoaging is characterized by chronic inflammation in response to ultraviolet (UV) radiation. UV radiation causes skin cells to produce reactive oxygen species (ROS), which causes oxidative stress and inflammation. ROS can reversibly or irreversibly destroy different cellular compounds, including nucleic acids, proteins, free amino acids, lipids, lipoproteins, carbohydrates, and connective tissue macromolecules. Ferroptosis is a kind of programmed cell death caused by iron dependence and lipid peroxidation and has been recently discovered. Its occurrence is primarily related to iron metabolism, antioxidants, lipid peroxidation, and other processes. In addition, high levels of ROS can trigger oxidative stress, altering the redox balance within cells and thus initiating ferroptosis. Ferroptosis has been implicated in UV-driven skin photoaging. Moreover, UV radiation from sunlight can regulate numerous ferroptosis-linked genes. This review will focus on the function of ferroptosis in UV radiation-damaged skin cells. We hope to draw attention to the significance of ferroptosis regulation in the prevention and treatment of skin photoaging.

Kurozu, a traditional Japanese black vinegar (JBV), is produced from steamed unpolished rice, koji, and water through saccharification, alcoholic fermentation, and acetic fermentation. These processes result in a vinegar rich in amino acids, vitamins, organic acids, and proteins. While Kurozu has demonstrated benefits, including anti-oxidative and anti-adipogenic activities, its effects on health at the organismal level remain poorly understood. This study aimed to evaluate the impact of Kurozu on healthspan of Caenorhabditis elegans (C. elegans) using the C. elegans Health lifespan Auto-monitoring System (C-HAS). Kurozu concentrated liquid (KCL) was tested at concentrations ranging from 0.005% to 0.5%. Results showed that 0.5% KCL significantly extended lifespan and healthspan, particularly when heat-killed (HK) E. coli OP50 was provided as the food source. In contrast, the lifespan- and healthspan-extending effects at 0.5% KCL were abolished when live E. coli was used as the food source. This suggests that active components in KCL may be metabolized by live bacteria, diminishing their beneficial effects. Further reproducibility tests at 0.5% and 1% KCL concentrations confirmed the healthspan-extending effects under conditions of dead bacterial feeding. This study highlights the health-promoting impact of KCL and provides new insights into its role as a functional food ingredient.

Aging is the primary risk factor for the development of many chronic diseases, including dementia, cardiovascular disease, and diabetes. There is significant interest in identifying novel "geroprotective" agents, including by repurposing existing drugs, but such treatments may affect organ systems differently. One current example is the nucleoside reverse transcriptase inhibitor 3TC, which has been increasingly studied as a potential gerotherapeutic. Recent data suggest 3TC may reduce inflammation and improve cognitive function in older mice; however, the effects of 3TC on other tissues in aged animals are less well characterized. Here, we use transcriptomics (RNA-seq) and targeted metabolomics to investigate the influence of 3TC supplementation on skeletal muscle in older mice. We show that 3TC: (a) does not overtly affect muscle mass or functional/health markers; (b) largely reverses age-related changes in gene expression and metabolite signatures; and (c) is potentially beneficial for mitochondrial function in old animals via increases in antioxidant enzymes and decreases in mitochondrial reactive oxygen species. Collectively, our results suggest that, in addition to its protective effects in other tissues, 3TC supplementation does not have adverse effects in aged muscle, and may even protect muscle/mitochondrial health in this context.

Physical function declines with aging, yet there is considerable heterogeneity, with some individuals declining very slowly while others experience accelerated functional decline. To gain insight into mechanisms promoting high physical function with aging, we performed proteomics, targeted metabolomics, and targeted kynurenine-focused metabolomic analyses on serum specimens from three groups of octogenarians: High-functioning master athletes (HF, n = 16), healthy normal-functioning non-athletes (NF, n = 12), and lower functioning non-athletes (LF, n = 11). Higher performance status was associated with evidence consistent with: Lower levels of circulating proinflammatory markers, as well as unperturbed tryptophan metabolism, with the normal function of the kynurenic pathway; higher circulating levels of lysophosphatidylcholines that have been previously associated with better mitochondrial oxidative capacity; lower activity of the integrated stress response; lower levels of circulating SASP protein members; and lower levels of proteins that reflect neurodegeneration/denervation. Extending the observations of previous studies focused on the biomarkers of aging that predict poor function, our findings show that many of the same biomarkers associated with poor function exhibit attenuated changes in those who maintain a high function. Because of the cross-sectional nature of this study, results should be interpreted with caution, and bidirectional causality, where physical activity behavior is both a cause and outcome of differences in the biomarker changes, remains a possible interpretation.

Delayed effects of acute radiation exposure (DEARE) and radiation late effects are a suite of conditions that become apparent months to years after initial exposure to radiation in both humans and non-human primates. Many of these disorders, including cardiac complications, insulin resistance, bone loss, hypertension, and others, are also more common among aging cohorts independent of radiation exposure. This study characterized disease incidence, age of onset, and multimorbidity for 20 common, chronic diseases in 226 irradiated and 51 control rhesus macaques (Macaca mulatta) from the Wake Forest Non-Human Primate Radiation Late Effects Cohort (RLEC) to identify the excess risk of chronic disease caused by radiation-induced tissue damage. Irradiated animals were exposed to 4.0-8.5 Gy of ionizing radiation (mean 6.17 ± 1.29 Gy) one year on average prior to joining the cohort. In addition to the acute impact of early-life irradiation, these animals have been aging postirradiation for up to 15 years (mean 5.2 ± 3.0 years). Lifespan is an average of 5.1 years shorter in irradiated animals and radiation is associated with significantly increased rates of periodontitis, cataracts, testicular atrophy, tumors, diabetes, and brain lesions. While most of these chronic diseases occur in non-irradiated macaques, irradiated animals have significantly earlier age of onset for periodontitis, cataracts, bone loss, being overweight, and arthritis. This accelerated onset leads to 2.9 ± 1.9 comorbid conditions among irradiated animals compared to 1.9 ± 1.2 diagnoses among controls by young adulthood (age 8) and 5.2 ± 2.4 compared to 3.4 ± 1.8 conditions by middle age (15 years). Subsets of these comorbid conditions cluster among animals with fibrosis-related disorders (diabetes, lung injury, liver disease, kidney disease, heart disease, and tumors) commonly diagnosed together independent of prevalence. A second cluster of comorbidities centers around bone loss and is associated with being underweight and female reproductive problems. While there are significant differences in disease burden between irradiated and control animals, there was no dose effect of radiation on lifespan, age to first diagnosis, or comorbidities and substantial heterogeneity across each of these measures. This underlying heterogeneity in response to radiation suggests the existence of a yet unidentified determinant of resilience.