Longevity Papers

Age-related hearing loss (ARHL) has emerged as a significant and potentially modifiable risk factor for neurodegenerative disorders, including Alzheimer's disease. A growing body of evidence links ARHL to structural and functional changes in the brain, with implications for cognitive decline and dementia onset. However, both ARHL and dementia are multifactorial conditions shaped not only by biological mechanisms but also by broader social determinants of health. Inequities in access to hearing care, underrepresentation of marginalised populations in research, and variability in intervention outcomes emphasise the need for a more inclusive and integrated approach to prevention. This review synthesises current evidence on the neurocognitive consequences of ARHL, the potential mechanistic pathways linking hearing loss to dementia, and the role of inequity. It includes a novel perspective by highlighting the need for cross-cultural, population neuroscience approaches incorporating exposome and equity frameworks that capture phenotypic variability across diverse populations. This review outlines key priorities for advancing neurocognitive and translational research on hearing loss, neurodegeneration, and global health equity. Addressing these gaps is essential to developing equitable strategies for dementia prevention and optimising cognitive health across the lifespan.

Sepsis is a life-threatening organ dysfunction associated with a robust systemic inflammatory and immune response to infection. Its pathological consequences lead to multiple organ deficits. Klotho was initially introduced as an antiaging molecule. Its deficiency significantly reduces lifespan, and its overexpression protects against organ injury. It reduces oxidative stress and apoptosis and has anti-inflammatory and antifibrotic properties. In this review, we discuss the underlying mechanisms of sepsis-related klotho down-regulation and the protective role of klotho in sepsis. In developing sepsis-induced multiple organ damage, klotho can modulate multiple downstream signals including nuclear factor-kappa β, mitogen activated protein kinase, and apoptosis. Multiple studies show klotho's protective effects in sepsis through activation of nuclear factor erythroid-related factor 2, Forkhead transcription factor O, and restoration of internal antioxidant activity. The proposed protective action of klotho is a promising therapeutic strategy for managing sepsis and ameliorating its related organ damage.

The aging process is associated with detrimental effects on the integrity of the intestinal barrier, consequently elevating susceptibility to various diseases. Qula exhibits outstanding nutritional composition and has a characteristic taste profile, positioning it as a prime candidate for probiotic exploration given its rich reservoir of probiotic potential. In the present study, a probiotics screening strategy was developed based on the production of short-chain fatty acids (SCFA) to reverse aging-related intestinal barrier dysfunction. After screening, Limosilactobacillus fermentum TD-3 and Lactococcus lactis MQ1-1 isolated from traditional dairy product Qula were selected based on their acid and bile salt resistance, adhesion, and antibacterial properties. In the aging mice, the combination of probiotic mixture (PM) of Lb. fermentum TD-3 and Lc. lactis MQ1-1 enhanced intestinal barrier integrity by activating mitogen-activated protein kinase (AMPK) phosphorylation, which suppressed myosin light-chain kinase (MLCK) activity to increase the expression of tight junctions. Meanwhile, PM decreased colon oxidative stress (SOD, GSH-Px, and malondialdehyde) and inflammation (IL-6, IL-1β, TNFα, and IL-10), and restored the composition of the intestinal microbiota composition. Specifically, PM enriched the relative abundance of SCFAs producing bacteria, including g__norank_f__Muribaculaceae and g__Limosilactobacillus, g__Bifidobacterium, and g__Allobaculum, thereby increasing the acetic acid and butyric acid production. Thus, the combination of Lb. fermentum TD-3 and Lc. lactis MQ1-1 activated the AMPK signaling pathway by regulating the gut microbiota and metabolites. This study innovatively established a precision screening system for probiotics targeting SCFA, and isolated and identified a PM from traditional fermented dairy products (Qula) to relieve aging-associated intestinal barrier dysfunction.

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. The central underlying mechanisms of cardiovascular diseases are vascular aging and associated arterial stiffness. Arterial stiffness is characterized by structural (e.g., tunica media calcification, alterations in vascular smooth muscle cells, and fibrosis) and functional (e.g., loss of Windkessel function, elevated pulse pressure, and development of isolated systolic hypertension) vascular changes that cause microvascular dysfunction and end-organ damage (e.g., heart failure, vascular dementia, hypertensive retinopathy, and chronic kidney disease). Current research indicates that arterial stiffness is an independent risk factor for cardiovascular diseases and represents a potential target for personalized prevention and therapeutic approaches. In this review, we summarize the pathophysiological mechanisms of vascular aging and arterial stiffness, outline the resulting end-organ damage, present different methods for the measurement of arterial stiffness, highlight the potential role of prevention and therapy, and provide future perspectives for arterial stiffness research. The purpose of this review is to provide a state-of-the-art interdisciplinary and translational approach to arterial stiffness, highlighting unique pathophysiological mechanisms (e.g., perivascular adipose tissue, extracellular vesicles), clinical relevance, and future directions.

In China, community-dwelling older adults with intrinsic capacity (IC) impairments often turn first to primary care centers, where they face increasingly complex health needs. Given the high prevalence of IC impairment among older adults in Chinese communities, there is a pressing need to explore context-specific, nurse-led multi-domain interventions to support functional ability and healthy aging.

Study of cellular senescence is critical in aging research and anti-senescence therapy drug development. Current methods for the evaluation of the widely accepted cellular senescence marker senescence-associated beta galactosidase (SA-β-gal) activity assay rely on bright-field imaging, which is non-quantitative and tedious to perform. We have developed an effective and reproducible multiplex high-content analysis system for high-throughput screen and evaluation of senescence modulators. The IC

Aging is closely related to the decline of male reproductive endocrine function, which is manifested as insufficient testosterone production. It is well known that stem cell pool stability is crucial for maintaining tissue function. However, the relationship between aging and the stem Leydig cell (SLC) pool homeostasis remains unclear. Here, we demonstrate that extracellular matrix (ECM) stiffness increases in aging testes, and SLC pool homeostasis is imbalanced. Mechanistically, high ECM stiffness increases calcium influx mediated by Piezo1, leading to mitochondrial dysfunction and excessive reactive oxygen species (ROS). Excessive ROS promotes Gli1 degradation via the ubiquitin-proteasome pathway, ultimately inhibiting the proliferation and differentiation ability of SLCs. Together, these findings reveal the role of ECM stiffness, a biomechanical property in testes, in regulating SLC pool homeostasis and suggest that pretreatment of SLCs with low ECM stiffness in vitro may be an effective strategy for their expansion and for restoring testosterone levels in aging males.

Aging as well as the presence of a-synuclein (a-syn) oligomers in the brain are indisputably linked to Parkinsons disease (PD). A central concept of geroscience is that the biological processes of aging drive the onset of aging-associated diseases. The extent to which the biological processes of aging directly contribute to PD and the inter-relationship with a-syn oligomers for the onset of PD symptoms remains unclear. Using an inducible a-syn oligomer mouse model of PD, we demonstrate that the induction of PD associated a-syn oligomers for the same timespan caused PD associated symptoms only in aged, but not in young mice. Biochemical studies revealed that a-syn oligomer formation precedes motor decline in these aged mice, and age together with a-syn expression determine the motor phenotype. Single-nucleus RNA sequencing (snRNA-seq) identified a PD disease signature that was particularly linked to basal ganglia neurons (BGNs) and was in part shared with an aging transcriptional signature. PD symptoms, as well as the PD Signature, were significantly altered by a short-term pharmacological attenuation of the activity of the small RhoGTPase CDC42 in already aged animals with PD symptoms. Attenuation of activity of CDC42 is known to target the general biological processes of aging. Interestingly, the intervention did not affect the amount of a-syn oligomers in the animals, while still improving phenotypes. Together, the data demonstrates that the biological processes of aging are a major causative driver for the onset of PD in the a-syn model of PD.

Senescence is a multifactorial and individualised process of age-related physiological decline. Cellular markers, such as telomere length and DNA methylation, can reveal subtle changes associated with chronological age or expected lifespan. In this study, we evaluated the utility of fin tissue as a surrogate for assessing telomere length and proportion of DNA methylation in the gonads of a small, short-lived laboratory fish, the turquoise killifish (Nothobranchius furzeri). We collected fin and gonadal tissues from both females and males at three different ages, and extracted DNA to measure telomere length via terminal restriction fragment (TRF) analysis and global DNA methylation levels using double-digest restriction-associated DNA sequencing (ddRADseq). Our results show a notable correspondence between telomere length and DNA methylation patterns in fin and gonadal tissues. These findings support the use of fin biopsies as a non-lethal method for assessing ageing biomarkers in the gonads of small freshwater fish.

The longitudinal directionality between depressive symptoms and biological aging acceleration has yet to be thoroughly investigated. This study included 5442 Chinese adults aged 45-80 years from the 2011 and 2015 survey waves of China Health and Retirement Longitudinal Study. Multiple biomarker-based biological age was estimated using the Klemera and Doubal method, and biologically older was defined as biological age larger than chronological age. Depressive symptoms were identified using a threshold of ≥ 10 on the 10-item Center for Epidemiological Studies Depression Scale. Multivariate logistic regression was employed to explore two unidirectional associations between biological aging and depression. Cross-lagged panel models (CLPM) were also constructed to simultaneously examine the bidirectional relationship and the strength of the association. In the logistic regression model adjusted for potential confounders, biologically older at baseline was associated with a higher risk of subsequent depression (OR = 1.202, 95% CI: 1.020, 1.417) compared with biologically younger; conversely, individuals with baseline depression had a higher risk of being biologically older later (OR = 1.372, 95% CI: 1.148, 1.639) when compared to those without depression. CLPM identified bidirectional relationship over time, with standardized coefficients of 0.03 (P < 0.01) for both longitudinal directional pathways, suggesting an equal contribution of biological aging acceleration and depression to their dynamic interplay. This study reveals a reciprocal interaction between biological aging acceleration and depression in mid-to-late life, suggesting that targeted interventions aimed at decelerating biological aging or alleviating depressive symptoms may confer reciprocal benefits over time.

The hypothalamic-pituitary-ovarian (HPO) axis is a complex endocrine feedback mechanism controlling ovulation in female vertebrates. Balance of the HPO axis requires correct secretion of sex steroids from the ovarian follicle to inhibit release of gonadotropins from the pituitary. Several conditions of ovarian dysfunction such as menopause, Primary Ovarian Insufficiency (POI) and Polycystic Ovary Syndrome (PCOS) involve imbalances in the HPO axis, contributing to infertility. Intriguingly, these disorders also share a higher incidence of cognitive and emotional dysregulations, as well as a heightened risk of certain neurodegenerative conditions with age. It is understood that estradiol exerts neuroprotective functions, but gonadotropin signaling is less understood. High concentrations of circulating Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) have shown to contribute to neurodegenerative disease states, but are not addressed as part of traditional Hormone Replacement Therapy (HRT). To identify the mechanistic connections between ovarian disorders and heightened susceptibility of the brain to pathological aging, a multi-system experimental approach is required, considering each HPO axis player as an individual effector. In this review, we will summarize current knowledge on the effects of estradiol, progesterone, FSH and LH on neuronal susceptibility to pathology. We will describe ways in which the HPO axis becomes imbalanced during ovarian dysfunction, and how systemic inflammation can become an additional HPO axis effector. Finally, we will recommend solutions to the presented gaps in knowledge, and suggest avenues of future research to pursue development of therapeutics targeting both ovarian and brain health in patients.

The induction of beige adipocytes is significantly reduced in aged mice due to the senescence of adipocyte progenitor cells (APCs). Recent studies have revealed the existence of beige adipocyte subtypes, suggesting that APCs comprise a heterogeneous population. Therefore, in this study, we aimed to elucidate the mechanism through which long-term cold exposure induces the production of beige adipocytes even in aged mice. Single-cell RNA sequencing identified carbonic anhydrase 4 (Car4)-positive APCs. The number of Car4-positive APCs increased with age and cold exposure. Car4 knockdown (KD) mitigated intracellular pH reduction and significantly suppressed beige adipocyte differentiation. Furthermore, Car4 KD cells demonstrated reduced expression of genes in the glutathione pathway and increased susceptibility to reactive oxygen species (ROS), which was alleviated by glutathione supplementation. Our findings suggest that ROS resistance is an adaptation to the cellular aging environment. Our study provides insights into the age-related decline in beige adipocyte induction and identifies Car4 as a potential therapeutic target for enhancing energy expenditure in elderly individuals. This may pave the way for the development of new strategies to combat age-related metabolic diseases and offer hope for improved health and longevity in an aging population.

To investigate the role of RNA methylation in retinal pigment epithelial (RPE) cells in age-related macular degeneration (AMD).

Cognitive enhancement and neuroplasticity are interconnected terms. Neuroplasticity is an intrinsic brain capability that enables it to adapt and learn throughout life. It involves significant reorganization of neural circuits which is evident not only during normal human development but also occurs following early injury. As aging exerts a detrimental effect on various bodily systems, the extent of neuroplasticity also declines considerably. Recent evidences emphasize that cognitive enhancement can lead to positive neuroplastic changes. Moreover, neuroplastic mechanisms can be harnessed for therapeutic purposes in clinical populations in an effective manner. This approach can also pave a way for cognitive reserve and healthy aging, facilitating the protection against age-associated cognitive impairment and development of neurodegenerative disorders. However, there is an urgent need for more rigorous scientific methods to assess the effectiveness of these interventions, which is crucial for progressing in this area. In this review we aim to illuminate the promising potential of plastic processes in the nervous system. The integrated approach, combining neuromodulatory techniques such as brain stimulation with cognitive enhancement methods, is intriguing and could offer a new avenue for enhancing cognitive functions. Overall, this paper lays the groundwork for further exploration and emphasizes the importance of developing effective interventions that leverage the brain's capacity for change. Future research must refine the methodologies used to measure outcomes, ensure generalization and practical applicability, and develop strategies for implementation in real-world settings. This will ultimately enhance our understanding of how to optimize cognitive health throughout the lifespan.

Prediabetes is increasing in India and progresses rapidly to type 2 diabetes. The impact of vitamin D3 supplementation on telomerase activity and leukocyte telomere length (LTL) among people with prediabetes has been poorly researched.

A recent publication presented the results of a survey given to longevity experts that attended the 2022 Systems Aging Gordon Research Conference. Corroborating results from a prior survey and broader discussions in the field, the authors found that there was little consensus on fundamental topics, including what causes aging. While this disagreement is not particularly surprising, the spread of answers to the following prompt was unexpected: "The average lifespan in developed countries will be increased by >10 years in the next 20 years." On a five-point agreeability scale, a slight, significant majority of respondents indicated agreement with this projection. To get a sense of how ambitious this prediction is, a previous analysis concluded that preventing every single cancer death would only increase life expectancy at birth by around three years. Moreover, the majority of gains in life expectancy since 1900 are due to improvements in preventing and managing infectious and contagious diseases. Given all of this, the lengthy lag between discovery and translation, the time required to prepare for and launch longevity-oriented clinical trials, and the limited number of reproducible interventions that robustly extend lifespan in male and female mice, it is unlikely that 10+ year increases to average lifespan are just around the corner in developed countries. While aging is undoubtedly modifiable and further improvements in longevity are achievable, the field's optimism should not distract from what is realistically attainable and the amount of work and time required to successfully identify, test, and translate pro-longevity interventions.

Cognitive functioning in later life is influenced by reserves accumulated through employment and family roles over the life course. This study examined men's and women's combined employment, parenthood, and partnership roles between ages 15 and 49 years, and their associations with later-life memory. We used retrospective and prospective data from nine waves of the Survey of Health, Aging and Retirement in Europe (SHARE) for 5638 men (24 199 observations) and 6371 women (27 114 observations) in Italy, France, the Netherlands, and Sweden. Multichannel sequence analysis (MCSQA) and hierarchical clustering identified six work-family life course types for men and nine for women. Random-effects linear regression models indicate that weak labor market attachment is associated with lower memory performance among women, whereas the absence of family roles is more strongly negatively associated with memory among men. Women's cognitive gaps were most pronounced in Italy and least in Sweden and the Netherlands, while men's gaps were greater in Sweden and France. These findings suggest that gendered life courses contribute to different patterns of cognitive and relational reserve accumulation for men and women, and that welfare states buffer the negative consequences of adverse life courses on cognitive health. This article is part of a Special Collection on Cross-National Gerontology.

The biological feasibility of human rejuvenation remains a subject of intense debate, yet answering this question is critical for guiding research strategies. Should aging research focus on reversing aging in older individuals, or on pausing its progression at earlier ages? We address this question with evolutionary biology. Classic evolutionary theories of aging - damage accumulation, antagonistic pleiotropy, and the disposable soma - consider aging as a detrimental byproduct of evolution. From this perspective, rejuvenation should confer strong fitness advantages and therefore be expected to evolve in species experiencing substantial aging in the wild. Its rarity in nature should thus be interpreted as evidence of its mechanistic implausibility. Yet, rejuvenation does occur in a few species, and, paradoxically, it is typically induced by stress but not used under optimal conditions. Using mathematical modeling of lifespan plasticity in eusocial insects, we show that this pattern cannot be reconciled with classic theories of aging, revealing an internal contradiction between these theories and the observed avoidance of rejuvenation. By contrast, the pathogen control hypothesis - which interprets aging as an adaptive, programmed process -offers a consistent evolutionary framework for understanding and potentially achieving rejuvenation.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a largely unknown duration and pathophysiology of the pre-diagnostic phase, especially for the common non-monogenic form. Methods: We leveraged the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with up to 30 years of follow-up to identify incident ALS cases across five European countries. Pre-diagnostic plasma samples from initially healthy participants underwent high-throughput proteomic profiling (7,285 protein markers, SomaScan). Cox proportional hazards models based on 4,567 participants (including 172 incident ALS cases) were used to identify protein biomarkers associated with future ALS diagnosis. Top results were indirectly validated in two independent case-control studies of prevalent ALS (n=417 ALS, 852 controls). Functional annotation included cross-disease comparisons, gene set and tissue enrichment testing, organ-specific proteomic clocks, and the application of large-language models (LLM). Findings: Five proteins (SECTM1, CA3, THAP4, KLHL41, SLC26A7) were identified as significant pre-diagnostic ALS biomarkers (FDR=0.05), detectable approximately two decades before diagnosis. Of these, all except SECTM1 were indirectly validated in independent cohorts of prevalent ALS cases, supporting their clinical significance. Additionally, 22 nominally significant (p<0.05) pre-diagnostic biomarkers were FDR-significant in prevalent ALS with consistent effect directions. Cross-disease comparisons with pre-diagnostic Parkinson and Alzheimer disease suggested a largely specific pre-diagnostic ALS biomarker signature. Gene ontology and tissue enrichment highlighted early involvement of immune, muscle, metabolic, and digestive processes. Furthermore, analyses of proteomic clocks revealed accelerated aging in brain-cognition, immune, and muscle tissues before clinical diagnosis. Druggability and LLM analyses revealed possible therapeutic targets and novel strategies, emphasizing translational relevance. Interpretation: Our study provides first evidence of ultra-early molecular changes in common ALS up to two decades prior to clinical onset, mainly affecting immune, muscle, metabolic, digestive, and cognitive systems. Our study nominates several compelling candidates for risk stratification studies and novel therapeutic targets for early intervention.

The comparative biology of aging leverages the remarkable diversity in aging rates and lifespans across species to uncover naturally evolved adaptations that promote longevity, disease resistance and injury resilience. The beauty of comparative biology is that it discovers adaptations that evolved outside of the protected laboratory environment, shaped by natural selection under real-world pressures. In this Review, we outline key approaches in comparative biology of aging studies, including the study of public mechanisms, which are shared between species, and private mechanisms, which are species-specific. Additionally, we present insights gained through high-throughput omics technologies-including genomics, transcriptomics, epigenomics, proteomics and metabolomics-and illustrate how these findings advance our understanding of how to ameliorate the hallmarks of aging, enhance cancer resistance and improve regeneration, with a focus on mammals. Finally, we offer practical guidance for designing and interpreting comparative studies aimed at understanding and translating longevity mechanisms.

Skeletal muscle is essential for life as it enables physical movement, maintains posture, is crucial for breathing, and serves as a major site for energy and carbohydrate metabolism. Pathological conditions that reduce skeletal muscle mass and function-such as muscular dystrophies, motor-neuron diseases, cancer, type-2 diabetes, or aging-have detrimental effects on human health, reducing quality of life and survival. Currently, exercise is the only validated treatment for increasing muscle mass and function, but it is impractical for bedridden patients or the frail elderly. Significant advances in understanding the molecular mechanisms underlying atrophy of slow- or fast-twitch muscle fibers have identified numerous previously unknown key players that may show promise as potential drug targets. Here, we review these recent advances and discuss the potential of these discovered mechanisms as therapeutic targets to combat muscle wasting.

The age-related functional decline of bone marrow mesenchymal stem cells significantly impairs bone regeneration capacity. Exosomes derived from umbilical cord mesenchymal stem cells (UCMSCs) have emerged as promising therapeutic agents in regenerative medicine and anti-aging research due to their bioactive cargo and low immunogenicity. This study investigated the rejuvenating potential of UCMSCs-derived exosomes (UCMSC-Exos) on senescent jaw bone marrow mesenchymal stem cells (JBMMSCs) and their ability to enhance bone repair in aged rats.

Most acquired cardiovascular diseases are more common in older people, and the biological mechanisms and manifestations of aging provide insight into cardiovascular pathophysiology. Measuring aging within the cardiovascular system may help to better understand risk profiles for specific individuals and direct targeted preventative therapy. In this review, we explore telomere attrition, cellular senescence, epigenetic modifications, and mitochondrial dysfunction as key molecular mechanisms of aging. These phenomena are associated with cardiovascular disease through endothelial dysfunction and systemic inflammation, which are measurable in clinical practice with a variety of clinical, laboratory, and imaging techniques. Finally, we discuss that the next tools for modelling cardiovascular aging must be capable of incorporating a vast amount of diverse data from a given patient, pointing to recent developments in artificial intelligence and machine learning.

Older adulthood is associated with declines across a wide range of cognitive functions, limiting the ability to perform tasks necessary for independent living. Changes in cognitive flexibility are a promising candidate mechanism underlying age-related changes in cognition, but the causes of inflexibility in older adulthood remain elusive. Here we focus on a core feature of flexible cognition: the ability to rapidly transition between different cognitive states when required to do so by changes in the environment or our goals (e.g., moving between states of low vs. high attentional focus). We put forward a dynamical systems model proposing that aging-related cognitive inflexibility arises in part from slowing of transitions between distinct configurations of cognitive control, even when the task is held constant. To test this model, we had participants across the lifespan perform a cognitive task under different performance goals, which induced different control configurations. Using computational modeling, we were able to measure dynamic changes in control configurations to meet different performance goals. This allowed us to simultaneously test three potential sources of age-related decreases in cognitive flexibility: 1) diminished control capacity in environments that require more switching; 2) diminished range of control adjustments; and 3) slower transitions between control states. Of these, we found that age was only associated with transition speed. When given sufficient time to maintain a given goal, older adults were able to adjust control to a similar extent as younger adults; however, when goals changed more frequently, they were more likely to undershoot their target control configuration for that goal, consistent with predictions from our model for longer transition times. Our findings demonstrate that cognitive dynamics, rather than the overall reductions in cognitive ability, are critical for understanding the mechanisms through which cognitive inflexibility arises in older adulthood.

Cognitive aging is a complex process influenced by diverse life experiences and environmental factors. However, some traditional studies have oversimplified this process by assuming that cognitive aging trajectories follow a uniform process and that all individuals will experience similar declines. This framework minimizes the impact of external factors, neglecting the diversity observed in the aging population. In fact, research has shown significant inter- and intraindividual variability in cognitive trajectories, with some individuals maintaining stable or even improving cognitive function, while others experience rapid decline. To address this gap, emerging research proposes promising alternatives to the homogenous modelling approaches used, focusing on the identification of latent classes of cognitive trajectories. In this work, we build on this by examining the complex interaction of heterogeneous cognitive trajectories with external factors during the aging process, using episodic memory as a measure of cognitive function. We use longitudinal data from 1746 individuals aged 60 and older, assessed at three times over eight years. Our findings revealed three distinct cognitive trajectories - low cognitive performance with early decline , unmodulated cognitive change and high cognitive performance with late decline - each uniquely influenced by specific lifestyle factors. These findings challenge the current theoretical model of cognitive aging by identifying that factors such as concentration activities and social engagement significantly influence the trajectories of low cognitive performance with early decline and high cognitive performance with late decline, whereas the trajectory of unmodulated cognitive change is largely unaffected by environmental influences. Overall, our results highlight the critical role of individual environmental susceptibility in shaping cognitive trajectories. This research provides key insights into the heterogeneity of cognitive aging and underscores the need for a research paradigm shift in understanding cognitive trajectories' heterogeneity. While further research is required to determine how these findings translate into practice, tailoring interventions to these newly identified cognitive trajectories, we can significantly improve individual and public health outcomes through more precise and effective social prescribing interventions.

Recent work has shown testudines can escape actuarial senescence for extended periods. However, understanding how the interplay between somatic aging and reproductive investment in highly fecund, long-lived ectotherms align with broader phylogenetic patterns remains a critical knowledge gap. Here, we present a comprehensive demographic analysis of age-specific changes in reproduction and mortality using a unique dataset on captive, known-aged green sea turtles Chelonia mydas. Despite substantial intraspecific variation, cumulative egg production showed no decline, increasing linearly for over two decades. However, mortality patterns followed the Gompertz Law, increasing exponentially with age. These results demonstrate a significant decoupling between sustained reproductive performance and age-specific mortality, building on a body of work that challenges the notion of uniformly arrested senescence. Nevertheless, life history strategies across testudines, including sea turtles, produce similar aging rates and remain low relative to endothermic tetrapods, reflecting conserved life-history patterns.

Objectives: The rapid aging of the U.S. population has raised concerns about age-related cognitive decline and Alzheimers disease. As of 2024, 18% of Americans are 65 years and older, from 12.4% in 2004, contributing to a projected 7.2 million cases of Alzheimers disease among older adults in 2025. Diet is a key modifiable factor for cognitive decline. Therefore, we aimed to characterize diet quality and nutrient intake and to examine the associations between specific dietary components and cognitive performance in older adults in the American Midwest. Design: The study was designed as a cross-sectional observational study. Setting: Community-based recruitment in Brookings, South Dakota, and surrounding areas Participants: A final analytical sample of 72 community-dwelling adults aged 65 years and older Measurements: Cognitive performance was assessed using subtests from the Consortium to Establish a Registry for Alzheimers Disease (CERAD) battery, evaluating episodic memory (Word List Memory/Recall/Recognition), visuospatial skills (Constructional Praxis), and executive function (Verbal Fluency). A composite cognitive score was calculated from memory and visuospatial subtests. Habitual dietary intake was evaluated using structured 24-hour recalls to calculate nutrient intake and the Healthy Eating Index score, supplemented by the Short HEI questionnaire. Demographics, health history, depressive symptoms (Patient Health Questionnaire 9), and sleep quality (Pittsburgh Sleep Quality Index) were also collected. Results: Participants demonstrated suboptimal diet quality (mean HEI score 54.4; recommended >80), with only 9.7% meeting fiber recommendations, 11% meeting calcium or vitamin A recommendations, and 1.4% meeting vitamin D requirements. In bivariate comparisons, higher cognitive performance was observed in younger participants (75.5 vs. 79.5 years; p<0.01) and females (78% vs. 50%; p=0.024). Regression models identified significant positive associations between cognitive scores and intakes of dietary fiber (p=0.007), unsaturated fats (mono- and polyunsaturated; p<0.05), protein (p=0.018), carotenoids (alpha-carotene, p=0.001; beta-carotene, p=0.026; lutein+zeaxanthin, p=0.016), vitamins A (p=0.044) and E (p=0.034), and minerals including magnesium (p=0.006), potassium (p=0.004), copper (p=0.008), zinc (p=0.024), and calcium (p=0.035). Refined grain intake was inversely associated with cognition (p=0.011). Conclusion: In this population, dietary components like fiber and micronutrients were positively associated with better cognitive function, and the overall nutrient intake shortfalls observed highlight the need for targeted dietary interventions to support healthy brain aging. Key Words: cognition, aging, nutrition, dietary fiber, carotenoids

Human populations are experiencing an increase in aging, which is associated with cognitive deficits. Animal models of aging have shown that these behavioral impairments are associated with neuroarchitecture modifications in the prefrontal cortex (PFC) and hippocampus; however, most studies have focused on rats or lack multiple key ages. In this study, we evaluated spatial and recognition memory in male mice at critical ages [3 months (M), 6, 12 and 18] using the Morris water maze (MWM) and novel object recognition test (NORT), respectively. Moreover, we quantified dendritic arborization, spine density and the type of spines in the PFC, CA1 hippocampus and nucleus Accumbens Core (NAcC). Locomotion, assessed in the first phase of NORT, revealed age-dependent reductions. Notably, the 18 M group revealed significant recognition memory deficits. Spatial memory impairments were especially evident at the 12 M group in the MWM. Spine density was increased at 6 M in the NAcC, whereas a reduction was noted at 12 M and 18 M in the PFC. Morphological assessment of spines indicated age-dependent changes, including a notable increase in the proportion of thin spines in the CA1 and PFC regions. However, dendritic arborization remained largely unchanged across the examined brain regions and age groups. Overall, our findings observed age-dependent alterations in memory and morphological alterations in spines in mice, emerging as possible contributors to cognitive decline. These results highlight the potential for anti-aging interventions targeting synaptic structures to enhance cognitive health and extend the healthspan of aging individuals.

Ageing populations and longer life expectancies challenge healthcare systems due to rising noncommunicable diseases (NCDs) and multi-morbidity. Designing healthier living environments may reduce population risks of NCD onset, but knowledge is needed on environmental factors related to NCDs in older adults. We therefore examined associations between residential neighbourhood built, physico-chemical, and sociodemographic environmental factors and NCD prevalence in the Netherlands among older adults. Cross-sectional data from 1578 older adults from the Longitudinal Aging Study Amsterdam (2008-09) were matched with environmental data from the Dutch Geoscience and Health Cohort Consortium (GECCO). Multivariable logistic regression analyses were conducted to assess the odds of having a single NCD versus no NCD and multi-morbidity versus no NCD, adjusted for sociodemographic factors. Participants had a mean age of 73.2 years, 55% were female, and 77% reported at least one NCD. Multi-morbidity was more common in women, who were also older and had lower education and income. Higher green space density within 500 m was significantly associated with lower odds of single NCD [odds ratio (OR): 0.52, 95% confidence interval (CI): 0.33-0.83]. A higher number of cars in a household also showed lower odds of single NCD (OR: 0.14, 95% CI: 0.04-0.55). No significant associations were observed for physico-chemical exposures. Results were consistent in sensitivity analyses. The findings underscore the need for urban planning and policies that support healthy ageing while embracing a longevity-ready perspective, accounting for the built, physico-chemical, and sociodemographic environments across the life-course.

Nucleus pulposus (NP) cell senescence is a critical factor in the progression of intervertebral disc degeneration (IVDD). Our analysis demonstrates that FTO and YAP1 expression levels are significantly diminished in degenerative NP tissues from both human and rat models, which correlates with increased m6A modification of YAP1 transcripts. To investigate the underlying mechanisms, we utilized IL-1β to induce senescence in cultured NP cells. Our findings reveal that FTO knockdown leads to a decrease in YAP1 levels while simultaneously increasing senescence markers. In contrast, the overexpression of YAP1 alleviates the senescence phenotype in FTO-deficient cells, underscoring the protective role of YAP1 in NP cells. This study proposes a novel regulatory pathway in which FTO modulates YAP1 through m6A demethylation, suggesting potential therapeutic targets for mitigating NP cell senescence and IVDD.

Muscle tissue is important for locomotion and metabolic health. Muscle disuse (e.g. post-operative) occurs more often in older adults, and results in rapid muscle wasting. Currently, there is no effective treatment to combat immobilization-induced atrophy, which is why novel therapeutic strategies are needed. Antagonism of cannabinoid receptor 1 (CB1) can stimulate muscle protein synthesis, thereby protecting against glucocorticosteroid-induced atrophy. However, its therapeutic potential against (age-related) immobilization-induced atrophy remains unknown. Therefore, we investigated the effect of CB1 antagonism on muscle responses following immobilization in young and old, sarcopenic male mice. One hind limb of young and old male C57BL/6 mice was immobilized for five days, during which they were treated with the CB1 antagonist Rimonabant (10 mg/kg/d) or vehicle. Hereafter, mice were euthanized and muscles were collected. Endocannabinoid, anabolic and catabolic markers were analyzed in the gastrocnemius muscle via western blotting. Rimonabant attenuated immobilization-induced gastrocnemius muscle mass loss in both ages (-7.9% vs. vehicle: -11.2%; p = 0.0027). Immobilization increased expression of the anabolic regulators (p-S6rp, p-4E-BP1), and of the catabolic markers (LC3b-II/I, MAFbx), which remained unaffected by Rimonabant treatment. Surprisingly, Rimonabant amplified the immobilization-induced decrease in muscle protein synthesis (-45.8% vs. vehicle: -27%; p = 0.0180), to a larger extent in young vs. old mice (p = 0.0005). Immobilization decreased the expression of the enzyme NAPE-PLD, responsible for synthesis of the endocannabinoid anandamide, whereas its degrading enzyme FAAH was higher expressed. More research is needed to unravel the mechanisms underlying the muscle sparing effect of Rimonabant, and anandamide's role in muscle degeneration.

Aging varies widely across species yet exhibits universal statistical regularities, such as Gompertzian mortality and scaling laws, challenging efforts to link microscopic mechanisms with macroscopic outcomes. We present a minimal phenomenological model that captures these patterns by reducing complex physiology to three variables: a dynamic factor characterizing reversible physiological responses to stress, an entropic damage variable reflecting irreversible information loss, and a regulatory noise term. This framework reveals two fundamental aging regimes. In stable species, including humans, aging is driven by linear damage accumulation that gradually erodes resilience, producing a hyperbolic trajectory toward a maximum lifespan. In unstable species, such as mice and flies, intrinsic instability drives exponential divergence of biomarkers and mortality. Model predictions agree with DNA methylation dynamics, biomarker autocorrelation, and survival curves across taxa. Crucially, this regime-based view informs intervention strategies at three levels: (i) targeting dynamic hallmarks, (ii) reducing physiological noise, and (iii) slowing or reversing entropic damage - offering a roadmap from near-term healthspan gains to potential extension of human lifespan beyond current limits.

Background: Cognitive reserve (CR) explains individual resilience to age-related cognitive decline, yet its neurobiological basis remains elusive. Current CR proxies lack direct mechanistic links, necessitating a system-level approach integrating brain structure-function interactions. Methods: We developed a novel CR metric using structural MRI and resting-state fMRI from 1,280 older adults. A youth-derived structural-functional prediction model estimated maximal attainable brain function in elders. CR was quantified as the deviation between observed and predicted function. Cross-sectional and longitudinal analyses assessed CR's spatial distribution, cognitive associations, and pathological relevance in MCI/AD cohorts. Results: CR hubs localized to prefrontal, cingulate, and precuneus regions, organized within high-order networks. Higher CR predicted slower cognitive decline (r = -0.21, p < 0.001) and correlated with reduced A{beta} deposition (r = -0.63, p < 0.001). CR demonstrated domain-specific associations with memory, attention, and processing speed. MCI exhibited broader CR reductions than AD, particularly in frontotemporal regions, likely reflecting stage-specific neuroplastic dynamics: early MCI retains partial compensatory capacity but inefficient CR utilization under mounting pathological stress, whereas advanced AD transitions to irreversible structural damage that disrupts CR's adaptive "software" mechanisms. Conclusions: This study establishes CR as a dynamic neuroprotective framework, bridging functional resilience and structural integrity. CR's spatial specificity and inverse link to amyloid pathology highlight its potential as an early biomarker for resisting pathological aging.

The bone marrow (BM) niche plays a critical role in maintaining hematopoietic stem cell function but is highly vulnerable to damage from chemotherapy and radiation. However, current therapeutic strategies for BM niche failure remain significantly limited. The previous study demonstrate that costal cartilage-derived stem cells (CDSCs) exhibit substantial self-renewal and bone-forming capacity; however, whether and how CDSCs contribute to BM microenvironment maintenance remains unknown. In this study, the co-transplantation of CDSCs with multipotent progenitors (MPPs) successfully rescued lethally irradiated mice. By contrast, transplantation of mesenchymal stem cells with MPPs or MPPs alone fails to rescue the mice, suggesting a potential role of CDSCs in hematopoietic reconstitution. RNA-seq and experimental data suggest that CDSCs are involved in rejuvenating the BM niche. Mechanistically, CDSCs not only differentiate into niche components, including bone marrow stromal cells, endothelial cells, and osteoblasts, but also secrete pro-hematopoietic cytokines, thereby rejuvenating the irradiated microenvironment. Additionally, CDSCs protect residual hematopoietic stem and progenitor cells from radiation-induced apoptosis and DNA damage while enhancing niche repair. Finally, through synergy with cyclosporine A, CDSCs markedly enhance hematopoietic recovery in mice with aplastic anemia. Collectively, these findings establish CDSCs as a versatile platform for treating BM failure via microenvironmental restoration.

Unraveling the lifespan trajectories of human brain development is critical for understanding brain health and disease. Recent research demonstrates that electroencephalography signals are composed of periodic and aperiodic components reflecting distinct physiological substrates. This dissociation raises the possibility that they follow different developmental tendencies. Here, we delineate the lifespan trajectories of aperiodic and periodic neural oscillations using a large international cohort (N=1,563, ages 5 to 95, resting state, eyes closed). We reveal two fundamental developmental patterns: a Monotonic decrease in aperiodic activity and a Growth-and-Decline pattern for periodic activity. Both components have inflections around age 20 and transition to a stable senescent phase around age 40. Spatially, anterior regions mainly exhibit aperiodic activity, while periodic activity concentrate on posterior regions and these patterns remain stable throughout life. Crucially, multimodal analysis shows these trajectories map onto distinct biological substrates. The periodic component\'s Growth and Decline trajectory aligns with GABAergic function and myelination. In contrast, the monotonically decreasing trajectory of aperiodic activity mirrors fundamental biomarkers of biological aging, such as DNA methylation and telomere length. Transforming age to a logarithmic scale simplifies these nonlinear trajectories into a linear decreasing and a piecewise concave linear model for aperiodic and periodic components. This form provides a robust and parsimonious framework for quantifying maturation and identifying neurological deviations.

It has been shown that the gut and the brain are linked through a multimodal, bidirectional pathway called the gut-brain axis. In the gut-to-brain way, the gut microbiota has been shown to be the main regulator. In clinical practice, evidence of microbiota and brain interactions comes from the association of gut microbiota alterations with neurological and psychiatric conditions. However, until now, it remains unknown how the gut microbiota influences brain activity. In this paper, we show that different microbiota profiles from healthy older people are associated with different spontaneous activity in medial posterior cortical areas. These areas are associated with memory, language, and emotion processing abilities. Therefore, the results obtained provide evidence that non-pathological gut microbiota profiles are correlated to spontaneous cortical activity associated with cognitive functions that typically deteriorate with age. This implies that early nutritional interventions that modify microbiota composition could help delay or ameliorate natural age-related cognitive decline.

The function of osteoporosis-induced bone marrow adipocyte (BMAds) accumulation remains inadequately understood. Here, we analyze bone marrow lipidomic data and reveal that BMAds deteriorate the skeletal microenvironment by secreting large amounts of lipids, altering the senescence status of neighboring cells by affecting their mitochondrial function. To specifically target BMAds under osteoporotic conditions, we design a polycation-loaded biomimetic dual-site framework (CZP@LC) that interferes with lipid crosstalk between BMAds and neighboring bone marrow cells. Shutting down abnormal lipid metabolism and secretion in adipocytes mitigates mitochondrial dysfunction in neighboring cells, which prevents bone marrow cells from senescing. The inhibition of lipid synthesis in BMAds blocks bone marrow stromal cells from differentiating into adipocytes, interrupting the vicious cycle. Moreover, interruption of lipid communication rescues osteoblasts from mitochondrial dysfunction-induced senescence and restores osteogenesis. Here we demonstrate the metabolic mechanisms of BMAds and lipid crosstalk in osteoporosis, provide a potential avenue for targeted biotherapy.

Circadian rhythms are essential biological systems operating on a 24-h cycle, playing a crucial role in regulating sleep, cognitive function, immune responses, and hormone secretion. This review explores the intricate relationship between circadian rhythms and aging, with a focus on the underlying molecular mechanisms. It discusses age-related changes in sleep patterns and the role of circadian disruption in the progression of neurodegenerative diseases such as Parkinson's and Alzheimer's. Special attention is given to the core CLOCK genes, including BMAL1 and Per2, and their regulatory influence on these processes. The review also highlights the impact of circadian misalignment on metabolic disorders, particularly obesity, diabetes, and cardiovascular disease. Emerging therapeutic strategies targeting circadian pathways-ranging from pharmacological agents to lifestyle modifications-are presented as promising approaches to support healthy aging. This review provides the deeper understanding of how aging affects circadian regulation may pave the way for targeted interventions aimed at extending lifespan and enhancing overall quality of life.

Zuogui pill (ZGP) and Yougui pill (YGP) are classical kidney-tonifying formulas in Traditional Chinese Medicine, widely used clinically but with their potential to delay ageing and improve ageing biomarkers remaining unclear. This study combined network pharmacology and Caenorhabditis elegans models to investigate the anti-ageing effects and mechanisms of ZGP and YGP. Both formulas significantly extended lifespan (ZGP dose-dependently at 5-20 mg/mL; YGP at 20 mg/mL) and improved ageing biomarkers, as evidenced by enhanced motility, reduced lipofuscin accumulation and endogenous ROS levels, and increased resistance to heat and oxidative stress. Network analysis identified quercetin and kaempferol as the top-ranked shared active components. Subsequent experimental validation demonstrated that kaempferol (0.05-0.2 mM) replicated these pro-longevity effects and was shown to act by inducing mitophagy: it triggered an initial decrease followed by a long-term increase in mitochondrial content, concomitant with upregulated expression of mitophagy genes. Crucially, the lifespan-extending effects of kaempferol, ZGP, and YGP were completely abolished in bec-1 and pink-1 null mutants. This study establishes that ZGP and YGP delay ageing and improve ageing biomarkers in C. elegans by activating BEC-1/PINK-1-dependent mitophagy. Kaempferol was identified as a major active component mediating this effect, highlighting a key mechanism for the pro-longevity properties of these traditional formulas.

Age-related cognitive decline in learning and decision-making may arise from increased variability of neural responses. Here, we investigated how ageing affects behavioral and neural variability by recording >18,000 neurons across 16 brain regions (including cortex, hippocampus, thalamus, midbrain, and basal ganglia) in younger and older mice performing a visual decision-making task. Older mice showed more variable response times, reproducing a common finding in human ageing studies. Ageing globally increased firing rates, post-stimulus neural variability (quantified using the Fano Factor), and decreased \'variability quenching\' (the reduction in neural variability upon stimulus presentation). Older animals showed higher overall firing rates across areas of visual and motor cortex, striatum, midbrain, and hippocampus, but lower firing rates in thalamic areas. Age-related attenuation in stimulus-induced variability quenching was most prominent in visual and motor cortex, striatum, and thalamic area. These findings show how large-scale neural recordings can help uncover regional specificity of ageing effects in single neurons, improving our understanding of the neural basis of age-related cognitive decline.

Early-life nutritional deprivation may influence lifelong health, but its role in the broader process of reproductive aging remains underexplored. Guided by the Developmental Origins of Health and Disease framework, this study investigates the impacts of fetal/infant and adolescent exposure to famine on age at natural menopause, a key indicator of reproductive aging.

Testosterone deficiency (TD) is a clinically significant condition strongly associated with aging and metabolic syndrome. While previous studies have established links between muscle mass and TD, evidence regarding the relationship between muscle quality index (MQI) and TD remains limited. This study aimed to investigate the association between MQI and TD in adult males in the United States and to develop an interpretable machine learning (ML) model based on SHapley Additive exPlanation (SHAP) for predicting TD risk.

Cardiovascular aging is a complex biological process involving progressive cellular and molecular changes that impair heart and vascular function. This review evaluates both fundamental mechanisms and therapeutic strategies, focusing on how recent advances in pharmacology, gene therapy, and regenerative medicine can be translated into clinical practice to mitigate age-related cardiovascular decline. We conducted a comprehensive analysis of peer-reviewed studies from 2000 to 2023, examining molecular pathways of cardiovascular aging and their modulation through pharmacological, genetic, and lifestyle interventions. The review prioritized clinical trials, translational research, and meta-analyses to assess therapeutic efficacy and safety. Current evidence highlights the effectiveness of senolytic drugs such as dasatinib and quercetin in reducing age-related cardiovascular dysfunction, while rapamycin and metformin show promise in improving cardiac longevity through metabolic regulation. Gene therapies, including clustered regularly interspaced short palindromic repeats (CRISPR)-based interventions, demonstrate potential in preclinical models for cardiac regeneration. Stem cell therapies and nanotechnology-based drug delivery systems are emerging as innovative approaches to enhance tissue repair. In addition, lifestyle modifications such as Mediterranean diet adherence and exercise significantly improve vascular health in aging populations. However, challenges remain in drug delivery, patient-specific responses, and long-term safety of novel therapies. The integration of targeted pharmacological treatments, advanced regenerative techniques, and personalized lifestyle interventions represents a transformative approach to managing cardiovascular aging. Future research should focus on optimizing therapeutic combinations, refining delivery methods, and validating biomarkers for clinical monitoring. A multidisciplinary strategy combining these advances will be essential to improve cardiovascular outcomes in aging populations.

Exposure to infectious disease in early life may have long-term ramifications for health and lifespan. However, reducing pathogen exposure may not be uniformly beneficial. The rise of modern sanitation and reduction of infectious diseases has been implicated in increasing levels of allergy and immune dysregulation: termed, the "hygiene hypothesis." This study leverages quasi-experimental variation from combining precampaign hookworm exposure with the Rockefeller Sanitary Commission's deworming campaign in the early 20th century to rigorously examine the impacts of childhood hookworm exposure on adult lifespan and morbidity. Findings show deworming before age five leads to 2.5 additional months of life in a large sample of adult death records. Further, decreasing hookworm exposure is related to improvements in biomarkers for inflammation and skin-tested allergies, in contrast to predictions of the "hygiene hypothesis." Placebo tests using health outcomes that should not be affected by deworming do not show similar patterns. Overall, childhood deworming leads to improvements in morbidity and lifespan decades later.

Short and long sleep durations have been inconsistently linked to aging and health outcomes, potentially due to underexplored nonlinear associations. Using phenotypic and genomic data from the UK Biobank (n=442,664), we applied multivariable linear regression, restricted cubic splines, and Mendelian randomization (MR) to analyze nonlinear relationships between self-reported sleep duration and biomarkers of accelerated aging: PhenoAge acceleration (PhenoAgeAccel), BioAge acceleration (BioAgeAccel), and leukocyte telomere length (LTL). Functional annotation analyses were performed to assess potential shared biological pathways using epigenomic profiles. Observational analyses supported U-shaped phenotypic associations between sleep duration and PhenoAgeAccel/BioAgeAccel, with optimal sleep around 7 h/d. For LTL, linear models suggested a U-shape, while spline models indicated an inverted reverse J-pattern. MR analyses corroborated the deleterious impacts of insufficient, but not excessive, sleep, by revealing a threshold nonlinear relationship between increasing genetically-predicted sleep duration up to 7 h/d and lower PhenoAgeAccel/BioAgeAccel, and a linear relationship with longer LTL. Cell-type enrichment analyses connected short sleep to BioAgeAccel/LTL through pathways related to muscle maintenance and immune function. These findings suggest that extending sleep may mitigate accelerated aging, though further research is needed to clarify the underlying biological mechanisms and whether excessive sleep also contributes causally to biological aging.

Declining oocyte quality is the major contributor to female subfertility in aged mammals. Currently, there are no effective interventions to ameliorate aged oocyte quality. Here we found that oocytes at metaphase I from the cumulus-oocyte complexes of aged mice showed reduced cortical F-actin and lower levels of mevalonate (MVA) pathway metabolites, including MVA, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate. We further showed that MVA supplementation improved FPP levels, cortical F-actin and the quality of aged oocytes. Mechanistically, we found that MVA supplementation induced granulosa cells to synthesize FPP, which was subsequently transferred to aged oocytes. Transported FPP increased the prenylation of small GTPases, including CDC42 and RAC1, and promoted membrane localization of CDC42-N-WASP-Arp2/3 and RAC1-WAVE2-Arp2/3 complexes, promoting cortical F-actin reassembly and reducing aneuploidy of aged oocytes. We also identified a natural chemical compound, 8-isopentenyl flavone, with an isopentenyl side chain from Epimedium brevicornu Maxim, which could increase CDC42 and RAC1 prenylation, improving the cortical F-actin and the competence of aged oocytes, and ameliorating reproductive outcomes in aged female mice. Collectively, increasing the prenylation of small GTPases via MVA metabolites or 8-isopentenyl flavone provides a therapeutic approach for boosting female fertility during reproductive aging.

Nucleoside Reverse Transcriptase Inhibitors (NRTIs), widely used to treat HIV and hepatitis B, have recently been shown to possess anti-inflammatory properties by inhibiting inflammasome activation. Epidemiological studies have revealed a significantly reduced incidence of age-related diseases, such as Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM), among patients chronically treated with NRTIs, but not with other classes of antiretroviral drugs. In this short review, we explore the mechanistic and clinical evidence linking NRTIs to reduced inflammaging, with particular attention to their effects on endogenous retroelements such as LINEs, SINEs and human endogenous retroviruses (HERVs). These elements, increasingly active with age, contribute to sterile inflammation and disease progression. NRTIs may mitigate this process by blocking reverse transcriptase-dependent formation of RNA:DNA hybrids and other immunostimulatory nucleic acid species. Although mitochondrial toxicity has been a concern, it mainly applies to older NRTIs and is much less pronounced with newer, safer compounds. NRTIs thus represent a compelling case for drug repurposing in the context of age-related diseases. Efforts should be devoted to developing new drugs that overcome NRTIs side effects and retain the anti-inflammaging properties of the parent drugs.

Gastrointestinal nematode infections elicit robust type 2 immune responses that facilitate rapid parasite expulsion. Our previous studies demonstrated that 18-month-old mice exhibit both impaired nematode clearance and reduced type 2-cytokine production, suggesting that aging diminishes the host's potential to mount effective immune defenses. To further investigate the underlying mechanisms, we compared young (3 months old) and aged mice (18 months old) infected with the nematode Heligmosomoides polygyrus (Hp), focusing on the interplay between type 2 immune responses and intestinal ecology. Hp infected young mice exhibited increased expression of Th2 cytokines (e.g., il-4) and short-chain fatty acid (SCFA) receptors GPR41/GPR43, while these responses were markedly diminished in aged mice. Correspondingly, cecal SCFA levels-particularly acetate and propionate-increased in Hp infected young mice but decreased in aged counterparts. Moreover, Hp infection induced a pronounced shift in the cecal microbiota composition of young mice, notably a reduced Bacillota/Bacteroidota ratio (F/B) ratio, a change much less evident in aged mice. These findings suggest that the age-related decline in type 2 immune responses to gastrointestinal nematode infection is linked to reduced gut microbiota responsiveness, which may compromise host resistance to the gastrointestinal parasites.

Targeted regulation of 70 kilodalton Heat Shock Protein (HSP70) chaperones, particularly the essential cognate heat shock protein (HSC70) and its Caenorhabditis elegans ortholog, HSP-1, may hold the key to improving cellular proteostasis and ameliorating aging-associated conditions linked to protein misfolding and aggregation. However, tools to selectively modulate HSP70 chaperone activity remain elusive. In this study, we pioneer the development of two novel nanobodies, B12 and H5, which specifically bind to both recombinant and endogenous HSP-1. We show that these nanobodies, differing by only two amino acids in their complementarity-determining regions, bind specifically to HSP-1 and effectively reduce both HSP-1 ATPase activity and protein folding capacity in a dose-dependent manner in vitro. We further demonstrate in vivo expression of B12, but not H5, in transgenic C. elegans strains reduces heat-stress survival and proteotoxic-stress resistance, mirroring the effects of hsp-1 knockdown via RNA interference. Our findings suggest that these nanobodies can serve as effective and specific tools for modulating HSP-1 chaperone activity in vivo. These discoveries provide a foundation for future research exploring the therapeutic potential of HSP70-targeting nanobodies in aging and protein misfolding diseases.

There is growing interest in the use of molecular features as predictors of age, age-related disease risk and mortality. A major shortcoming of this field, however, is the lack of suitable translational research models to identify and understand the underlying mechanisms of these predictive biomarkers in human populations. In particular, we lack a system which, like humans, is genetically variable, lives in diverse environments, and experiences aging-related chronic conditions treated in the context of a sophisticated health care system. Here, we present results from our analysis of data from the Dog Aging Project (DAP), a long-term longitudinal study of aging in companion dogs. Using longitudinal survival models on data from 937 dogs of the deeply phenotyped Precision Cohort within the DAP, we present the striking finding of a strong, highly significant positive correlation between the effect of individual metabolites on all-cause mortality in humans, and the association of those same metabolites on all-cause mortality in dogs. We also find that across these independent human studies, the biomarkers identified are also highly correlated, strongly suggesting a general signature of mortality within the plasma metabolome across humans, and now in dogs as well. Given the many similarities between dogs and humans with respect to genetics, environment, disease, and disease treatment, and the fact that dogs are so much shorter lived than humans, we argue that dogs represent an extremely valuable translational model in our ongoing effort to understand the underlying molecular causes and consequences of age-related morbidity and mortality in humans.

Interventions that extend lifespan in animal models could, in principle, decelerate the aging process as a whole. Alternatively, they could act by suppressing one or more individual late-life pathologies that contribute to mortality. Here we show how, in the nematode Caenorhabditis elegans, late-life pathologies can compete in a hierarchical fashion to cause death, such that removal of one cause of death can unmask another. Under standard culture conditions, a major cause of death in elderly C. elegans is infection by their bacterial food source. We report that only when such infection is prevented is lifespan extended by suppression of a second senescent pathology, teratoma-like uterine tumors. Thus, as in mammals, lifespan in wild-type C. elegans can be limited by naturally-occurring neoplasia. By contrast, blocking bacterial infection attenuated the life-shortening effects of vitellogenesis, and did not unmask a life-shortening effect of distal gonad degeneration. Thus, depending on the masking or unmasking of competing causes of mortality in the hierarchy of causes of death, nematode lifespan limitation in different contexts can reflect action of distinct life-limiting senescent pathologies. This underscores how increases in lifespan do not necessarily reflect a reduction in overall aging rate.

The fast-paced improvements in mortality in high-income countries since the early 1900s have led to a sustained increase in life expectancy. However, whether this linear trend will continue or life expectancy gains will decelerate in the near future remains unclear. To answer this question, we apply multiple established and recently developed mortality forecasting methods to estimate cohort life expectancy for individuals born between 1939 and 2000 in 23 high-income countries. Across all forecasting methods, our results robustly and consistently indicate a deceleration in cohort life expectancy. The previously observed pace of improvement, 0.46 y per cohort, declines by 37% to 52%, depending on the method used. Robustness checks suggest that these findings are unlikely to be solely due to downward bias in cohort life expectancy forecasts. Furthermore, an age-decomposition analysis indicates that this deceleration is primarily driven by a slower pace of mortality improvement at very young ages. Over half of the total deceleration is attributable to mortality trends under age 5, while more than two-thirds is explained by mortality trends under age 20. This pattern had already emerged in the observed data for the cohorts included in our analysis. Thus, even if these estimates turned out to be overly pessimistic, it is unlikely that the deceleration will reverse in the near future.

Mitochondria are crucial for cell survival and function, partly through peptides encoded by the mitochondrial genome. Although mitochondrial dysfunction is a hallmark of age-related diseases and senescence, the role of mitochondrial-genome-encoded peptides in pancreatic β-cell senescence during type 1 and type 2 diabetes pathogenesis is largely unexplored. Here we show that MOTS-c levels decrease with aging and senescence in pancreatic islet cells. Treating aged C57BL/6 mouse pancreatic islets with MOTS-c reduced pancreatic islet senescence by modulating nuclear gene expression and metabolites involved in β-cell senescence. MOTS-c treatment improved pancreatic islet senescence and glucose intolerance in S961-treated C57BL/6 and in nonobese diabetic mice. In humans, circulating MOTS-c levels are lower in type 2 diabetes patients compared with healthy controls. Our findings suggest that mitochondrial-encoded MOTS-c regulate pancreatic islet cell senescence and that MOTS-c could act as a senotherapeutic agent to prevent pancreatic islet cell senescence and diabetes progression.

Diabetic retinopathy (DR) is the leading cause of blindness among working-age adults, yet its pathogenesis remains incompletely understood. The retinal pigment epithelium (RPE) plays a vital role in maintaining retinal homeostasis. In this study, the expression of senescence marker protein p16 is observed to be upregulated in the RPE of early DR mouse models. Transcriptomic profiling reveals that PDZ domain protein 1 (PDZK1) expression is downregulated in RPE cells after 48 hours of high-glucose stimulation. Overexpression of PDZK1 reduces senescence markers in RPE cells, promoting cell proliferation and transport functions. Mechanistically, PDZK1 alleviates RPE cell senescence by interacting with 14-3-3ε to regulate the mTOR pathway, which is closely related to reducing oxidative stress and enhancing autophagy flux. In streptozotocin-induced DR mouse models, both PDZK1 overexpression-mediated senescence inhibition and Nutlin-3a-induced clearance of senescent RPE cells successfully downregulate retinal senescence markers and improve early-stage DR lesions. In summary, this study identifies a novel PDZK1-14-3-3ε-mTOR axis governing high-glucose-induced RPE cell senescence, and provides the first direct evidence linking RPE cell senescence to DR pathogenesis. These findings reveal a promising therapeutic strategy for DR intervention.

Sarcopenia profoundly impacts the quality of life and longevity in elderly populations. Notably, alterations in thyroid hormone (TH) levels during ageing are intricately linked to the development of sarcopenia. In skeletal muscle, the primary action of TH is mediated through the thyroid hormone receptor alpha (TRα). Emerging evidence suggests that decreased TRα expression may precipitate mitochondrial dysfunction in ageing skeletal muscle tissues. Yet, the precise mechanisms and the potential causative role of TRα deficiency in sarcopenia are not fully understood. This study suggests that TRα may regulate mitochondrial calcium (Ca

Older adults often show improved emotional regulation with age, a phenomenon known as the aging paradox. This age-related increase in emotional regulation capacity is attributed to enhanced prefrontal cortex control over amygdala reactivity. However, because racial discrimination and economic disadvantage cause chronic stress, typical age-related neural associations may be altered in marginalized groups. Using task-functional MRI data from 8,711 UK Biobank participants aged 50-78, we investigated whether age-related associations in emotion-related brain function, specifically amygdala activation and vmPFC-amygdala connectivity, varied across racial and socioeconomic status (SES) groups. We found that older age was associated with decreased amygdala activation, which is consistent with improved emotional regulation. Yet, lower socioeconomic status was associated with increased amygdala activation, suggesting heightened stress-related reactivity. No significant age-related effects on vmPFC-amygdala connectivity were observed at the population level. Black participants showed a stronger age-related decline in functional connectivity compared to other racial groups. These findings call for more inclusive and diverse neuroimaging studies to better understand brain health across marginalized groups.

Emerging digitally delivered non-pharmacological interventions (dNPIs) offer scalable, low-risk solutions for enhancing cognitive function in older adults, yet their effectiveness remains inconsistent due to a lack of personalization and precise mechanisms of action. Generic, population-based designs often fail to predict individual gains, underscoring the need for more tailored approaches. To address this, we propose a closed-loop human-machine interface (HMI) framework for personalizing dNPIs by optimizing the engagement of neurocognitive resources for cognitive enhancement. Our framework tackles three major challenges: (1) comprehensive and effective neurobehavioral representations for cognitive decoding, (2) tailoring interventions for domain-specific cognitive processes, and (3) ensuring aging-friendly design on usability, validity, and reliability for long-term adherence. We provide reviews and perspectives to guide the development of closed-loop HMIs by outlining the operational details of three key components-sensor, controller, and external actuator-that monitor, analyze, and modulate neurobehavioral activities through real-time adaptive interventions. Centering on neurobehavioral characteristics of older adults, we propose to advance closed-loop HMIs toward (1) deploying multimodal sensor network that captures activities from both central and peripheral nervous systems, (2) artificial intelligence (AI)-powered cognitive decoding and modulation that integrates multi-modal easy-to-acquire neurobehavioral signals and predicts the cross-modal harder-to-acquire signals, and (3) targeting neurobehavioral processes via internal and/or external regulation. We envision that the proposed closed-loop HMI framework could provide personalized dNPI with enhanced effectiveness and scalability for cognitive enhancement in older adults, promoting brain resilience and healthy longevity in the aging population.

Insulin related hormones regulate key life processes in the animal kingdom, from metabolism to growth, lifespan and aging, through an evolutionarily conserved insulin and insulin-like hormones signalling axis (IIS). In humans the IIS axis is controlled by insulin, two Insulin like Growth Factors, two isoforms of the insulin receptor (hIRA and hIRB), and its homologous IGF1R. In Drosophila, this signalling engages seven insulin-like hormones (DILP1 to 7) and a single receptor (dmIR) that follows the blueprint of hIR/hIGF1R. This report describes two cryoEM structures of the dmIR ectodomain dmIRECD:DILP2 complex, revealing their structural homology with dmIR:DILP5 complex. The high excess of DILP2 yielded two dmIRECD complexes in asymmetric conformations, similar to that observed in some complexes of hIR and in the dmIR-ECD:DILP5 complex. This stoichiometric and structural heterogeneity, yielding one- and two-DILP2:receptor complexes were not observed in DILP5:dmIR-ECD assembly. Also, the resistance of dmIR-ECD to form more DILP2 saturated complexes, despite very high excess of this hormone, suggest that the specificities of DILPs may lie in their kon/koff kinetic parameters. This work expands understanding of the dmIR conformational flexibility, suggesting also that insect dmIR follows more hIR rather than hIGF1R receptor signal transduction pattern induced by various DILPs.

Imbalances in nicotinamide adenine dinucleotide (NAD