Longevity Papers

Aging is a critical factor in the onset and progression of neurodegenerative diseases and cognitive decline, with aging-related neuroinflammation and cellular senescence being major contributors. In the aging brain, the cerebral vascular endothelium overexpresses vascular cell adhesion molecule 1 (VCAM1), activating microglia and leading to neuroinflammation and cognitive impairment. Quercetin, a natural neuroprotective agent widely used for treating neurodegenerative diseases, their therapeutic efficacy, however, is limited by its poor water solubility and inability to penetrate the blood-brain barrier (BBB). To address these challenges, we developed a multifunctional micellar platform (Anti-VCAM1-GM1@Q) to improve age-related neurodegenerative diseases. The micelles incorporate anti-VCAM1 antibodies to target cerebral vascular endothelial cells and block VCAM1. Additionally, monosialoganglioside (GM1) was utilized to deliver quercetin due to its biparental properties, high BBB permeability, and neuroprotective effects. Anti-VCAM1-GM1@Q micelles demonstrated strong anti-aging properties. They improved quercetin's bioavailability, effectively penetrated the BBB, targeted cerebral vascular endothelial cells, and reduced neuroinflammation. In animal models, these micelles provided effective neuroprotection, improved memory function and age-related cognitive impairment, and mitigated age-related neurodegeneration. Notably, this system exhibited remarkable treatment efficacy and high safety, indicating substantial potential for clinical translational applications.

The global aging population has increased dynapenia prevalence, leading to mobility issues and poor sleep quality among older adults. Despite its impact, research on sleep quality in dynapenic outpatients is limited. This study investigates how physiological status, community participation, and daily activity function influence sleep quality in this group.

Cellular senescence has emerged as one of the central hallmarks of aging and drivers of chronic comorbidities, including periodontal diseases. Senescence can also occur in younger tissues and instigate metabolic alterations and dysfunction, culminating in accelerated aging and pathological consequences. Senotherapeutics, such as the combination of dasatinib and quercetin (DQ), are being increasingly used to improve the clinical outcomes of chronic disorders and promote a healthy life span through the reduction of senescent cell burden and senescence-associated secretory phenotype (SASP). Recent evidence suggests that senescent cells and SASP can contribute to the pathogenesis of periodontal diseases as well. In this study, we investigated the effect of DQ interventions on periodontal tissue health using preclinical models of aging. In vitro, DQ ameliorated biological signatures of senescence in human gingival keratinocytes upon persistent exposure to periodontal bacteria,

During the early stage of tissue injury, macrophages play important roles in the activation of stem cells for further regeneration. However, the regulation of macrophages during bone regeneration remains unclear. Here, the extracellular matrix (ECM) tenascin-C (TNC) is found to express in the periosteum and recruit inflammatory macrophages. TNC-deficiency in the periosteum delays bone repair. Transplantation of macrophages derived from injured periosteum is able to rescue the decreased skeletal stem cells and impaired bone regeneration caused by TNC deficiency. The cell communication analysis identifies ITGA7 as a TNC receptor contributing to the recruitment of inflammatory macrophages. TNC expression declines in aged mice and the exogenous delivery of TNC significantly promotes bone regeneration after aging through the recruitment of macrophages. Taken together, this study reveals the regulation of macrophage recruitment and its function in the activation of skeletal stem cells after bone injury, providing a strategy to accelerate bone regeneration by TNC delivery.

Sarcopenia is an age-related disease that is related to nutritional intake and chronic low-grade inflammation. The aim of this study was to investigate the association of dietary intake, inflammatory markers and sarcopenia among the community-dwelling older adults.

A decline in skeletal muscle mass and function known as skeletal muscle sarcopenia is an inevitable consequence of aging. Sarcopenia is a major cause of decreased muscle strength, physical frailty and increased muscle fatigability, contributing significantly to an increased risk of physical disability and functional dependence among the elderly. There remains a significant need for a novel therapy that can improve sarcopenia and related problems in aging. Iron accumulation, especially catalytic iron (labile iron) through increased oxidative stress, could be one of the contributing factors to sarcopenia. Our study aimed to examine the effect of an iron chelator on age-related sarcopenia in mice.

Aging is the strongest risk factor for Alzheimer’s disease (AD). Accordingly, identifying biomarkers of accelerated aging is a major focus of AD prevention research. Current MRI‐based “aging clocks” (i.e., brain age) derive from cross‐sectional associations with chronological age. However, chronological age differs fundamentally from biological aging. We introduce a novel brain MRI proxy for biological aging in midlife developed in the Dunedin Study, a population‐representative longitudinal birth cohort, and demonstrate its ability to differentiate and predict AD in the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

Protein aggregation is a hallmark of neurodegenerative diseases and is also observed in the brains of elderly individuals without such conditions, suggesting that aging drives the accumulation of protein aggregates. However, the comprehensive understanding of age-dependent protein aggregates involved in brain aging remains unclear. Here, we investigated proteins that become sarkosyl-insoluble with age and identified hyaluronan and proteoglycan link protein 2 (HAPLN2), a hyaluronic acid-binding protein of the extracellular matrix at the nodes of Ranvier, as an age-dependent aggregating protein in mouse brains. Elevated hyaluronic acid levels and impaired microglial function reduced the clearance of HAPLN2, leading to its accumulation. HAPLN2 oligomers induced microglial inflammatory responses both in vitro and in vivo. Furthermore, age-associated HAPLN2 aggregation was also observed in the human cerebellum. These findings suggest that HAPLN2 aggregation results from age-related decline in brain homeostasis and may exacerbate the brain environment by activating microglia. This study provides new insights into the mechanisms underlying cerebellar aging and highlights the role of HAPLN2 in age-associated changes in the brain.

The human brain integrity relies on the synergistic interplay between neural activity and supporting vascular and metabolic processes throughout life. This relationship, ruled by allostatic mechanisms, regulates brain architecture and activity. White matter hyperintensities (WMH) serve as indicators of the vascular impact on brain structure. While the strong association between vascular/metabolic systems and brain structure/function is established, the precise mechanisms linking allostasis to WMH remain elusive. We hypothesized that allostasis influences white matter through neuroinflammatory mechanisms, and WMH mediate neuroinflammatory effects on EEG measures.

Epigenetic clocks are biomarkers of biological age based on DNA methylation (DNAm) patterns and are widely used as predictors of health and aging outcomes. Multiple epigenetic clocks have been developed and reflect different aspects of the multidimensional aging process, above and beyond chronological age. To date, no study has examined the relationship of epigenetic aging with circulating biomarkers of Alzheimer’s Disease (AD). We investigated the association of 6 epigenetic clocks with plasma glial fibrillary acidic protein (GFAP), amyloid beta 40 and 42, phosphorylated tau 181 (p‐tau181), and neurofilament light chain (NfL) in diverse Hispanic/Latino adults.

Central arterial stiffening is associated with brain white matter (WM) damage and gray matter (GM) volume loss in older adults, but little is known about this association from an adult lifespan perspective.

In single cells, variably sized nanoscale chromatin structures are observed, but it is unknown whether these form a cohesive framework that regulates RNA transcription. Here, we demonstrate that the human genome is an emergent, self-assembling, reinforcement learning system. Conformationally defined heterogeneous, nanoscopic packing domains form by the interplay of transcription, nucleosome remodeling, and loop extrusion. We show that packing domains are not topologically associated domains. Instead, packing domains exist across a structure-function life cycle that couples heterochromatin and transcription in situ, explaining how heterochromatin enzyme inhibition can produce a paradoxical decrease in transcription by destabilizing domain cores. Applied to development and aging, we show the pairing of heterochromatin and transcription at myogenic genes that could be disrupted by nuclear swelling. In sum, packing domains represent a foundation to explore the interactions of chromatin and transcription at the single-cell level in human health.

Aging is associated with sustained low-grade inflammation, which has been linked to age-related diseases and mortality. Long-term exercise programs have been shown to be effective to for attenuating this process; however, subsequent detraining might negate some of these benefits. Master athletes, as a model of lifelong consistent exercise practice, have been suggested to present similar inflammatory profiles to untrained young adults. Nonetheless, it is unclear whether maintaining training habits throughout life can completely counteract low-grade inflammation associated with aging.

SuperAgers—individuals age 80+ with episodic memory performance at least as good as those 20‐30 years younger—provide a unique perspective on cognitive resilience and resistance in aging. The SuperAging Research Initiative (SRI), spearheaded by The University of Chicago and involving multiple academic partners, investigates factors underpinning robust cognitive aging. One key SRI project, leverages a fully remote data collection paradigm to: 1) discern activity patterns that characterize SuperAgers and 2) explore the 'complexity hypothesis in aging'—whether dynamic physiological responsiveness is a hallmark of exceptional cognitive aging. Here we report on feasibility and initial outcomes from this project.

Brain aging is a complex process influenced by various genetic, lifestyle, and environmental factors, as well as by age‐related and often co‐existing pathologies. MRI and AI methods have been instrumental in understanding neuroanatomical changes that occur during aging in large and diverse populations.

KLOTHO‐VS heterozygosity (KL‐VS

Adult neural stem cells are

Physical activity (PA) is associated with lower dementia risk; however, underlying molecular pathways are poorly understood. We leveraged large‐scale plasma proteomics to identify biological signatures of objectively‐monitored PA in cognitively unimpaired (CU) older adults and cross‐validated signatures in independent exercise intervention and Alzheimer’s disease (AD) cohorts.

Aging and chronic inflammation are associated with overabundant myeloid-primed multipotent progenitors (MPPs) among hematopoietic stem and progenitor cells (HSPCs). Although hematopoietic stem cell (HSC) differentiation bias has been considered a primary cause of myeloid bias, whether it is sufficient has not been quantitatively evaluated. Here, we analyzed bone marrow data from the IκB- (Nfkbia+/-Nfkbib-/-Nfkbie-/-) mouse model of inflammation with elevated NFκB activity, which reveals increased myeloid-biased MPPs. We interpreted these data with differential equation models of population dynamics to identify alterations of HSPC proliferation and differentiation rates. This analysis revealed that short-term HSC differentiation bias alone is likely insufficient to account for the increase in myeloid-biased MPPs. To explore additional mechanisms, we used single-cell RNA sequencing (scRNA-seq) measurements of IκB- and wild-type HSPCs to track the continuous differentiation trajectories from HSCs to erythrocyte/megakaryocyte, myeloid, and lymphoid primed progenitors. Fitting a partial differential equations model of population dynamics to these data revealed not only less lymphoid-fate specification among HSCs but also increased expansion of early myeloid-primed progenitors. Differentially expressed genes along the differentiation trajectories supported increased proliferation among these progenitors. These findings were conserved when wild-type HSPCs were transplanted into IκB- recipients, indicating that an inflamed bone marrow microenvironment is a sufficient driver. We then applied our analysis pipeline to scRNA-seq measurements of HSPCs isolated from aged mice and human patients with myeloid neoplasms. These analyses identified the same myeloid-primed progenitor expansion as in the IκB- models, suggesting that it is a common feature across different settings of myeloid bias.

The neural basis of memory aging remains elusive. The default mode network (DMN) supports memory encoding and retrieval, and its connectivity decreases in aging. Young adults with larger differences in resting‐state functional connectivity (rsFC) between higher‐order DMN and lower‐order sensory/motor network (SMN) have better cognition and memory. We combined resting‐state and task‐based fMRI during an associative memory task to explore how this cross‐hierarchical contrast of rsFC is linked to memory aging.

The ability to define neurodegenerative diseases of aging based of biology rather than clinically defined syndromic presentations follows from biomarker development and reflects underlying pathology in living people. The NIA‐AA Research Framework (Jack et al 2018 Alzheimers Dement) proposed the biological definition for Alzheimer’s disease (AD) and sought to provide a common language to identify and stage research participants, who were not cognitively impaired but had abnormal AD biomarkers; it has been revised. The biological classification of Huntington’s disease (Tabrizi et al 2022 Lancet Neurology) included a biological research definition with an integrated staging system, centered on biological, clinical, and functional assessments. Simuni et al (2024 Lancet Neurology) proposed the Neuronal Synuclein Disease (NDS) biological definition, also with integrated staging system, encompassing anyone with biomarker evidence of predominantly neuronal alpha‐synuclein pathology, including people with Parkinson’s disease, dementia with Lewy bodies, or related clinical phenotypes, based on the seed amplification assay biomarker. A key paradigm shift central across these neurodegenerative diseases is diagnosis is not based on the clinical manifestations, but rather disease occurs and can be diagnosed regardless of specific, or in some cases without any, clinical signs or symptoms. It’s recognized these disease processes begin before the onset of symptoms, possibly decades before. Thus, these biological definitions translate this long‐touted recognition into actional research frameworks. There are numerous implications for such a paradigm shift. For one, this allows people to enroll in clinical studies and in clinical trials before the manifestation of classic clinical syndromes, and is likely the only way to test potential therapies for indications that prevent clinical symptoms in people with underlying disease. Further, by separating the syndrome from biology, these definitions recognize that syndromic presentations are not always specific for the underlying pathology, addressing the ongoing challenge of clinical heterogeneity in trials. Another implication of these biological definitions is the co‐occurrence of multiple pathologies, a long under‐recognized entity, can be prospectively studied in living people across the entire clinical spectrum from asymptomatic to severe functional impairment. As these biological definitions iterate upon newly obtainable and validated biomarker data from observational cohorts a more complete molecular characterization of neurodegeneration in aging, independent of syndromic classification, can begin to emerge.

No study has synthesized evidence from randomized controlled trials (RCTs) testing the acute and chronic effects of reallocating sedentary time (ST) to physical activity (PA) on cognitive and brain health across the lifespan.

Animal models provide a valuable basis for identification of conserved pathological substrates and processes underlying age‐related diseases as well as neurobiological features supporting cognitive resilience in the aging brain. Behavioral measures are a fundamental component in the assessment of cognitive processes but are rarely standardized across laboratories. Currently, there is a scarcity of centralized and standardized data infrastructure for behavioral experiment data collected across laboratories which presents a barrier for data sharing, hypothesis generation, and collaboration. A key goal of the Reserve and Resilience Collaboratory has been to create consensus approaches and definitions for the study of cognitive aging. We have designed a standard reporting framework and a centralized database across several labs.

Previous studies have documented age‐related changes in behavior and cognitive functions and investigated the molecular changes in aging brain using inbred mouse strains such as C57BL/6, BALB/c etc. In this study using a genetically heterogenous mouse population (UM‐HET3) we investigated age‐related changes in motor and memory functions and their association with blood cell measures.

The SuperAging Research Initiative (SRI) seeks to identify factors that promote cognitive healthspan. SuperAgers are defined as individuals aged 80 and older with episodic memory performance that is at least average for people who are two to three decades younger. A goal of the SRI is to identify the genomic contributors to SuperAging and herein we describe the interim results of DNA‐ and plasma protein‐based analyses.

The choroid plexus (CP), a vital component in the brain’s ventricles, is crucial for cerebrospinal fluid (CSF) production and maintenance of the brain’s physiological environment. It plays a key role in regulating neuroinflammatory responses, clearing harmful substances, producing neurotrophic factors and signaling molecules, and forming blood‐CSF barrier. Consequently, changes to the CP’s structural integrity could disrupt brain homeostasis and lead to cognitive impairment. Indeed, recent research has highlighted CP alterations in aging as well as in various cognitive disorders including Alzheimer’s and Parkinson’s diseases. This study investigates the correlation between the macrostructural and microstructural integrity of the CP and longitudinal cognitive changes in cognitively unimpaired individuals.

Physical activity (PA) is associated with increased release of brain derived neurotrophic factor (BDNF), a mechanism that may underlie protective effects of PA on cognitive and brain aging. The Met allele of the BDNF Val66Met single‐nucleotide polymorphism reduces activity‐dependent BDNF release and is associated with increased phosphorylated tau (p‐tau181) in dementia populations. We sought to determine whether BDNF Val66Met influences the effects of PA on plasma p‐tau181 and cognition in older adults without dementia.

Atypical presentations of Alzheimer’s disease (AD), which demonstrate more cortical involvement relative to medial temporal lobe (MTL), are generally associated with younger age of onset. Age, defined chronologically, is a primary driver of AD pathology and neurodegeneration. However, some young onset cases are typical, amnestic presentations and some older onset cases present more cortical atrophy. We hypothesize that a biological definition of age, defined using epigenetic clock measures, may be even more tightly linked to atypicality than chronological age.

Insulin Resistance (IR) is implicated in brain aging and Alzheimer’s disease (AD) pathogenesis. Dietary changes may promote brain health in older adults with metabolic abnormalities. An extensive animal literature suggests pro‐cognitive and beneficial systemic and brain effects of intermittent fasting (IF) that may mitigate AD risk. We conducted a randomized clinical trial comparing brain effects and the potential for AD biomarker modulation of IF and a continuous diet.

During normal aging, it has been observed that brain regional volume and thickness can be altered due to atrophy. While both 3 Tesla (3T) and 7 Tesla (7T) MRI are used to study such changes, it is unknown how individual brain morphology is characterized differently when 7T MRI allows for higher‐resolution and higher tissue contrast images. In this study, we employ a large cohort of healthy subjects that have undergone both 3T and 7T MRI scans to investigate how 7T MRI improves correlation strength between brain morphometrics and aging.

There is growing recognition that exercise is a potent stimulus for improving cognitive and brain function in both humans and rodents. While the mechanisms underlying the effect of exercise on cognition are very likely multifactorial, it is clear that the secretion and function of several classical factors are involved. Work done in rodents implicates several growth factors, including BDNF, IGF‐1, and VEGF, in the ability of exercise to induce neuroplastic changes within key brain regions associated with learning and memory. However, confirming these growth factors as mediators of exercise efficacy in human trials has been less successful. This is likely related to several things, including a disconnect between human and rodent exercise studies in terms of design and analysis. We suggest that biological sex alone and in interaction with important genetic polymorphisms implicated in cognitive decline as vital moderating factors that must be considered in the search for exercise biomarkers. A sex difference exists in exercise efficacy for cognition, with older females showing greater benefits for executive functions than older males. The ε4 variant of the apolipoprotein E (

The brain undergoes structural changes during aging, such as gray matter loss, enlarged ventricles, and sulcal widening. However, previous studies have primarily investigated these changes in isolation, without describing the complex spatial relationships between overall brain shape and regions. Here, we tested how gradients of expansion and compression of the global shape of the brain as well as between homologous brain regions across hemispheres are affected by age, and whether these changes further contribute to clinical impairment and cognitive deficits in older adults.

Alterations in grey matter (GM) are known to contribute to cognitive decline in aging and dementia. Recent evidence suggests that individuals with higher cardiorespiratory fitness (CRF) may have a lower risk of GM atrophy and subsequent cognitive decline. However, the role of cortical myelination in cognitive decline and its association with CRF remains elusive. We used two microstructure MRI measures: MWF, which is a direct measure of myelin content, and R1, which is sensitive to lipids, the main constituents of myelin, to first, investigate the relationship between myelination and longitudinal changes in cognition, and second, determine whether higher CRF is associated with higher myelination in cortical regions.

Calculating an individual’s risk for preclinical and symptomatic Alzheimer disease (AD) involves considering their experiences across the lifespan. This includes assessment of childhood experiences as risk factors for dementing disorders in later life.

Persons with prediabetes and type 2 diabetes (T2D) are known to have higher risk of cognitive impairment (CI), including age‐related cognitive decline, mild cognitive impairment (MCI), and dementia; however, the characteristics of CI and the determinants and mechanisms in prediabetes and T2D remain unclear. Addressing these gaps is critical since over half of the U.S. population aged 60 years and older, who are at risk for AD/ADRD, have prediabetes or T2D.

Alzheimer’s disease (AD) has a typical age of onset exceeding 65 years. The age‐dependency of the condition led us to track the appearance of DNA damage in the frontal cortex of individuals who died with a diagnosis of AD. The focus on DNA damage was motivated by evidence that increasing levels of irreparable DNA damage are a major driver of the aging process. This connection between aging and genomic integrity is compelling because DNA damage has also been identified as a possible cause of cellular senescence. The number of senescent cells increase with ages, and their senescence‐associated secreted products likely contribute to age‐related illnesses.

Up to 40% of current AD cases may have been preventable through protective factors, such as physical and cognitive activities, preventing neurodegeneration. Reserve, resilience, and resistance are key concepts in cognitive neuroscience of aging, and they share common adaptive mechanisms. In this paper we propose a development and validation of a new scale, called dynamic Neurocognitive Adaptation (dNA).

I will look at the impact of new language acquisition on cognitive performance and reserve in older adults, an area not extensively explored in contrast to the well‐documented cognitive benefits in lifelong bilinguals. Previous research has shown that lifelong bilingualism may enhance cognitive reserve, evidenced by better performance on specific tasks of executive function, reflecting superior cognitive control and interference management in aging (Van den Noort, et al., 2019). Drawing on the cognitive demands of language learning, which include executive functions such as inhibition, selection, and conflict management (Ghazi Saidi et al., 2013; 2017a; 2017b), we and others hypothesize that new language learning in older adults can boost these cognitive processes, which often decline with age (Albinet, et al., 2012; Lee & Chung, 2012).

Molecular omics studies of aging brains have identified genes and proteins related to cognitive decline. Identifying proteins that are linked to specific cognitive abilities has potential to catalyze the development of targeted therapies for specific cognitive deficits. Posttranslational modifications of proteins with glycans modify protein function. Here, we identified glycopeptiforms associated with decline in specific cognitive domains.

Measures of cardiovascular health have long been associated with brain health. For example, aerobic capacity (VO2max) is associated with preservation of functional and structural brain integrity in later life. Recent work has highlighted the utility of relative brain age (RBA; the age‐corrected difference between a brain’s chronological and estimated biological ages) to examine the rate of biological brain aging. However, the impact of cardiovascular factors on RBA remains underexplored. Here, we examine estimates of biological brain aging (via RBA) in the context of two key measures of cardiovascular health: aerobic fitness (VO2max), and heart rate variability (HRV) ‐ a measure of autonomic regulation associated with cognitive control, emotional regulation, and risk of neurological conditions, including dementia.

The global population of adults over the age of 65 is expected to surpass 2 billion by 2050. Alongside this rise in the aging population, the incidence of age‐related cognitive decline and dementia will continue to grow. Importantly, women are at an elevated risk of cognitive decline compared to men. Therefore, it is imperative to identify modifiable risk and protective factors for aging women. The Lancet Commission highlighted low social contact as a modifiable risk factor for dementia and the Scaffolding Theory of Aging and Cognition‐Revised suggests potential neural structural benefits of such sources of enrichment. Structural neuroimaging allows for the examination of grey matter volume directly, in vivo. It was hypothesized that women with greater social interaction would demonstrate greater grey matter volume.

Although previous studies have demonstrated cognitive impairment in elderly individuals with sarcopenia and its neuronal substrates, there is no comprehensive model integrating multiple brain pathologies to predict cognitive impairment associated with sarcopenia. The aim of this study was to explore a comprehensive prediction model for cognitive impairment in sarcopenia using multimodal neuroimaging methods in non‐demented older adults.

Previous studies have reported that poor sleep quality is associated with several adverse outcomes including multimorbidity, particularly in the aging population. Another common occurrence in the elderly is frailty. We aim to study the mediating effect of objective physical frailty parameters on the association between sleep quality and multimorbidity in an aging rural Indian population.

Although physical activity (PA) has been linked to cognitive health, the nuanced relationships between different dimensions of PA and cognitive impairment remain inconclusive. This study investigated associations between late-life PA levels, midlife-to-late-life activity patterns, and cognitive impairment in Chinese older adults, considering potential moderation by apolipoprotein E (APOE) ε4 genotype.

Leukocyte telomere length (LTL) serves as a proxy for tissue‐specific TL and peripheral immune aging. Its association with aging‐related brain endophenotypes, cognitive functioning, and Alzheimer's disease (AD) risk is established, but the underlying molecular mechanisms remain elusive. Investigating LTL's association with AD biomarkers is crucial for identifying its role in brain resilience and disease progression.

Studies suggest that approximately 60 to 70 percent of the variability observed in cognitive abilities during aging can be attributed to genetic factors. Therefore, investigating the longitudinal multiomics changes associated with alterations in cognitive measures, such as the Mini‐Mental State Examination (MMSE) score, is of utmost importance.

Marital status is an important but often overlooked sociodemographic factor that could shape cognitive health in late adulthood. Being married is shown to be linked to lower risk of dementia, but less is understood about underlying mechanisms contributing to this relationship, such as brain reserve (BR) and cognitive reserve (CR). Further, less is known about how living arrangement, independent of marital status, is associated with late‐life cognition. The current study examines (1) associations between marital status, BR, and CR among diverse older adults and (2) whether living arrangement is linked to BR and CR among unmarried adults.

Frailty is a complex clinical state that is associated with poorer health outcomes and increased dementia risk in older adults. It is routinely measured using the Frailty Index, which is a proportional score based on the number of ‘deficits’ that an individual has. Whilst such measures are useful for risk assessment, the aggregation of highly heterogeneous deficit profiles in genetic studies may obscure important insights into the underlying biology of frailty.

Neutrophil extracellular traps (NETs) are large structures composed of chromatin, histones and granule-derived proteins released extracellularly by neutrophils. They are generally considered to be a part of the antimicrobial defense strategy, preventing the dissemination of pathogens. However, overproduction of NETs or their ineffective clearance can drive various pathologies, many of which are associated with advanced age and involve uncontrolled inflammation, oxidative, cardiovascular and neurodegenerative stress as underlying mechanisms. Targeting NETs in the elderly as an anti-aging therapy seems to be a very attractive therapeutic approach. Therapeutic apheresis with a specific filter to remove NETs could be a promising strategy worth considering.

The common marmoset (Callithrix jacchus) is an important animal model in neuroscience and neurological diseases, presenting primate‐specific evolutionary features such as an expanded frontal cortex. We established a new consortium with funding support from the National Institute on Aging to generate, characterize, and validate MArmosets as Research MOdels of AD (MARMO‐AD). This consortium develops and studies gene‐edited marmoset models carrying genetic risk for AD, comparing them against wild‐type aging marmosets from birth throughout their lifespan, using non‐invasive longitudinal assessments. Here, we aim to characterize healthy aging trajectories by investigating their resting state functional connectivity in a population of marmosets.

The decline of oocyte quality with advanced maternal age has a detrimental effect on female fertility. However, there is limited knowledge of therapeutic options and their mechanisms to improve oocyte quality in reproductively older women. In this study, we demonstrated that supplementation of salidroside improves the oocyte quality of reproductively old mice. Salidroside improved the maturation, fertilization, and developmental competence of oocytes from reproductively old mice by maintaining the normal spindle/chromosome structure and mitochondrial function. Oocyte transcriptomic and micro-proteomic analysis revealed that salidroside restores oocyte quality by enhancing mitophagy in reproductively old mice. Our studies provide a new theoretical foundation for utilizing salidroside to improve oocyte quality in reproductively old females in the context of natural fertility or assisted reproduction.

Many studies have demonstrated an association between sleep and cognition in older adults. The Long Life Family Study (LLFS) has followed families enriched with longevity since 2006 and has shown that this cohort has slower rates of cognitive decline than their spouse controls and the general public. Understanding how sleep and cognition are related in this population can improve our understanding of the key to long life.

To examine the association of social connections with blood leukocyte telomere length (LTL) and all-cause mortality in older Costa Ricans.

In prior work we identified cortical resilience proteins associated with the linear trajectories of cognitive decline independent of the effects of neuropathology. Some of these proteins were associated with slower and some with faster cognitive decline. We tested the hypothesis that the temporal onset and duration of effects of cortical resilience proteins associated with cognitive trajectories may vary in aging adults.

While physical activity is found to be associated with a lower risk of dementia in numerous studies, less is known whether this association varies over time. We aim to examine the potential time‐varying associations of physical activity with risk of dementia from midlife to late life.

Vascular risk factors are known contributors to cognitive decline and dementia; however, their impact on cognitive change in diverse samples is understudied. In this study, we investigated the effect of the AHA Life’s Simple 7 (LS7) on cognitive decline in the bi‐ethnic San Antonio Longitudinal Study of Aging (SALSA) cohort.

Although sex determination is a fundamental process in vertebrate development, it is very plastic. Diverse genes became major sex determinants in teleost fishes. Deciphering how individual sex-determining genes orchestrate sex determination can reveal new actors in sexual development. Here, we demonstrate that the Y-chromosomal copy of the TGF-β family member gdf6 (gdf6Y) in Nothobranchius furzeri, an emerging model organism in aging research, gained the function of the male sex determinant through allelic diversification while retaining the skeletal developmental function shared with the X-chromosomal gdf6 allele (gdf6X). Concerning sex determination, gdf6Y is expressed by somatic supporting cells of the developing testes. There it induces the male sex in a germ cell-independent manner in contrast to sex determination in zebrafish and the medaka. Looking for downstream effectors of Gdf6Y, we identified besides TGF-β signaling modulators, especially the inhibitor of DNA binding genes id1/2/3, the mRNA decay activator zfp36l2 as a new GDF6 signaling target.

Compared to men, insulin‐resistant women have more brain atrophy, cognitive impairment, and higher dementia risk, but the mechanisms for this sex difference are unknown. We examined sex differences in how blood insulin relates to cortical thickness in cognitively intact older adults. Gaining a better understanding of the relationship between insulin and brain health could help inform the development of insulin‐targeting treatments and reduce the risk of dementia associated with insulin resistance.

Physiological and mental functions decline as the person ages. However, studies have found that a group of people who are more than 80 years have better cognitive functioning than their peers and also similar to 2‐3 decades younger counterpart group. These people are termed as “Superagers”. Earlier research has revealed that handgrip strength can predict frailty and eventually decline in cognition in healthy individuals. It is important to determine the patterns of functioning and risk factors of these superagers to ensure a greater quality of life for them in the future. Therefore, this study aims to look for the patterns of handgrip strength among the superagers in comparison to the typical agers.

Aging is linked to significant white matter abnormalities, which are often studied using traditional diffusion tensor imaging (DTI) metrics; however, these traditional metrics have limited sensitivity/specificity to neurobiological characteristics. Here, we use fixel‐based analysis (FBA) – an approach with more precision in areas of crossing fibers – to study age‐related white matter microstructural decline.

Women’s reproductive experiences may enact reorganization of physiological systems with lifelong health consequences. We test the hypothesis that women’s history of breastfeeding will be positively associated with neurocognitive benefits in post‐menopausal women. This hypothesis is justified by breastfeeding’s well‐established benefits for mothers’ glucose homeostasis, beta‐cell function, adipose tissue mobilization, and lipid metabolism, which would plausibly be beneficial for later‐life brain health.

The African turquoise killifish Nothobranchius furzeri represents an emerging short-lived model for aging research. Captive strains of this species are characterized by large differences in lifespan. To identify the gene expression correlates of this lifespan differences, we analyzed a public transcriptomic dataset consisting of four different tissues in addition to embryos. We focused on the GRZ and the MZM0410 captive strains, which show a near twofold difference in lifespan, but similar growth and maturation and validated the results in a newly-generated dataset from a third longer-lived strain. The two strains show distinct transcriptome expression patterns already as embryos and the genotype has a larger effect than age on gene expression, both in terms of number of differentially expressed genes and magnitude of regulation. Network analysis detected RNA processing and histone modifications as the most prominent categories upregulated in GRZ that also showed idiosyncratic expression patterns such as high expression of DND is somatic tissues. The short-lived GRZ strain shows transcriptional aging signatures already at sexual maturity (anticipated aging) in all four tissues suggesting that short lifespan is the results of events that occur early in life rather than the progressive accumulation of strain-dependent differences. The GRZ strain is the most commonly used N. furzeri strain in intervention studies and our results warrant replication of at least key intervention studies in longer-lived strains.

Epigenetic clocks are a common group of tools used to measure biological aging-the progressive deterioration of cells, tissues, and organs. Epigenetic clocks have been trained almost exclusively using blood-based tissues, but there is growing interest in estimating epigenetic age using less-invasive oral-based tissues (i.e., buccal or saliva) in both research and commercial settings. However, differentiated cell types across body tissues exhibit unique DNA methylation landscapes and age-related alterations to the DNA methylome. Applying epigenetic clocks derived from blood-based tissues to estimate epigenetic age of oral-based tissues may introduce biases. We tested the within-person comparability of common epigenetic clocks across five tissue types: buccal epithelial, saliva, dry blood spots, buffy coat (i.e., leukocytes), and peripheral blood mononuclear cells. We tested 284 distinct tissue samples from 83 individuals aged 9-70 years. Overall, there were significant within-person differences in epigenetic clock estimates from oral-based versus blood-based tissues, with average differences of almost 30 years observed in some age clocks. In addition, most epigenetic clock estimates of blood-based tissues exhibited low correlation with estimates from oral-based tissues despite controlling for cellular proportions and other technical factors. Notably, the Skin and Blood clock exhibited the greatest concordance across all tissue types, indicating its unique ability to estimate chronological age in oral- and blood-based tissues. Our findings indicate that application of blood-derived epigenetic clocks in oral-based tissues may not yield comparable estimates of epigenetic age, highlighting the need for careful consideration of tissue type when estimating epigenetic age.

Ageing underlies functional decline of the brain and is the primary risk factor for several neurodegenerative conditions, including Alzheimer's disease (AD). However, the molecular mechanisms that cause functional decline of the brain during ageing, and how these contribute to AD pathogenesis, are not well understood. The objective of this study was to identify biological processes that are altered during ageing in the hippocampus and that modify Ad risk and lifespan, and then to identify putative gene drivers of these programmes. We integrated common human genetic variation associated with human lifespan or Ad from genome-wide association studies with co-expression transcriptome networks altered with age in the mouse and human hippocampus. Our work confirmed that genetic variation associated with Ad was enriched in gene networks expressed by microglia responding to ageing and revealed that they were also enriched in an oligodendrocytic gene network. Compellingly, longevity-associated genetic variation was enriched in a gene network expressed by homeostatic microglia whose expression declined with age. The genes driving this enrichment include CASP8 and STAT3, highlighting a potential role for these longevity-associated genes in the homeostatic functions of innate immune cells, and these genes might drive 'inflammageing'. Thus, we observed that gene variants contributing to ageing and AD balance different aspects of microglial and oligodendrocytic function. Furthermore, we also highlight putative Ad risk genes, such as LAPTM5, ITGAM and LILRB4, whose association with Ad falls below genome-wide significance but show strong co-expression with known Ad risk genes in these networks. Indeed, five of the putative risk genes highlighted by our analysis, ANKH, GRN, PLEKHA1, SNX1 and UNC5CL, have subsequently been identified as genome-wide significant risk genes in a subsequent genome-wide association study with larger sample size, validating our analysis. This work identifies new genes that influence ageing and AD pathogenesis, and highlights the importance of microglia and oligodendrocytes in the resilience of the brain against ageing and AD pathogenesis. Our findings have implications for developing markers indicating the physiological age of the brain and new targets for therapeutic intervention.

Age-related declines in cardiac function and exercise tolerance interfere with healthy living and decrease healthy life expectancy in older individuals. Tamogi-take mushrooms (Pleurotus cornucopiae) are known to contain high levels of Ergothioneine (EGT), an antioxidant with potential health benefits. In this study, we assessed the possibility that long-term consumption of Tamogi-take mushrooms might attenuate age-related decline in cardiac and vascular endothelial function in mice. We found that long-term intake of Tamogi-take mushrooms significantly maintained cardiac and vascular endothelial function and improved exercise tolerance in mice. Long-term mushroom consumption also increased levels of Nrf2 (Nuclear factor E2-related factor 2) protein in heart tissues and increased translation of HO-1 (Heme Oxygenase 1) proteins, which have antioxidant effects in heart and aortic tissues. Finally, long-term Tamogi-take mushroom consumption inhibited ROS accumulation with aging and reduced expression of inflammatory biomarkers. We conclude that ingestion of Tamogi-take mushrooms could serve as a dietary intervention to promote cardiovascular health, support healthy aging and slow the progression of age-related diseases.

Traditional approaches to studying astrocyte heterogeneity have mostly focused on analyzing static properties, failing to identify whether subtypes represent intermediate or final states of reactive astrocytes. Here we show that previously proposed neuroprotective and neurotoxic astrocytes are transitional states rather than distinct subtypes, as revealed through time-series multiomic sequencing. Neuroprotective astrocytes are an intermediate state of the transition from a nonreactive to a neurotoxic state in response to neuroinflammation, a process regulated by the mTOR signaling pathway. In Alzheimer's disease (AD) and aging, we observed an imbalance in neurotoxic and neuroprotective astrocytes in animal models and human patients. Moreover, targeting mTOR in astrocytes with rapamycin or shRNA mitigated astrocyte neurotoxic effects in neurodegenerative mouse models. Overall, our study uncovers a mechanism through which astrocytes exhibit neuroprotective functions before becoming neurotoxic under neuroinflammatory conditions and highlights mTOR modulation specifically in astrocytes as a potential therapeutic strategy for neurodegenerative diseases.

We previously reported that elevated expression of phospholipid hydroperoxide glutathione peroxidase 4, an enzyme that regulates membrane lipid hydroperoxides, can mitigate sarcopenia in mice. However, it is still unknown whether a pharmacological intervention designed to modulate lipid hydroperoxides might be an effective strategy to reduce sarcopenia in aged mice. Here we asked whether a newly developed compound, CMD-35647 (CMD), can reduce muscle atrophy induced by sciatic nerve transection. We treated mice daily with vehicle or CMD (15 mg/kg, i.p. injection) starting 1 day prior to denervation. CMD treatment reduced hydroperoxide generation and blunted muscle atrophy by over 17% in denervated muscle. To test whether CMD can reduce ageing-induced muscle atrophy and weakness, we treated mice with either vehicle or CMD (15 mg/kg, i.p. injection) 3 days per week for 8 months, starting at 18 months of age until 26 months of age. We measured muscle mass, functional status of neuromuscular junctions, muscle contractile function and mitochondrial function in control and CMD-treated 26-month-old female mice. Treatment with CMD conferred protection against muscle atrophy in both tibialis anterior and extensor digitorum longus that was associated with maintenance of fibre size of MHC 2b and 2x fibres. Mitochondrial respiration was also protected in CMD-treated mice. We also found that muscle force generation was protected with CMD treatment despite denervation in ∼25% of the muscle fibres. Overall, this study shows that pharmacological interventions designed to reduce lipid hydroperoxides might be effective for preventing sarcopenia. KEY POINTS: Sarcopenia in aged mice is associated with muscle loss, contractile dysfunction, denervation, and reduced mitochondrial respiration. CMD-35647 is a pharmocological compound that can neutralize lipid hydroperoxides. 8 month treatment of CMD-35647 mitigated muscle atrophy in tibialis anterior and extensor digitorum longus. 8 month treatment of CMD-35647 improved muscle function in aged mice independent of the neuromuscular junction. Aged mice treated with CMD-35647 had greater respiration in red gastrocnemius muscle when compared to vehicle treated mice.

Age-related hearing loss (ARHL) is a widespread problem in the elderly, significantly impairing their quality of life. Despite its high prevalence, no fundamental treatment for ARHL has been established. Nicotinamide adenine dinucleotide (NAD

Older people living with HIV-1 (PLWH) experience a dual burden from the combined effects of aging and HIV-1 infection, resulting in significant immune dysfunction. Despite receiving HAART, immune reconstitution is not fully optimized. The objective of this study was to investigate the impact of aging and HAART on T cell subsets and function in PLWH across different age groups, thereby providing novel insights into the prognosis of older PLWH.

Disturbances of the sleep-wake cycle and other circadian rhythms typically precede the age-related deficits in learning and memory, suggesting that these alterations in circadian timekeeping may contribute to the progressive cognitive decline during aging. The present study examined the role of immune cell activation and inflammation in the link between circadian rhythm dysregulation and cognitive impairment in aging.

Nucleotide availability is crucial for DNA replication and repair; however, the coordinating mechanisms in vivo remain unclear. Here, we show that the circadian clock in the liver controls the activity of the pentose phosphate pathway (PPP) to support de novo nucleotide biosynthesis for DNA synthesis demands. We demonstrate that disrupting the hepatic clock by genetic manipulation or mistimed feeding impairs PPP activity in male mice, leading to nucleotide imbalance. Such defects not only elicit DNA replication stress to limit liver regeneration after resection but also allow genotoxin-induced hepatocyte senescence and STING signalling-dependent inflammation. Mechanistically, the molecular clock activator BMAL1 synergizes with hypoxia-inducible factor-1α (HIF-1α) to regulate the transcription of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD), which is enhanced during liver regeneration. Overexpressing G6PD restores the compromised regenerative capacity of the BMAL1- or HIF-1α-deficient liver. Moreover, boosting G6PD expression genetically or through preoperative intermittent fasting potently facilitates liver repair in normal mice. Hence, our findings highlight the physiological importance of the hepatic clock and suggest a promising pro-regenerative strategy.

With the development of deep learning (DL) techniques, there has been a successful application of this approach to determine biological age from latent information contained in retinal images. Retinal age gap (RAG) defined as the difference between chronological age and predicted retinal age has been established previously to predict the age-related disease. In this study, we performed discovery genome-wide association analysis (GWAS) on the RAG using the 31,271 UK Biobank participants and replicated our findings in 8034 GoDARTS participants. The genetic correlation between RAGs predicted from the two cohorts was 0.67 (P = 0.021). After meta-analysis, we found 13 RAG loci which might be related to retinal vessel density and other aging processes. The SNP-wide heritability (h

Oxidative stress plays a crucial role in organ aging and related diseases, yet the endogenous regulators involved remain largely unknown. This work highlights the importance of metabolic homeostasis in protecting against oxidative stress in the large intestine. By developing a low-input and user-friendly pipeline for the simultaneous profiling of five distinct cysteine (Cys) states, including free SH, total Cys oxidation (Sto), sulfenic acid (SOH), S-nitrosylation (SNO), and S-glutathionylation (SSG), we shed light on Cys redox modification stoichiometries and signaling with regional resolution in the aging gut of monkeys. Notably, the proteins modified by SOH and SSG were associated primarily with cell adhesion. In contrast, SNO-modified proteins were involved in immunity. Interestingly, we observed that the Sto levels ranged from 0.97% to 99.88%, exhibiting two distinct peaks and increasing with age. Crosstalk analysis revealed numerous age-related metabolites potentially involved in modulating oxidative stress and Cys modifications. Notably, we elucidated the role of fumarate in alleviating intestinal oxidative stress in a dextran sulfate sodium (DSS)-induced colitis mouse model. Our findings showed that fumarate treatment promotes the recovery of several cell types, signaling pathways, and genes involved in oxidative stress regulation. Calorie restriction (CR) is a known strategy for alleviating oxidative stress. Two-month CR intervention led to the recovery of many antioxidative metabolites and reshaped the Cys redoxome. This work decodes the complexities of redoxomics during the gut aging of non-human primates and identifies key metabolic regulators of oxidative stress and redox signaling.

Senescent cells are known to contribute to aging and age-related diseases. One key way they influence aging is by secreting senescence-associated secretory phenotype (SASP) factors along with several damage-associated molecular pattern (DAMP) molecules. Consequently, inhibiting SASP and DAMP signaling (senomorphics) has emerged as a therapeutic strategy. Urolithin A (UA), a gut-derived metabolite produced from ellagitannins and ellagic acid found in berries, nuts, and pomegranates, has demonstrated potent anti-inflammatory properties and protective effects against aging and age-related conditions in experimental models. Here we demonstrate that UA lowers the expression and release of pro-inflammatory SASP and DAMP factors at least in part, on the downregulation of cytosolic DNA release and subsequent decrease in cGAS-STING signaling.

The maintenance of cellular redox balance is crucial for cell survival and homeostasis and is disrupted with aging. Selenoproteins, comprising essential antioxidant enzymes, raise intriguing questions about their involvement in hematopoietic aging and potential reversibility. Motivated by our observation of mRNA downregulation of key antioxidant selenoproteins in aged human hematopoietic stem cells (HSCs) and previous findings of increased lipid peroxidation in aged hematopoiesis, we employed tRNASec gene (Trsp) knockout (KO) mouse model to simulate disrupted selenoprotein synthesis. This revealed insights into the protective roles of selenoproteins in preserving HSC stemness and B-lineage maturation, despite negligible effects on myeloid cells. Notably, Trsp KO exhibited B lymphocytopenia and reduced HSCs' self-renewal capacity, recapitulating certain aspects of aged phenotypes, along with the upregulation of aging-related genes in both HSCs and pre-B cells. While Trsp KO activated an antioxidant response transcription factor NRF2, we delineated a lineage-dependent phenotype driven by lipid peroxidation, which was exacerbated with aging yet ameliorated by ferroptosis inhibitors such as vitamin E. Interestingly, the myeloid genes were ectopically expressed in pre-B cells of Trsp KO mice, and KO pro-B/pre-B cells displayed differentiation potential toward functional CD11b+ fraction in the transplant model, suggesting that disrupted selenoprotein synthesis induces the potential of B-to-myeloid switch. Given the similarities between the KO model and aged wild-type mice, including ferroptosis vulnerability, impaired HSC self-renewal and B-lineage maturation, and characteristic lineage switch, our findings underscore the critical role of selenoprotein-mediated redox regulation in maintaining balanced hematopoiesis and suggest the preventive potential of selenoproteins against aging-related alterations.

Ataxia-telangiectasia (A-T) is a pleiotropic genome instability syndrome resulting from the loss of the homeostatic protein kinase ATM. The complex phenotype of A-T includes progressive cerebellar degeneration, immunodeficiency, gonadal atrophy, interstitial lung disease, cancer predisposition, endocrine abnormalities, chromosomal instability, radiosensitivity, and segmental premature aging. Cultured skin fibroblasts from A-T patients exhibit premature senescence, highlighting the association between genome instability, cellular senescence, and aging. We found that lung fibroblasts derived from ATM-deficient mice provide a versatile experimental system to explore the mechanisms driving the premature senescence of primary fibroblasts lacking ATM.

Extracellular vesicles (EVs) are implicated in inter-organ communication, which becomes particularly relevant during aging and exercise. DNA methylation-based aging clocks reflect lifestyle and environmental factors, while regular exercise is known to induce adaptive responses, including epigenetic adaptations. Twenty individuals with High-fitness (aged 57.7 ± 9.8 years) and twenty Medium-Low-fitness (aged 57.5 ± 9.7 years) subjects provided blood samples. EVs were isolated from the samples using a size exclusion chromatography (SEC)-based method, and their protein content was analyzed by mass spectrometry (MS). Acceleration of the biological age estimator DNAmFitAge (AgeAccelFit) was associated with the protein cargo of EVs, whereas PhenoAge and GrimAge acceleration did not show a significant relationship. This finding suggests that the epigenetic aging-modulating role of exercise may involve inter-organ communication via EVs. Set Enrichment Analysis was performed to identify enriched Gene Ontology (GO) terms for sets of proteins that were either correlated with AgeAccelFit or detected exclusively in individuals with high levels of aerobic fitness. The protein cargo of EVs further suggests that inter-organ communication influences inflammation, the immune system, cellular repair, adhesion, metabolism and coagulation. Our findings help to understand the preventive role of exercise, which could be mediated in part by EVs.

Mitochondria produces energy through oxidative phosphorylation (OXPHOS), maintaining calcium homeostasis, survival/death cell signaling mechanisms, and redox balance. These mitochondrial functions are especially critical for neurons. The hippocampus is crucial for memory formation in the brain, which is a process with high mitochondrial function demand. Loss of hippocampal function in aging is related to neuronal damage, where mitochondrial impairment is critical. Synaptic and mitochondrial dysfunction are early events in aging; both are regulated reciprocally and contribute to age-associated memory loss together. We previously showed that prolonged treatment with Curcumin or Mitoquinone (MitoQ) improves mitochondrial functions in aged mice, exerting similar neuroprotective effects. Curcumin has been described as an anti-inflammatory and antioxidant compound, and MitoQ is a potent antioxidant directly targeting mitochondria; however, whether Curcumin exerts a direct impact on the mitochondria is unclear. In this work, we study whether Curcumin could have a mechanism similar to MitoQ targeting the mitochondria. We utilized hippocampal slices of 4-6-month-old C57BL6 mice to assess the cellular changes induced by acute Curcumin treatment ex-vivo compared to MitoQ. Our results strongly suggest that both compounds improve the synaptic structure, oxidative state, and energy production in the hippocampus. Nevertheless, Curcumin and MitoQ modify mitochondrial function differently; MitoQ improves the mitochondrial bioenergetics state, reducing ROS production and increasing ATP generation. In contrast, Curcumin reduces mitochondrial calcium levels and prevents calcium overload related to mitochondrial swelling. Thus, Curcumin is described as a new regulator of mitochondrial calcium homeostasis and could be used in pathological events involving calcium deregulation and excitotoxicity, such as aging and neurodegenerative diseases.

Metabolic alterations are related to tumorigenesis and other age-related diseases that are accelerated by "Westernized" diets. In fact, hypercaloric nutrition is associated with an increased incidence of cancers and faster aging. Conversely, lifespan-extending strategies, such as caloric restriction, impose beneficial effects on both processes. Here, we investigated the metabolic consequences of hypercaloric-induced aging on tumor growth in female mice. Our findings indicate that a high-fat high-sucrose diet increases tumor growth mainly due to the boosted oxidation of glucose and fatty acids. Consequently, through an increased expression of lactate, IGFBP3, and PTHLH, tumors modulate liver and white adipose tissue metabolism. In the liver, the induced tumor increases fibrosis and accelerates the senescence process, despite the lower systemic pro-inflammatory state. Importantly, the induced tumor induces the wasting and browning of white adipose tissue, thereby reversing diet-induced insulin resistance. Finally, we suggest that tumor growth alters liver-adipose tissue crosstalk that upregulates Fgf21, induces senescence, and negatively modulates lipids and carbohydrates metabolism even in caloric-restricted-fed mice.

With increasing age, motor performance declines. This decline is associated with less favorable health outcomes such as impaired activities of daily living, reduced quality of life, or increased mortality. Through regular assessment of motor performance, changes over time can be monitored, and targeted therapeutic programs and interventions may be informed. This can ensure better individualization of any intervention approach (e.g. by considering the current motor performance status of a person) and thus potentially increase its effectiveness with regard to maintaining current performance status or delaying further decline. However, in older adults, motor performance assessment is time consuming and requires experienced examiners and specific equipment, amongst others. This is particularly not feasible in care facility/nursing home settings. Wearable robotic devices, such as exoskeletons, have the potential of being used to assess motor performance and provide assistance during physical activities and exercise training for older adults or individuals with mobility impairments, thereby potentially enhancing motor performance. In this manuscript, we aim to (1) provide a brief overview of age-related changes of motor performance, (2) summarize established clinical and laboratory test procedures for the assessment of motor performance, (3) discuss the possibilities of translating established test procedures into exoskeleton-based procedures, and (4) highlight the feasibility, technological requirements and prerequisites for the assessment of human motor performance using lower limb exoskeletons.

Functional compensation is a common notion in the neuroscience of healthy ageing, whereby older adults are proposed to recruit additional brain activity to compensate for reduced cognitive function. However, whether this additional brain activity in older participants actually helps their cognitive performance remains debated. We examined brain activity and cognitive performance in a human lifespan sample (

As individuals grow older, their T cell repertoire progressively shifts from being dominated by naive T lymphocytes to featuring a preponderance of memory T cells. This phenomenon is well documented in immunological literature and frequently attributed to repeated antigenic stimulation over the course of a lifetime, coupled with thymic involution and other age-associated changes. Although memory T cells are crucial for rapid responses to previously encountered pathogens, there is increasing interest in whether this dramatically shifted balance might predispose certain individuals to a higher risk of autoimmunity, especially when compounded by chronic stress and recurrent infections. In this article, we propose a conceptual model linking the age-related inversion of the naive-to-memory T cell ratio to an elevated likelihood of immune dysregulation. We integrate mathematical equations to capture the dynamic interactions among key variables, present simulated data in four informative graphs, and discuss the implications and limitations of our approach. Our goal is to invite a deeper consideration of how infection history, stress-induced immune breakdowns, and the intrinsic remodeling of T cell populations with age could collectively contribute to autoimmunity.

The mammalian dentate gyrus (DG) is involved in certain forms of learning and memory, and DG dysfunction has been implicated in age-related diseases. Although neurogenic potential is maintained throughout life in the DG as neural stem cells (NSCs) continue to generate new neurons, neurogenesis decreases with advancing age, with implications for age-related cognitive decline and disease. In this study, we used single-cell RNA sequencing to characterize transcriptomic signatures of neurogenic cells and their surrounding DG niche, identifying molecular changes associated with neurogenic aging from the activation of quiescent NSCs to the maturation of fate-committed progeny. By integrating spatial transcriptomics data, we identified the regional invasion of inflammatory cells into the hippocampus with age and show here that early-onset neuroinflammation decreases neurogenic activity. Our data reveal the lifelong molecular dynamics of NSCs and their surrounding neurogenic DG niche with age and provide a powerful resource to understand age-related molecular alterations in the aging hippocampus.

Within the aging cortex, amyloid beta peptide (Aβ) is a crucial element of the senile plaques, a hallmark feature often observed in cases of Alzheimer's disease (AD). The UPR (unfolded protein response), a cellular mechanism for protein folding, is switched on by Aβ accumulation. Endoplasmic reticulum (ER) stress has been identified as playing a role in aging and the development of neurodegenerative diseases. The exact molecular pathways leading to perishing of cells from Aβ-induced ER stress, as well as the impact of voluntary exercise on these mechanisms, are still subjects awaiting a definitive answer yet. In the current study, 18 male Wistar rats were included: 6 young rats (3 months old; 200-250 g) in the Young Control group, and 12 old rats (18 months old; 400-430 g) randomly allocated to the Old Control and Old Exercise groups. The rat cages had running wheels for them to voluntarily run on for 8 weeks. This was followed by Western blotting, immunohistochemical staining, biochemical as well as morphological analyses. Voluntary exercise reduced Aβ1-42 deposition (P < 0.001) and inhibited the activation of caspase-8 (P < 0.001) and caspase-12 (P < 0.01), and on top of that down-regulated the expression of ATF6 (P < 0.001), CHOP (P < 0.01), and p-PERK (P < 0.05) proteins in the hippocampus of old male rats. Exercise amplified the population of Bcl-2-expressing cells and decreased the population of Bax-expressing cells in the hippocampus of the Old Exercise group (P < 0.001). Voluntary exercise inhibited the apoptotic pathways and suppressed the activation of UPR signaling pathways. Hence, voluntary exercise may be a therapeutic strategy and a promising approach to prevent AD through modulation of Aβ-induced ER stress.

Importance: SuperAgers are oldest-old adults (ages 80+) whose memory performance resembles that of adults in their 50s to mid-60s. Factors underlying their exemplary memory are underexplored in large, racially diverse cohorts. Objective: To determine the frequency of APOE genotypes in non-Hispanic Black and non-Hispanic White SuperAgers compared to middle-aged (ages 50-64), old (ages 65-79), and oldest-old (ages 80+) controls and Alzheimers disease (AD) dementia cases. Design: This multicohort study selected data from eight longitudinal cohort studies of normal aging and AD. Setting: Variable recruitment criteria and follow-up intervals, including both population-based and clinical-based samples. Participants: Inclusion in our analyses required APOE genotype, that participants be age 50+, and are identified as either non-Hispanic Black or non-Hispanic White. In total, 18,080 participants were included in the present study with a total of 78,549 datapoints. Main Outcomes and Measures: Harmonized, longitudinal memory, executive function, and language scores were obtained from the Alzheimers Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC). SuperAgers, controls, and AD dementia cases were identified by cognitive scores using a residual approach and clinical diagnoses across multiple timepoints when available. SuperAgers were compared to AD dementia cases and cognitively normal controls using age-defined bins (middle-aged, old, oldest-old). Results: Across racialized groups, SuperAgers had significantly higher proportions of APOE-{varepsilon}2 alleles and lower proportions of APOE-{varepsilon}4 alleles compared to cases. Similar differences were observed between SuperAgers and middle-aged and old controls. Non-Hispanic White SuperAgers had significantly lower proportions of APOE-{varepsilon}4 alleles and significantly higher proportions of APOE-{varepsilon}2 alleles compared to all cases and controls, including oldest-old controls. In contrast, non-Hispanic Black SuperAgers had significantly lower proportions of APOE-{varepsilon}4 alleles compared to cases and younger controls, and significantly higher proportions of APOE-{varepsilon}2 alleles compared only to cases. Conclusions and Relevance: In the largest study to date, we demonstrated strong evidence that the frequency of APOE-{varepsilon}4 and -{varepsilon}2 alleles differ between non-Hispanic White SuperAgers and AD dementia cases and cognitively normal controls. Differences in the role of APOE in SuperAging by race underlines distinctions in mechanisms conferring resilience across race groups given likely differences in genetic ancestry.

Maximizing the life-long reproductive output would lead to the prediction that short-lived and fast aging species would undergo no - if any - reproductive senescence. Turquoise killifish (Nothobranchius furzeri) are naturally short-lived teleosts, and undergo extensive somatic aging, characterized by molecular, cellular, and organ dysfunction following the onset of sexual maturation. Here, we tested whether naturally short-lived and fast aging male turquoise killifish maximize reproduction and display minimal - if any, reproductive senescence. We analysed age-related changes in sperm traits, the proportion of fertilized eggs, as well as embryo survival. Contrary to the expectation of no reproductive aging, we found that turquoise killifish males undergo extensive reproductive aging, consisting in the age-dependent decline in sperm quality, decreased proportion of fertilized eggs and lower embryo survival. Our results indicate that male turquoise killifish do not trade-off age-dependent soma decline with life-long sustained reproductive fitness. Instead, somatic and reproductive aging appear to occur simultaneously. Our findings question generalized soma vs. reproductive senescence trade-off models and highlight the importance of integrating species-specific ecological and demographic constraints to explain observed life history traits.

Osteoporosis (OP) is a prevalent age-related bone metabolic disease. Aging and mitochondrial dysfunction are involved in the onset and progression of OP, but the specific mechanisms have not been elucidated. The aim of this study was to identify novel potential biomarkers associated with aging and mitochondria in OP. In this study, based on GEO database, aging-related and mitochondria-related differentially expressed genes (AR&MRDEGs) were screened. The AR&MRDEGs were enriched in mitochondrial structure and function. Then, 6 key genes were identified by WGCNA and multiple machine learning, and a novel diagnostic model was constructed. The efficacy of diagnostic model was validated using external datasets. The results showed that diagnostic model had favorable diagnostic prediction ability. Next, key gene regulatory networks were constructed and single-gene GSEA analysis was performed. In addition, based on a single-cell dataset from OP, single-cell differentially expressed genes (scDEGs) were identified. The results revealed that aging-related and mitochondria-related genes (AR&MRGs) were enriched in the ERK pathway in tissue stem cells (TSCs), and in mitochondrial membrane potential depolarization in monocytes. Cellular communication analysis showed that TSCs were active, with numerous signaling interactions with monocytes, macrophages and immune cells. Finally, the expression of key gene was verified by quantitative real-time PCR (qRT-PCR). This study is expected to provide strategies for the diagnosis and treatment of OP targeting aging and mitochondria.

Background: One-carbon metabolism (OCM), a biochemical pathway dependent on micronutrients including folate and vitamin B12, plays an essential role in aging-related physiological processes. DNA methylation-based aging biomarkers may be influenced by OCM. Objective: This study investigated associations of OCM-related biomarkers with epigenetic aging biomarkers in the National Health and Nutrition Examination Survey (NHANES). Methods: Blood DNA methylation was measured in adults aged greater or equal to 50 years in the 1999-2000 and 2001-2002 cycles of NHANES. The following epigenetic aging biomarkers were included: Horvath1, Horvath2, Hannum, PhenoAge, GrimAge2, DunedinPoAm, and DNA methylation telomere length (DNAmTL). We tested for associations of serum folate, red blood cell (RBC) folate, vitamin B12, homocysteine, and methylmalonic acid concentrations with epigenetic age deviation (EAD) among 2,346 participants with epigenetic and nutritional status biomarkers using survey weighted general linear regression models adjusting for sociodemographics, BMI, and behavioral factors. Results: A doubling of serum folate concentration was associated with -0.82 years (95% confidence interval (CI) = -1.40, -0.23) lower GrimAge EAD, -0.13 SDs (-0.22, -0.03) lower DunedinPoAm, and 0.02 kb (0.00, 0.04) greater DNAmTL EAD. Associations were attenuated after adjusting for smoking status and alcohol intake, folate antagonists. Conversely, a doubling in homocysteine concentration was associated with 1.05 years (0.06, 2.04) greater PhenoAge EAD, 1.93 years (1.16, 2.71) greater GrimAge2 EAD, and 0.26 SDs (0.10, 0.41) greater DunedinPoAm. Associations with GrimAge2 EAD and DunedinPoAm were robust to alcohol and smoking adjustment. Conclusions: In a nationally representative sample of U.S. adults, greater folate, a carbon donor, was associated with lower EAD, and greater homocysteine, an indicator of OCM deficiencies, was associated with greater EAD; however, some associations were influenced by smoking status. Future research should focus on high-risk populations. Randomized controlled trials with long-term follow-up are also needed to established causality and investigate the clinical relevance of changes in EAD.

As the global population continues to age, understanding the complex role of cellular senescence and its implications in healthy lifespans has gained increasing prominence. Cellular senescence is defined as the irreversible cessation of cell proliferation, accompanied by the secretion of a range of pro-inflammatory factors, collectively termed the senescence-associated secretory phenotype (SASP), in response to various cellular stresses. While the accumulation of senescent cells has been strongly implicated in the aging process and the pathogenesis of age-related diseases owing to their pro-inflammatory properties, recent research has also highlighted their essential roles in processes such as tumour suppression, tissue development, and repair. This review provides a comprehensive examination of the dual nature of senescent cells, evaluating their deleterious contributions to chronic inflammation, tissue dysfunction, and disease, as well as their beneficial roles in maintaining physiological homeostasis. Additionally, we explored the therapeutic potential of senolytic agents designed to selectively eliminate detrimental senescent cells while considering the delicate balance between transient and beneficial senescence and the persistence of pathological senescence. A deeper understanding of these dynamics is critical to develop novel interventions aimed at mitigating age-related dysfunctions and enhancing healthy life expectancies.

Understanding the complex biological process of aging is of great value, especially as it can help develop therapeutics to prolong healthy life. Predicting biological age from gene expression data has shown to be an effective means to quantify aging of a subject, and to identify molecular and cellular biomarkers of aging. A typical approach for estimating biological age, adopted by almost all existing aging clocks, is to train machine learning models only on healthy subjects, but to infer on both healthy and unhealthy subjects. However, the inherent bias in this approach results in inaccurate biological age as shown in this study. Moreover, almost all existing transcriptome-based aging clocks were built around an inefficient procedure of gene selection followed by conventional machine learning models such as elastic nets, linear discriminant analysis etc. To address these limitations, we proposed DeepQA, a unified aging clock based on mixture of experts. Unlike existing methods, DeepQA is equipped with a specially designed Hinge-Mean-Absolute-Error (Hinge-MAE) loss so that it can train on both healthy and unhealthy subjects of multiple cohorts to reduce the bias of inferring biological age of unhealthy subjects. Our experiments showed that DeepQA significantly outperformed existing methods for biological age estimation on both healthy and unhealthy subjects. In addition, our method avoids the inefficient exhaustive search of genes, and provides a novel means to identify genes activated in aging prediction, alternative to such as differential gene expression analysis.

Throughout the animal kingdom, several members of the basic helix-loop-helix (bHLH) family act as proneural genes during early steps of nervous system development. Roles of bHLH genes in specifying terminal differentiation of postmitotic neurons have been less extensively studied. We analyze here the function of 5 Caenorhabditis elegans bHLH genes, falling into 3 phylogenetically conserved subfamilies, which are continuously expressed in a very small number of postmitotic neurons in the central nervous system. We show (a) that 2 orthologs of the vertebrate bHLHe22/e23 genes, called hlh-17 and hlh-32, function redundantly to specify the identity of a single head interneuron class (AUA), as well as an individual motor neuron (VB2); (b) that the PTF1a ortholog hlh-13 acts as a terminal selector to control terminal differentiation and function of the sole octopaminergic neuron class in C. elegans, RIC; and (c) that the NHLH1/2 ortholog hlh-15 controls terminal differentiation and function of the peptidergic AVK head interneuron class, a known neuropeptidergic signaling hub in the animal. Strikingly, through null mutant analysis and cell-specific rescue experiments, we find that loss of hlh-15/NHLH in the peptidergic AVK neurons and the resulting abrogation of neuropeptide secretion from these neurons causes a substantially extended lifespan of the animal, which we propose to be akin to hypothalamic control of lifespan in vertebrates. Our functional analysis reveals themes of bHLH gene function during terminal differentiation that are complementary to the earlier lineage specification roles of other bHLH family members. However, such late functions are much more sparsely employed by members of the bHLH transcription factor family, compared to the function of the much more broadly employed homeodomain transcription factor family.

Background: Here, we assessed the role of the advanced glycation end-product (AGE) precursor methylglyoxal (MGO) and its non-crosslinking AGE MGO-derived hydroimidazolone (MGH-1) in aortic stiffening and explored the potential of a glycation stress-lowering compound (Gly-Low) to mitigate these effects. Methods: Young (3-6 month) C57BL/6 mice were supplemented with MGO (in water) and Gly-Low (in chow). Aortic stiffness was assessed in vivo via pulse wave velocity (PWV) and ex vivo through elastic modulus. Putative mechanisms underlying MGO and MGH-1-induced aortic stiffening were explored using complementary experimental approaches in aortic tissue and cultured human aortic endothelial cells (HAECs). Moreover, aortic stiffness was assessed in old (24 month) mice after consumption of Gly-Low-enriched chow. Results: MGO-induced glycation stress increased PWV in young mice by 21% (P<0.05 vs. control), which was prevented with Gly-Low (P=0.93 vs. control). Ex vivo, MGO increased aortic elastic modulus 2-fold (P<0.05), superoxide production by ~40% (P<0.05), and MGH-1 expression by 50% (P<0.05), which were all mitigated by Gly-Low. Chronic MGO exposure elevated biomarkers of cellular senescence in HAECs, comparable to a known senescence inducer Doxorubicin, an effect partially blocked by Gly-Low. Moreover, elevated aortic elastic modulus induced by Doxorubicin (P<0.05 vs. control) was prevented with Gly-Low (P=0.71 vs. control). Aortic RNA sequencing implicated preservation of endogenous cellular detoxification pathways with Gly-Low following exposure to MGH-1. Old mice supplemented with Gly-Low had lower PWV (P<0.05) relative to old control mice. Conclusions: MGO-induced glycation stress contributes to aortic stiffening and glycation stress lowering compounds hold promise for mitigating these effects.

Chronic kidney disease (CKD) is a major global health issue, projected to become the fifth leading cause of mortality by 2040. Renal tubular cell senescence is a key driver of kidney fibrosis, the final manifestation of CKD. However, current treatment strategies, do not target senescent cells, as the underlying mechanisms driving this dysfunctional phenotype remain poorly described. Here, we identify nicotinamide-N-methyltransferase (NNMT), as a critical mediator of tubular senescence and fibrosis in CKD. Using human RNAseq profiles of CKD, we show that NNMT expression in the renal tubulointerstitium is strongly associated with CKD pathology and transcriptional signatures of cellular senescence. In human diabetic kidney disease biopsies, NNMT levels correlate with the senescence marker p21, kidney function decline, and fibrosis. Spatial transcriptomics further highlights that NNMT-positive tubules are senescent, fibrotic, and surrounded by a pro-inflammatory microenvironment. Preclinical models of early-stage CKD, show upregulation of NNMT and association with senescence. Overexpression of NNMT in TGF-beta-stimulated tubular epithelial cells promotes senescence and partial epithelial-to-mesenchymal transition (EMT), while inhibition of NNMT in kidney cells and organoids is protective. Altogether, we identify NNMT as a novel therapeutic target in the early stages of CKD with the potential to reduce tubular senescence, fibrosis and significantly slow disease progression.

Obesity is linked to limited adipose tissue (AT) remodeling capacity, leading to hypertrophic adipocytes, senescence, and inflammation. We used a mouse model expressing mTert (p21+/Tert) from the Cdkn1a locus to investigate the role of mTERT in obesity-induced metabolic disorders. Conditional expression of mTERT reduces metabolic disorders associated with obesity. In AT, this is accompanied by a decrease in the number of senescent p21-positive cells, very short telomeres, and oxidative DNA damage. Single nucleus RNA-seq data reveal TERT expression attenuates senescence induced by HFD in particular in adipose stem and progenitor cells (ASPC). We show that ASPC expansion and differentiation are promoted in p21+/Tert obese mice, thereby reducing metabolic disorders. We further report that mTERT remodels the landscape of macrophages in AT of obese mice. Strikingly, inactivation of mTERT catalytic activity in p21+/Tert (p21+/TertCi) mice suppresses the promotion of adipocyte formation, but neither affects attenuation of senescence nor macrophage remodeling. These results highlight mTERT\'s canonical and non-canonical functions in reducing obesity-associated metabolic disorders. Conditional expression of TERT thus appears as a potential therapeutic option for obesity.

Aging is characterized by extensive metabolic dysregulation. Redox coenzyme nicotinamide adenine dinucleotide (NAD) can exist in oxidized (NAD+) or reduced (NADH) states, which together form a key NADH/NAD+ redox pair. Total levels of NAD decline with age in a tissue-specific manner, thereby playing a significant role in the aging process. Supplementation with NAD precursors boosts total cellular NAD levels and provides some therapeutic benefits in human clinical trials. However, supplementation studies cannot determine tissue-specific effects of an altered NADH/NAD+ ratio. Here, we created transgenic Drosophila expressing a genetically encoded xenotopic tool LbNOX to directly manipulate the cellular NADH/NAD+ ratio. We found that LbNOX expression in Drosophila impacts both NAD(H) and NADP(H) metabolites in a sex-specific manner. LbNOX rescues neuronal cell death induced by the expression of mutated alpha-B crystallin in the Drosophila eye, a widely used system to study reductive stress. Utilizing LbNOX, we demonstrate that targeting redox NAD metabolism in different tissues may have drastically different outcomes, as the expression of LbNOX solely in the muscle is much more effective for rescuing paraquat-induced oxidative stress compared to whole-body expression. Excitingly, we demonstrate that perturbing NAD(P) metabolism in non-neuronal tissues is sufficient to rejuvenate sleep profiles in aged flies to a youthful state. In summary, we used xenotopic tool LbNOX to identify tissues and metabolic processes which benefited the most from the modulation of the NAD metabolism thereby highlighting important aspects of rebalancing the NAD and NADP pools, all of which can be translated into novel designs of NAD-related human clinical trials.

Age-related macular degeneration (AMD) is a progressive disorder and the leading cause of central vision loss. Age is the most important risk factor, followed by genetics and smoking. However, ageing is a complex process, and biological age can deviate from chronological age between individuals and within different organ systems. Initially, we used machine learning to predict the biological age of the immune, cardiovascular, pulmonary, renal, musculoskeletal, metabolic and hepatic systems by analysing various physiological and physical markers in the UK Biobank cohort. Then, we investigated the association of each organ's biological age with incident AMD derived from electronic health record data as well as with different AMD genetic risk scores. We observed that most organ systems in participants who developed AMD after recruitment showed accelerated ageing compared with controls, with the immune system being the most affected, especially in younger males. Surprisingly, we found that AMD patients showed slower ageing of their hepatic system compared to controls, particularly in female patients. The overall AMD genetic risk score was associated with faster organ ageing across all tissues except cardiovascular and pulmonary, while genetic risk scores stratified by pathways differently influenced each organ system. In conclusion, we found differential organ ageing associated with AMD. Significantly, genetic risk variants of AMD are associated with differential ageing of various organ systems.

Exercise enhances health by supporting homeostasis, bolstering defenses, and aiding disease recovery. It activates autophagy, a conserved cellular process essential for maintaining balance, while dysregulated autophagy contributes to disease progression. Despite extensive research on exercise and autophagy independently, their interplay remains insufficiently understood.

Social connectedness is a modifiable lifestyle factor that delays age-related cognitive decline. Using cross-sectional, longitudinal, and experimental approaches, we examined whether theory of mind-inferring what others think or feel-is a potential mechanism underlying this relationship.

Brown adipose tissue (BAT) is an energy-consuming organ, and its functional dysregulation contributes to the development of metabolic diseases and obesity. BAT function is regulated by the sympathetic nervous system but declines with age, which is partly caused by reduced sympathetic nerve fibers innervating BAT. Thus far, the role of mesenchymal stromal/stem cells in age-related BAT dysfunction remains unknown. Here, we show that BAT dysfunction may be induced by a defect in the antioxidant capacity of stromal cells that localize in and around the nerve fibers (perineurial cells) of BAT. These cells express Meflin, a marker of mesenchymal stromal/stem cells. Specific deletion of the antioxidant enzyme superoxide dismutase 2 in Meflin-lineage cells caused sympathetic denervation and whitening of BAT and its functional impairment, as exemplified by a decline in the fat oxidation rate during the daytime. This phenotype was accompanied by overexpression of the neurorepulsive factor semaphorin 3A in perineurial cells. Notably, Meflin-deficient mice exhibited resistance to doxorubicin-induced BAT dysfunction. These results highlight the role of Meflin