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Women show resilience to cognitive aging, in the absence of dementia, in many populations. To dissect sex differences, we utilized the FCG and XY* mouse models. Female gonads and sex chromosomes improved cognition in aging mice of both sexes. Further, presence of a second X in male and female mice conferred cognitive resilience while its absence in females blocked it. In the hippocampal proteome of aging female mice, the second X increased proteins involved in synaptogenesis signaling - a potential pathway to improved cognition.
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Sex and gender-biological and social constructs-significantly impact the prevalence of protective and risk factors, influencing the burden of Alzheimer's disease (AD; amyloid beta and tau) and other pathologies (e.g., cerebrovascular disease) which ultimately shape cognitive trajectories. Understanding the interplay of these factors is central to understanding resilience and resistance mechanisms explaining maintained cognitive function and reduced pathology accumulation in aging and AD. In this narrative review, the ADDRESS! Special Interest Group (Alzheimer's Association) adopted a multidisciplinary approach to provide the foundations and recommendations for future research into sex- and gender-specific drivers of resilience, including a sex/gender-oriented review of risk factors, genetics, AD and non-AD pathologies, brain structure and function, and animal research. We urge the field to adopt a sex/gender-aware approach to resilience to advance our understanding of the intricate interplay of biological and social determinants and consider sex/gender-specific resilience throughout disease stages. HIGHLIGHTS: Sex differences in resilience to cognitive decline vary by age and cognitive status. Initial evidence supports sex-specific distinctions in brain pathology. Findings suggest sex differences in the impact of pathology on cognition. There is a sex-specific change in resilience in the transition to clinical stages. Gender and sex factors warrant study: modifiable, immune, inflammatory, and vascular.
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INTRODUCTION: Accumulating evidence indicates disproportionate tau burden and tau-related clinical progression in females. However, sex differences in plasma phosphorylated tau (p-tau)217 prediction of subclinical cognitive and brain changes are unknown. METHODS: We measured baseline plasma p-tau217, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) in 163 participants (85 cognitively unimpaired [CU], 78 mild cognitive impairment [MCI]). In CU, linear mixed effects models examined sex differences in plasma biomarker prediction of longitudinal domain-specific cognitive decline and brain atrophy. Cognitive models were repeated in MCI. RESULTS: In CU females, baseline plasma p-tau217 predicted verbal memory and medial temporal lobe trajectories such that trajectories significantly declined once p-tau217 concentrations surpassed 0.053 pg/ml, a threshold that corresponded to early levels of cortical amyloid aggregation in secondary amyloid positron emission tomography analyses. CU males exhibited similar rates of cognitive decline and brain atrophy, but these trajectories were not dependent on plasma p-tau217. Plasma GFAP and NfL exhibited similar female-specific prediction of medial temporal lobe atrophy in CU. Plasma p-tau217 exhibited comparable prediction of cognitive decline across sex in MCI. DISCUSSION: Plasma p-tau217 may capture earlier Alzheimer's disease (AD)-related cognitive and brain atrophy hallmarks in females compared to males, possibly reflective of increased susceptibility to AD pathophysiology.
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Doença de Alzheimer , Disfunção Cognitiva , Adulto , Humanos , Feminino , Masculino , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Tomografia por Emissão de Pósitrons , Atrofia/metabolismo , Biomarcadores , Peptídeos beta-Amiloides/metabolismoRESUMO
Platelet factors regulate wound healing and can signal from the blood to the brain1,2. However, whether platelet factors modulate cognition, a highly valued and central manifestation of brain function, is unknown. Here we show that systemic platelet factor 4 (PF4) permeates the brain and enhances cognition. We found that, in mice, peripheral administration of klotho, a longevity and cognition-enhancing protein3-7, increased the levels of multiple platelet factors in plasma, including PF4. A pharmacologic intervention that inhibits platelet activation blocked klotho-mediated cognitive enhancement, indicating that klotho may require platelets to enhance cognition. To directly test the effects of platelet factors on the brain, we treated mice with vehicle or systemic PF4. In young mice, PF4 enhanced synaptic plasticity and cognition. In old mice, PF4 decreased cognitive deficits and restored aging-induced increases of select factors associated with cognitive performance in the hippocampus. The effects of klotho on cognition were still present in mice lacking PF4, suggesting this platelet factor is sufficient to enhance cognition but not necessary for the effects of klotho-and that other unidentified factors probably contribute. Augmenting platelet factors, possible messengers of klotho, may enhance cognition in the young brain and decrease cognitive deficits in the aging brain.
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Envelhecimento , Longevidade , Animais , Camundongos , Fatores de Coagulação Sanguínea , Cognição , Fator Plaquetário 4RESUMO
Aging biomarkers may be related to each other through direct co-regulation and/or through being regulated by common processes associated with chronological aging or stress. Klotho is an aging regulator that acts as a circulating hormone with critical involvement in regulating insulin signaling, phosphate homeostasis, oxidative stress, and age-related inflammatory functioning. Both klotho and telomere length are biomarkers of biological aging and decrease with age; however, the relationship between them is not well understood. Here we test the association between klotho levels and the telomere length of specific sorted immune cells among a healthy sample of mothers caregiving for a child with autism spectrum disorder (ASD; i.e., experiencing higher caregiving stress) or a child without ASD, covarying age and body mass index, in order to understand if high stress associated with caregiving for a child with an ASD may be involved in any association between these aging biomarkers. In 178 caregiving women (n = 90 high-stress mothers of children with ASD, n = 88 low-stress mothers of neurotypical children), we found that klotho levels were positively associated with telomere length in PBMCs (an effect driven by CD4+ and CD8+CD28- T cells) among high-stress mothers of children with an ASD but not among low-stress mothers of neurotypical children. There were no significant associations between klotho and telomerase activity in either group, across cell types assessed here. Our results suggest that klotho levels and telomere length may be associated through a coordinated downregulation of longevity factors occurring under higher stress caregiving conditions.
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Transtorno do Espectro Autista , Cuidadores , Humanos , Feminino , Envelhecimento/genética , Biomarcadores , Telômero , Biologia , Encurtamento do TelômeroRESUMO
Cognitive dysfunction in aging is a major biomedical challenge. Whether treatment with klotho, a longevity factor, could enhance cognition in human-relevant models such as in nonhuman primates is unknown and represents a major knowledge gap in the path to therapeutics. We validated the rhesus form of the klotho protein in mice showing it increased synaptic plasticity and cognition. We then found that a single administration of low-dose, but not high-dose, klotho enhanced memory in aged nonhuman primates. Systemic low-dose klotho treatment may prove therapeutic in aging humans.
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Glucuronidase , Longevidade , Camundongos , Humanos , Animais , Idoso , Glucuronidase/metabolismo , Envelhecimento , Cognição , Primatas/metabolismoRESUMO
Aging results in a decline in neural stem cells (NSCs), neurogenesis, and cognitive function, and evidence is emerging to demonstrate disrupted adult neurogenesis in the hippocampus of patients with several neurodegenerative disorders. Here, single-cell RNA sequencing of the dentate gyrus of young and old mice shows that the mitochondrial protein folding stress is prominent in activated NSCs/neural progenitors (NPCs) among the neurogenic niche, and it increases with aging accompanying dysregulated cell cycle and mitochondrial activity in activated NSCs/NPCs in the dentate gyrus. Increasing mitochondrial protein folding stress results in compromised NSC maintenance and reduced neurogenesis in the dentate gyrus, neural hyperactivity, and impaired cognitive function. Reducing mitochondrial protein folding stress in the dentate gyrus of old mice improves neurogenesis and cognitive function. These results establish the mitochondrial protein folding stress as a driver of NSC aging and suggest approaches to improve aging-associated cognitive decline.
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Hipocampo , Células-Tronco Neurais , Camundongos , Animais , Células-Tronco Neurais/metabolismo , Neurogênese/fisiologia , Envelhecimento/fisiologia , Resposta a Proteínas não Dobradas , Proliferação de CélulasRESUMO
Males exhibit shorter life span and more cognitive deficits, in the absence of dementia, in aging human populations. In mammals, the X chromosome is enriched for neural genes and is a major source of biologic sex difference, in part, because males show decreased expression of select X factors (XY). While each sex (XX and XY) harbors one active X due to X chromosome inactivation in females, some genes, such as Kdm6a, transcriptionally escape silencing in females-resulting in lower transcript levels in males. Kdm6a is a known histone demethylase (H3K27me2/3) with multiple functional domains that is linked with synaptic plasticity and cognition. Whether elevating Kdm6a could benefit the aged male brain and whether this requires its demethylase function remains unknown. We used lentiviral-mediated overexpression of the X factor in the hippocampus of aging male mice and tested their cognition and behavior in the Morris water-maze. We found that acutely increasing Kdm6a-in a form without demethylase function-selectively improved learning and memory, in the aging XY brain, without altering total activity or anxiety-like measures. Further understanding the demethylase-independent downstream mechanisms of Kdm6a may lead to novel therapies for treating age-induced cognitive deficits in both sexes.
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Histona Desmetilases , Cromossomo X , Masculino , Humanos , Feminino , Animais , Camundongos , Idoso , Cromossomo X/metabolismo , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Encéfalo/metabolismo , Cognição , Envelhecimento/genética , MamíferosRESUMO
Introduction: Dementia as an inevitable aging consequence has been challenged and underscores the need for investigations of the factors that confer resilience. We examine whether the functionally advantageous KL-VS variant of the putative aging suppressor KLOTHO gene attenuates age-related cognitive decline and deleterious biomolecular changes. Methods: Trajectories of change in memory and executive function (N = 360; 2-12 visits) and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers-amyloid beta (Aß)42, total tau (t-tau), phosphorylated tau (p-tau) (N = 112; 2-4 samplings)-were compared between KL-VS non-carriers and heterozygotes in middle-aged and older adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center studies. Results: Memory and executive function declined (p's ≤ 0.001) and CSF t-tau, p-tau, t-tau/Aß42, and p-tau/Aß42 levels increased (all p's ≤ 0.004) with age. The rate of p-tau accumulation was attenuated for KL-VS heterozygotes (p = 0.03). Discussion: KL-VS heterozygosity may confer resilience to AD-associated biomolecular changes.
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BACKGROUND: Klotho is a longevity and neuroprotective hormone encoded by the KLOTHO gene, and heterozygosity for the KL-VS variant confers a protective effect against neurodegenerative disease. OBJECTIVE: Test whether klotho concentrations in serum or cerebrospinal fluid (CSF) vary as a function of KLOTHO KL-VS genotype, determine whether circulating klotho concentrations from serum and CSF differ from one another, and evaluate whether klotho levels are associated with Alzheimer's disease risk factors. METHODS: Circulating klotho was measured in serum (nâ=â1,116) and CSF (nâ=â183) of cognitively intact participants (aged 62.4 ± 6.5 years; 69.5% female). KLOTHO KL-VS zygosity (non-carrier; heterozygote; homozygote) was also determined. Linear regression was used to test whether klotho hormone concentration varied as a function of KL-VS genotype, specimen source, and demographic and clinical characteristics. RESULTS: Serum and CSF klotho were higher in KL-VS carriers than non-carriers. Klotho concentration was higher in CSF than in serum. Females had higher serum and CSF klotho, while younger age was associated with higher klotho in CSF. CONCLUSION: In a cohort enriched for risk for Alzheimer's disease, heterozygotic and homozygotic carriers of the KL-VS allele, females, and younger individuals have higher circulating klotho. Fluid source, KL-VS genotype, age, and sex should be considered in analyses of circulating klotho on brain health.
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Doença de Alzheimer , Doenças Neurodegenerativas , Feminino , Humanos , Masculino , Doença de Alzheimer/genética , Glucuronidase/genética , Heterozigoto , HormôniosRESUMO
Background: Neurocognitive deficits in pediatric cancer survivors occur frequently; however, individual outcomes are unpredictable. We investigate clinical, genetic, and imaging predictors of neurocognition in pediatric cancer survivors, with a focus on survivors of central nervous system (CNS) tumors exposed to radiation. Methods: One hundred eighteen patients with benign or malignant cancers (median diagnosis age: 7; 32% embryonal CNS tumors) were selected from an existing multi-institutional cohort (RadART Pro) if they had: 1) neurocognitive evaluation; 2) available DNA; 3) standard imaging. Utilizing RadART Pro, we collected clinical history, genomic sequencing, CNS imaging, and neurocognitive outcomes. We performed single nucleotide polymorphism (SNP) genotyping for candidate genes associated with neurocognition: COMT, BDNF, KIBRA, APOE, KLOTHO. Longitudinal neurocognitive testing were performed using validated computer-based CogState batteries. The imaging cohort was made of patients with available iron-sensitive (n = 28) and/or T2 FLAIR (n = 41) sequences. Cerebral microbleeds (CMB) were identified using a semi-automated algorithm. Volume of T2 FLAIR white matter lesions (WML) was measured using an automated method based on a convolutional neural network. Summary statistics were performed for patient characteristics, neurocognitive assessments, and imaging. Linear mixed effects and hierarchical models assessed patient characteristics and SNP relationship with neurocognition over time. Nested case-control analysis was performed to compare candidate gene carriers to non-carriers. Results: CMB presence at baseline correlated with worse performance in 3 of 7 domains, including executive function. Higher baseline WML volumes correlated with worse performance in executive function and verbal learning. No candidate gene reliably predicted neurocognitive outcomes; however, APOE ϵ4 carriers trended toward worse neurocognitive function over time compared to other candidate genes and carried the highest odds of low neurocognitive performance across all domains (odds ratio 2.85, P=0.002). Hydrocephalus and seizures at diagnosis were the clinical characteristics most frequently associated with worse performance in neurocognitive domains (5 of 7 domains). Overall, executive function and verbal learning were the most frequently negatively impacted neurocognitive domains. Conclusion: Presence of CMB, APOE ϵ4 carrier status, hydrocephalus, and seizures correlate with worse neurocognitive outcomes in pediatric cancer survivors, enriched with CNS tumors exposed to radiation. Ongoing research is underway to verify trends in larger cohorts.
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Cognitive deficits are a major biomedical challenge-and engagement of the brain in stimulating tasks improves cognition in aged individuals (Wilson et al., 2002; Gates et al., 2011) and rodents (Aidil-Carvalho et al., 2017), through unknown mechanisms. Whether cognitive stimulation alters specific metabolic pathways in the brain is unknown. Understanding which metabolic processes are involved in cognitive stimulation is important because it could lead to pharmacologic intervention that promotes biological effects of a beneficial behavior, toward the goal of effective medical treatments for cognitive deficits. Here we show using male mice that cognitive stimulation induced metabolic remodeling of the mouse hippocampus, and that pharmacologic treatment with the longevity hormone α-klotho (KL), mediated by its KL1 domain, partially mimicked this alteration. The shared, metabolic signature shared between cognitive stimulation and treatment with KL or KL1 closely correlated with individual mouse cognitive performance, indicating a link between metabolite levels and learning and memory. Importantly, the treatment of mice with KL1, an endogenous circulating factor that more closely mimicked cognitive stimulation than KL, acutely increased synaptic plasticity, a substrate of cognition. KL1 also improved cognition, itself, in young mice and countered deficits in old mice. Our data show that treatments or interventions mimicking the hippocampal metabolome of cognitive stimulation can enhance brain functions. Further, we identify the specific domain by which klotho promotes brain functions, through KL1, a metabolic mimic of cognitive stimulation.SIGNIFICANCE STATEMENT Cognitive deficits are a major biomedical challenge without truly effective pharmacologic treatments. Engaging the brain through cognitive tasks benefits cognition. Mimicking the effects of such beneficial behaviors through pharmacological treatment represents a highly valuable medical approach to treating cognitive deficits. We demonstrate that brain engagement through cognitive stimulation induces metabolic remodeling of the hippocampus that was acutely recapitulated by the longevity factor klotho, mediated by its KL1 domain. Treatment with KL1, a close mimic of cognitive stimulation, enhanced cognition and countered cognitive aging. Our findings shed light on how cognition metabolically alters the brain and provide a plausible therapeutic intervention for mimicking these alterations that, in turn, improves cognition in the young and aging brain.
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Glucuronidase , Longevidade , Envelhecimento , Animais , Cognição/fisiologia , Glucuronidase/química , Glucuronidase/metabolismo , Hidrolases/metabolismo , Proteínas Klotho , Masculino , Metaboloma , CamundongosRESUMO
Despite the association between cognitive impairment and delirium, little is known about whether genetic differences that confer cognitive resilience also confer resistance to delirium. To investigate whether older adults without postoperative delirium, compared with those with postoperative delirium, are more likely to have specific single nucleotide polymorphisms (SNPs) in the FKBP5, KIBRA, KLOTHO, MTNR1B, and SIRT1 genes known to be associated with cognition or delirium. This prospective nested matched exploratory case-control study included 94 older adults who underwent orthopedic surgery and screened for postoperative delirium. Forty-seven subjects had incident delirium, and 47 age-matched controls were not delirious. The primary study outcome was genotype frequency for the five SNPs. Compared with participants with delirium, those without delirium had higher adjusted odds of KIBRA SNP rs17070145 CT/TT [vs. CC; adjusted odds ratio (aOR) 2.80, 95% confidence interval (CI) 1.03, 7.54; p = 0.04] and MTNR1B SNP rs10830963 CG/GG (vs. CC; aOR 4.14, 95% CI 1.36, 12.59; p = 0.01). FKBP5 SNP rs1360780 CT/TT (vs. CC) demonstrated borderline increased adjusted odds of not developing delirium (aOR 2.51, 95% CI 1.00, 7.34; p = 0.05). Our results highlight the relevance of KIBRA, MTNR1B, and FKBP5 in understanding the complex relationship between delirium, cognition, and sleep, which warrant further study in larger, more diverse populations.
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GenótipoRESUMO
Alzheimer's disease (AD) is a pervasive neurodegenerative disorder that disproportionately affects women. Since neural anatomy and disease pathophysiology differ by sex, investigating sex-specific mechanisms in AD pathophysiology can inform new therapeutic approaches for both sexes. Previous bulk human brain RNA sequencing studies have revealed sex differences in dysregulated molecular pathways related to energy production, neuronal function, and immune response; however, the sex differences in disease mechanisms are yet to be examined comprehensively on a single-cell level. We leveraged nearly 74,000 cells from human prefrontal and entorhinal cortex samples from the first two publicly available single-cell RNA sequencing AD datasets to perform a case versus control sex-stratified differential gene expression analysis and pathway network enrichment in a cell type-specific manner for each brain region. Our examination at the single-cell level revealed sex differences in AD prominently in glial cells of the prefrontal cortex. In the entorhinal cortex, we observed the same genes and networks to be perturbed in opposing directions between sexes in AD relative to healthy state. Our findings contribute to growing evidence of sex differences in AD-related transcriptomic changes, which can fuel the development of therapies that may prove more effective at reversing AD pathophysiology.
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Doença de Alzheimer/genética , Córtex Entorrinal/metabolismo , Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Feminino , Humanos , Masculino , Análise de Sequência de RNA , Fatores Sexuais , Análise de Célula Única , Transcrição Gênica , TranscriptomaRESUMO
Importance: The X chromosome represents 5% of the human genome in women and men, and its influence on cognitive aging and Alzheimer disease (AD) is largely unknown. Objective: To determine whether the X chromosome is associated with sex-specific cognitive change and tau pathology in aging and AD. Design, Setting, Participants: This study examined differential gene expression profiling of the X chromosome from an RNA sequencing data set of the dorsolateral prefrontal cortex obtained from autopsied, elderly individuals enrolled in the Religious Orders Study and Rush Memory and Aging Project joint cohorts. Samples were collected from the cohort study with enrollment from 1994 to 2017. Data were last analyzed in May 2021. Main Outcomes and Measures: The main analysis examined whether X chromosome gene expression measured by RNA sequencing of the dorsolateral prefrontal cortex was associated with cognitive change during aging and AD, independent of AD pathology and at the transcriptome-wide level in women and men. Whether X chromosome gene expression was associated with neurofibrillary tangle burden, a measure of tau pathology that influences cognition, in women and men was also explored. Results: Samples for RNA sequencing of the dorsolateral prefrontal cortex were obtained from 508 individuals (mean [SD] age at death, 88.4 [6.6] years; 315 [62.0%] were female; 197 [38.8%] had clinical diagnosis of AD at death; 293 [58.2%] had pathological diagnosis of AD at death) enrolled in the Religious Orders Study and Rush Memory and Aging Project joint cohorts and were followed up annually for a mean (SD) of 6.3 (3.9) years. X chromosome gene expression (29 genes), adjusted for age at death, education, and AD pathology, was significantly associated with cognitive change at the genome-wide level in women but not men. In the majority of identified X genes (19 genes), increased expression was associated with slower cognitive decline in women. In contrast with cognition, X chromosome gene expression (3 genes), adjusted for age at death and education, was associated with neuropathological tau burden at the genome-wide level in men but not women. Conclusions and Relevance: In this study, the X chromosome was associated with cognitive trajectories and neuropathological tau burden in aging and AD in a sex-specific manner. This is important because specific X chromosome factors could contribute risk or resilience to biological pathways of aging and AD in women, men, or both.
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Envelhecimento/fisiologia , Doença de Alzheimer , Cromossomos Humanos X , Córtex Pré-Frontal Dorsolateral , Caracteres Sexuais , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Cognição , Disfunção Cognitiva , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/patologia , TranscriptomaRESUMO
Increasing evidence indicates that physical activity and exercise training may delay or prevent the onset of Alzheimer's disease (AD). However, systemic biomarkers that can measure exercise effects on brain function and that link to relevant metabolic responses are lacking. To begin to address this issue, we utilized blood samples of 23 asymptomatic late middle-aged adults, with familial and genetic risk for AD (mean age 65 years old, 50% female) who underwent 26 weeks of supervised treadmill training. Systemic biomarkers implicated in learning and memory, including the myokine Cathepsin B (CTSB), brain-derived neurotrophic factor (BDNF), and klotho, as well as metabolomics were evaluated. Here we show that aerobic exercise training increases plasma CTSB and that changes in CTSB, but not BDNF or klotho, correlate with cognitive performance. BDNF levels decreased with exercise training. Klotho levels were unchanged by training, but closely associated with change in VO2peak. Metabolomic analysis revealed increased levels of polyunsaturated free fatty acids (PUFAs), reductions in ceramides, sphingo- and phospholipids, as well as changes in gut microbiome metabolites and redox homeostasis, with exercise. Multiple metabolites (~30%) correlated with changes in BDNF, but not CSTB or klotho. The positive association between CTSB and cognition, and the modulation of lipid metabolites implicated in dementia, support the beneficial effects of exercise training on brain function. Overall, our analyses indicate metabolic regulation of exercise-induced plasma BDNF changes and provide evidence that CTSB is a marker of cognitive changes in late middle-aged adults at risk for dementia.
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Doença de Alzheimer , Fator Neurotrófico Derivado do Encéfalo/sangue , Catepsina B/sangue , Cognição , Exercício Físico , Proteínas Klotho/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Ácidos Graxos Ômega-3/sangue , Feminino , Microbioma Gastrointestinal , Humanos , Hidroxiprolina/sangue , Metabolismo dos Lipídeos , Masculino , Metabolômica , Pessoa de Meia-Idade , Prolina/análogos & derivados , Prolina/sangue , Fatores de RiscoRESUMO
BACKGROUND: Klotho is an anti-aging protein mainly expressed in the kidneys with a smaller amount expressed in adipose tissue. Klotho effects include roles in reducing oxidative stress, insulin signaling, adipogenesis and glucose metabolism. Few studies have investigated the role of dietary factors such as sugar sweetened beverages (SSBs) on serum α-klotho levels in young children. METHODS: Data was collected from 60 low-income Latina pregnant women and their infants in San Francisco from birth until 2 years of life and examined for associations between dietary factors and child secreted α-klotho protein levels at 2 years. RESULTS: Mean α-klotho levels were 1782.96 ± 874.56 pg/mL at 2 years of age. Any consumption of SSBs was independently associated with increased α-klotho levels (Beta = 682.79, 95%CI 67.50, 1298.09; p = 0.03). Household income ranging from $25,000 to $50,000 was also correlated to higher levels of α-klotho in children compared with lower income levels (<$25,000) (Beta = 1613.35, 95%CI 527.37, 2699.33; p = 0.005). CONCLUSIONS: The positive association between SSB intake and α-klotho levels at 2 years may reflect higher phosphate levels consistent with SSB intake. Higher socioeconomic status may be a proxy for reduced stress exposure in children, also associated with higher α-klotho levels. Future studies should evaluate the early impact of exposures to SSBs, stress and accelerated aging in children.