Hypothalamic MRI-derived microstructure is associated with neurocognitive aging in humans.

The hypothalamus regulates homeostasis across the lifespan and is emerging as a regulator of aging. In murine models, aging-related changes in the hypothalamus, including microinflammation and gliosis, promote accelerated neurocognitive decline. We investigated relationships between hypothalamic microstructure and features of neurocognitive aging, including cortical thickness and cognition, in a cohort of community-dwelling older adults (age range 65-97 years, n=124). Hypothalamic microstructure was evaluated with two magnetic resonance imaging diffusion metrics: mean diffusivity (MD) and fractional anisotropy (FA), using a novel image processing pipeline. Hypothalamic MD was cross-sectionally positively associated with age and it was negatively associated with cortical thickness. Hypothalamic FA, independent of cortical thickness, was cross-sectionally positively associated with neurocognitive scores. An exploratory analysis of longitudinal neurocognitive performance suggested that lower hypothalamic FA may predict cognitive decline. No associations between hypothalamic MD, age, and cortical thickness were identified in a younger control cohort (age range 18-63 years, n=99). To our knowledge, this is the first study to demonstrate that hypothalamic microstructure is associated with features of neurocognitive aging in humans.

Rare genetic coding variants associated with age-related episodic memory decline implicate distinct memory pathologies in the hippocampus.

Background: Approximately 40% of people aged 65 or older experience memory loss, particularly in episodic memory. Identifying the genetic basis of episodic memory decline is crucial for uncovering its underlying causes. Methods: We investigated common and rare genetic variants associated with episodic memory decline in 742 (632 for rare variants) Ashkenazi Jewish individuals (mean age 75) from the LonGenity study. All-atom MD simulations were performed to uncover mechanistic insights underlying rare variants associated with episodic memory decline. Results: In addition to the common polygenic risk of Alzheimer's Disease (AD), we identified and replicated rare variant association in ITSN1 and CRHR2 . Structural analyses revealed distinct memory pathologies mediated by interfacial rare coding variants such as impaired receptor activation of corticotropin releasing hormone and dysregulated L-serine synthesis. Discussion: Our study uncovers novel risk loci for episodic memory decline. The identified underlying mechanisms point toward heterogeneous memory pathologies mediated by rare coding variants.

Non-literacy biased, culturally fair cognitive detection tool in primary care patients with cognitive concerns: a randomized controlled trial.

Dementia is often undiagnosed in primary care, and even when diagnosed, untreated. The 5-Cog paradigm, a brief, culturally adept, cognitive detection tool paired with a clinical decision support may reduce barriers to improving dementia diagnosis and care. We performed a randomized controlled trial in primary care patients experiencing health disparities (racial/ethnic minorities and socioeconomically disadvantaged). Older adults with cognitive concerns were assigned in a 1:1 ratio to the 5-Cog paradigm or control. Primary outcome was improved dementia care actions defined as any of the following endpoints within 90 days: new mild cognitive impairment syndrome or dementia diagnoses as well as investigations, medications or specialist referrals ordered for cognitive indications. Groups were compared using intention-to-treat principles with multivariable logistic regression. Overall, 1,201 patients (mean age 72.8 years, 72% women and 94% Black, Hispanic or Latino) were enrolled and 599 were assigned to 5-Cog and 602 to the control. The 5-Cog paradigm demonstrated threefold odds of improvement in dementia care actions over control (odds ratio 3.43, 95% confidence interval 2.32-5.07). No serious intervention-related adverse events were reported. The 5-Cog paradigm improved diagnosis and management in patients with cognitive concerns and provides evidence to promote practice change to improve dementia care actions in primary care.ClinicalTrials.gov: NCT03816644 .

Cognitive reserve proxies are associated with age-related cognitive decline - Not age-related gait speed decline.

Cognition and gait share brain substrates in aging and dementia. Cognitive reserve (CR) allows individuals to cope with brain pathology and delay cognitive impairment and dementia. Yet, evidence for that CR is associated with age-related cognitive decline is mixed, and evidence for that CR is associated with age-related gait decline is limited. In 1,079 older (M Age = 75.4 years; 56.0% women) LonGenity study participants without dementia at baseline and up to 12 years of annual follow-up (M follow-up = 3.9 years, SD = 2.5 years), high CR inferred from cognitive (education years), physical (number of blocks walked per day; weekly physical activity days), and social (volunteering/working; living with someone) proxies were associated with slower rates of age-related decline in global cognition - not gait speed decline. Thus, cognitive, physical, and social CR proxies are associated with cognitive decline in older adults without dementia. The multifactorial etiology and earlier decline in gait than cognition may render it less modifiable by CR proxies later in life.

Hippocampal sclerosis and temporal lobe epilepsy following febrile status epilepticus: The FEBSTAT study.

OBJECTIVE: This study was undertaken to determine whether hippocampal T2 hyperintensity predicts sequelae of febrile status epilepticus, including hippocampal atrophy, sclerosis, and mesial temporal lobe epilepsy. METHODS: Acute magnetic resonance imaging (MRI) was obtained within a mean of 4.4 (SD = 5.5, median = 2.0) days after febrile status on >200 infants with follow-up MRI at approximately 1, 5, and 10 years. Hippocampal size, morphology, and T2 signal intensity were scored visually by neuroradiologists blinded to clinical details. Hippocampal volumetry provided quantitative measurement. Upon the occurrence of two or more unprovoked seizures, subjects were reassessed for epilepsy. Hippocampal volumes were normalized using total brain volumes. RESULTS: Fourteen of 22 subjects with acute hippocampal T2 hyperintensity returned for follow-up MRI, and 10 developed definite hippocampal sclerosis, which persisted through the 10-year follow-up. Hippocampi appearing normal initially remained normal on visual inspection. However, in subjects with normal-appearing hippocampi, volumetrics indicated that male, but not female, hippocampi were smaller than controls, but increasing hippocampal asymmetry was not seen following febrile status. Forty-four subjects developed epilepsy; six developed mesial temporal lobe epilepsy and, of the six, two had definite, two had equivocal, and two had no hippocampal sclerosis. Only one subject developed mesial temporal epilepsy without initial hyperintensity, and that subject had hippocampal malrotation. Ten-year cumulative incidence of all types of epilepsy, including mesial temporal epilepsy, was highest in subjects with initial T2 hyperintensity and lowest in those with normal signal and no other brain abnormalities. SIGNIFICANCE: Hippocampal T2 hyperintensity following febrile status epilepticus predicted hippocampal sclerosis and significant likelihood of mesial temporal lobe epilepsy. Normal hippocampal appearance in the acute postictal MRI was followed by maintained normal appearance, symmetric growth, and lower risk of epilepsy. Volumetric measurement detected mildly decreased hippocampal volume in males with febrile status.

Is the Montreal cognitive assessment culturally valid in a diverse geriatric primary care setting? Lessons from the Bronx.

BACKGROUND: Efficacy and validity of the MoCA for cognitive screening in ethnoculturally and linguistically diverse settings is unclear. We sought to examine the utility and discriminative validity of the Spanish and English MoCA versions to identify cognitive impairment among diverse community-dwelling older adults. METHODS: Participants aged ≥65 with cognitive concerns attending outpatient primary care in Bronx, NY, were recruited. MoCA and neuropsychological measures were administered in Spanish or English, and a neuropsychologist determined cognitive status (normal with subjective cognitive concerns [SCC], mild cognitive impairment [MCI], and dementia). One-way ANOVA compared cognitive statuses. ROC analyses identified optimal MoCA cutpoints for discriminating possible cognitive impairment. RESULTS: There were 231 participants, with mean age 73, 72% women, 43% Hispanic; 39% Black/African American; 113 (49%) completed testing in English and 118 (51%) in Spanish. Overall MoCA mean was 17.7 (SD = 4.3). Neuropsychological assessment identified 90 as cognitively normal/SCC, average MoCA 19.9 (SD = 4.1), 133 with MCI, average MoCA 16.6 (SD = 3.7), and 8 with dementia, average MoCA 10.6 (SD = 3.1). Mean English MoCA average was 18.6 (SD = 4.1) versus Spanish 16.7 (SD = 4.3). The published cutpoint ≤23 for MCI yielded a high false-positive rate (79%). ROC analyses identified ≤18.5 as the score to identify MCI or dementia using the English MoCA (65% sensitivity; 77% specificity) and ≤16.5 for the Spanish MoCA (64% sensitivity;73% specificity) in this sample of older adults with cognitive concerns. CONCLUSIONS: Current MoCA cutpoints were inappropriately high in a culturally/linguistically diverse urban setting, leading to a high false-positive rate. Lower Spanish and English MoCA cutpoints may improve diagnostic accuracy for identifying cognitive impairment in this group, highlighting the need for the creation and validation of accurate cognitive screeners for ethnoculturally and linguistically diverse older adults.

Organ aging signatures in the plasma proteome track health and disease.

Animal studies show aging varies between individuals as well as between organs within an individual1-4, but whether this is true in humans and its effect on age-related diseases is unknown. We utilized levels of human blood plasma proteins originating from specific organs to measure organ-specific aging differences in living individuals. Using machine learning models, we analysed aging in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5,676 adults across the human lifespan. We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ aging confers 20-50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart aging have a 250% increased heart failure risk and accelerated brain and vascular aging predict Alzheimer's disease (AD) progression independently from and as strongly as plasma pTau-181 (ref. 5), the current best blood-based biomarker for AD. Our models link vascular calcification, extracellular matrix alterations and synaptic protein shedding to early cognitive decline. We introduce a simple and interpretable method to study organ aging using plasma proteomics data, predicting diseases and aging effects.

Epidemiology of Motoric Cognitive Risk Syndrome in the Kerala Einstein Study: Protocol for a Prospective Cohort Study.

BACKGROUND: The southern India state of Kerala has among the highest proportion of older adults in its population in the country. An increase in chronic age-related diseases such as dementia is expected in the older Kerala population. Identifying older individuals early in the course of cognitive decline offers the best hope of introducing preventive measures early and planning management. However, the epidemiology and pathogenesis of predementia syndromes at the early stages of cognitive decline in older adults are not well established in India. OBJECTIVE: The Kerala Einstein Study (KES) is a community-based cohort study that was established in 2008 and is based in the Kozhikode district in Kerala state. KES aims to establish risk factors and brain substrates of motoric cognitive risk syndrome (MCR), a predementia syndrome characterized by the presence of slow gait and subjective cognitive concerns in individuals without dementia or disability. This protocol describes the study design and procedures for this KES project. METHODS: KES is proposing to enroll a sample of 1000 adults ≥60 years old from urban and rural areas in the Kozhikode district of Kerala state: 200 recruited in the previous phase of KES and 800 new participants to be recruited in this project. MCR is the cognitive phenotype of primary interest. The associations between previously established risk factors for dementia as well as novel risk factors (apathy and traumatic brain injury) and MCR will be examined in KES. Risk factor profiles for MCR will be compared between urban and rural residents as well as with individuals who meet the criteria for mild cognitive impairment (MCI). Cognitive and physical function, medical history and medications, sociodemographic characteristics, lifestyle patterns, and activities of daily living will be evaluated. Participants will also undergo magnetic resonance imaging and electrocardiogram investigations. Longitudinal follow-up is planned in a subset of participants as a prelude to future longitudinal studies. RESULTS: KES (2R01AG039330-07) was funded by the US National Institutes of Health in September 2019 and received approval from the Indian Medical Council of Research to start the study in June 2021. We had recruited 433 new participants from urban and rural sites in Kozhikode as of May 2023: 41.1% (178/433) women, 67.7% (293/433) rural residents, and 13.4% (58/433) MCR cases. Enrollment is actively ongoing at all the KES recruitment sites. CONCLUSIONS: KES will provide new insights into risk factors and brain substrates associated with MCR in India and will help guide future development of regionally specific preventive interventions for dementia. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/49933.

Visual-somatosensory integration (VSI) as a novel marker of Alzheimer's disease: A comprehensive overview of the VSI study.

Identification of novel, non-invasive, non-cognitive based markers of Alzheimer's disease (AD) and related dementias are a global priority. Growing evidence suggests that Alzheimer's pathology manifests in sensory association areas well before appearing in neural regions involved in higher-order cognitive functions, such as memory. Previous investigations have not comprehensively examined the interplay of sensory, cognitive, and motor dysfunction with relation to AD progression. The ability to successfully integrate multisensory information across multiple sensory modalities is a vital aspect of everyday functioning and mobility. Our research suggests that multisensory integration, specifically visual-somatosensory integration (VSI), could be used as a novel marker for preclinical AD given previously reported associations with important motor (balance, gait, and falls) and cognitive (attention) outcomes in aging. While the adverse effect of dementia and cognitive impairment on the relationship between multisensory functioning and motor outcomes has been highlighted, the underlying functional and neuroanatomical networks are still unknown. In what follows we detail the protocol for our study, named The VSI Study, which is strategically designed to determine whether preclinical AD is associated with neural disruptions in subcortical and cortical areas that concurrently modulate multisensory, cognitive, and motor functions resulting in mobility decline. In this longitudinal observational study, a total of 208 community-dwelling older adults with and without preclinical AD will be recruited and monitored yearly. Our experimental design affords assessment of multisensory integration as a new behavioral marker for preclinical AD; identification of functional neural networks involved in the intersection of sensory, motor, and cognitive functioning; and determination of the impact of early AD on future mobility declines, including incident falls. Results of The VSI Study will guide future development of innovative multisensory-based interventions aimed at preventing disability and optimizing independence in pathological aging.

Age-related changes in gait domains: Results from the LonGenity study.

BACKGROUND: Impairment in gait domains such as pace, rhythm, and variability are associated with falls, cognitive decline, and dementia. However, the longitudinal changes in these gait domains are poorly understood. The aim of this study was to examine age-related changes in gait domains overall and in those with cognitive impairment and mobility disability. METHODS: Participants were from the LonGenity study (n = 797; M Age=75.1 SD 6.5 years; 58.2% female) and were followed up to 12 years (Median=3.3; IQR: 1.1; 6.3). Gait speed and absolute values of step length, step time, cadence and, variability (standard deviation) of step length and step time during usual pace walking were assessed. Principal components analysis was used to obtain weighted combinations of three gait domains: pace (velocity, step length), variability (step length variability, step time variability) and rhythm (step time). Linear mixed effect models were used to examine age-related changes in gait domains overall, and in those with cognitive impairment and mobility disability at baseline. RESULTS: Pace declined, and rhythm increased (worsened) in an accelerating non-linear fashion. Variability gradually increased with age. Those with cognitive impairment had faster rates of change in pace and rhythm. Those with mobility disability had faster increases in rhythm. CONCLUSIONS: Age-related changes in gait domains are not uniform. Individuals with cognitive and mobility impairments are particularly vulnerable to accelerated change in pace and or rhythm.

Differences in Surgical Complications for Stage 1 Phalloplasty With Concurrent Versus Asynchronous Hysterectomy in Transmasculine Patients.

Background The authors sought to compare the perioperative morbidity of Stage 1 phalloplasty with asynchronous vs concurrent hysterectomy among transmasculine patients. Methods This retrospective study included transmasculine patients undergoing Stage 1 phalloplasty with either asynchronous or concurrent hysterectomy at Kaiser Permanente Northern California from January 1, 2017, to September 9, 2019. The primary outcome was differences in surgical site infection rates. Secondary outcomes included perioperative and other postoperative complications. Comparisons of demographics and outcomes were made by F-tests and Fisher's exact tests. A p value of < 0.05 was considered statistically significant. Results Of 66 transmasculine patients undergoing Stage 1 phalloplasty, 32 (48%) had an asynchronous hysterectomy and 34 (52%) had a concurrent hysterectomy. Overall, surgical site infection rates were low, and there were no significant differences between groups. Patients who had undergone asynchronous hysterectomy had more neourethral complications with Stage 1 phalloplasty than those undergoing concurrent procedures (28% vs 3%, p < 0.05). There were no significant differences in estimated blood loss, length of stay, urinary tract infection, overactive bladder or narcotic use between groups. Conclusion Overall, there were no differences between groups in most postoperative complication rates. Although more neourethral complications were found in those undergoing asynchronous hysterectomy prior to Stage I phalloplasty, this may be partially explained by increasing surgeon experience over time given this difference did not remain statistically significant after the first year of the study period. Gynecologists seeking to provide comprehensive and inclusive care to transmasculine patients should take these findings into consideration when counseling patients planning genital gender affirmation surgery.

The 5-Cog paradigm to improve detection of cognitive impairment and dementia: clinical trial protocol.

Cognitive impairment related to dementia is under-diagnosed in primary care despite availability of numerous cognitive assessment tools; under-diagnosis is more prevalent for members of racial and ethnic minority groups. Clinical decision-support systems may improve rates of primary care providers responding to positive cognitive assessments with appropriate follow-up. The 5-Cog study is a randomized controlled trial in 1200 predominantly Black and Hispanic older adults from an urban underserved community who are presenting to primary care with cognitive concerns. The study will validate a novel 5-minute cognitive assessment coupled with an electronic medical record-embedded decision tree to overcome the barriers of current cognitive assessment paradigms in primary care and facilitate improved dementia care.

Dementia is common, though under-recognized, in older adults (OAs). Primary care providers (PCPs) miss opportunities to help patients and their families manage the disease because of failure to, or delay to, make an appropriate diagnosis. Black and Hispanic OAs are more likely than White OAs to experience delayed diagnosis. Most available memory tests are too long for practical use by PCPs, and are ill suited to patients of diverse language, cultural and educational backgrounds. Studies have shown that even when patients test positive for dementia in primary care, PCPs often do not take follow-up action. Our improved memory test, the 5-Cog, is brief (5 min), not biased by language issues (uses pictures and symbols instead of words), and simple (doesn't require expensive technology and complex staff training). The 5-Cog is paired with a clinical decision support tool, providing tailored recommendations directly into the patient's medical record, and making it easier for PCPs to take appropriate action. This study will evaluate whether the 5-Cog paradigm results in improved dementia care.

Lessons from Detecting Cognitive Impairment Including Dementia (DetectCID) in Primary Care.

BACKGROUND: Cognitive impairment, including dementia, is frequently under-detected in primary care. The Consortium for Detecting Cognitive Impairment, including Dementia (DetectCID) convenes three multidisciplinary teams that are testing novel paradigms to improve the frequency and quality of patient evaluations for detecting cognitive impairment in primary care and appropriate follow-up. OBJECTIVE: Our objective was to characterize the three paradigms, including similarities and differences, and to identify common key lessons from implementation. METHODS: A qualitative evaluation study with dementia specialists who were implementing the detection paradigms. Data was analyzed using content analysis. RESULTS: We identified core components of each paradigm. Key lessons emphasized the importance of engaging primary care teams, enabling primary care providers to diagnose cognitive disorders and provide ongoing care support, integrating with the electronic health record, and ensuring that paradigms address the needs of diverse populations. CONCLUSION: Approaches are needed that address the arc of care from identifying a concern to post-diagnostic management, are efficient and adaptable to primary care workflows, and address a diverse aging population. Our work highlights approaches to partnering with primary care that could be useful across specialties and paves the way for developing future paradigms that improve differential diagnosis of symptomatic cognitive impairment, identifying not only its presence but also its specific syndrome or etiology.

Feasibility of Problem Adaption Therapy in a Diverse, Frail Older Adult Population (PATH-MHS).

The purpose of the Problem Adaptation Therapy - Montefiore Health System (PATH-MHS) pilot program was to demonstrate the feasibility and effectiveness of PATH across a culturally, educationally, and functionally diverse cohort of older adults. METHODS: Clinicians referred 145 participants with depression and cognitive impairment to PATH-MHS. We completed analyses of the change in depression, disability and the association between baseline characteristics and remission of depression. RESULTS: Most participants were Hispanic or Non-Hispanic Black and 54.7% (76) were primary Spanish speakers. Overall, there were significant decreases in the mean PHQ-9 and WHODAS 2.0 scores. In logistic regression models, neither age, education, gender, race/ethnicity, language nor long-term care status was significantly associated with remission of depression. CONCLUSIONS: This study demonstrates that we were able to engage a diverse, cognitively impaired, and frail cohort of older adults in PATH-MHS with significant reductions in depression and disability.

Relative Trajectories of Gait and Cognitive Decline in Aging.

BACKGROUND: Gait and cognition decline with advancing age, and presage the onset of dementia. Yet, the relative trajectories of gait and cognitive decline in aging are poorly understood-particularly among those with the motoric cognitive risk (MCR) syndrome. This study compared changes in simple and complex gait performance and cognition, as a function of age and MCR. METHODS: We examined gait and cognitive functions of 1 095 LonGenity study participants (mean age = 75.4 ± 6.7 years) with up to 12 years of annual follow-up. Participants were of Ashkenazi Jewish descent, free of dementia, ambulatory, and had a 12.2% MCR prevalence at baseline. Gait speed was measured at usual pace walking (single-task walking, STW-speed) and walking while talking (WWT-speed). Eleven neuropsychological test scores were examined separately, and as a global cognition composite. Linear mixed-effects models adjusted for baseline sex, education, parental longevity, cognitive impairment, and global health were used to estimate changes in gait and cognition, as a function of age and MCR. RESULTS: STW-speed, WWT-speed, and cognitive tests performance declined in a nonlinear (accelerating) fashion with age. STW-speed declined faster than WWT-speed and cognitive test scores. People with MCR showed faster rates of decline on figure copy and phonemic fluency. CONCLUSIONS: Gait declines at a faster rate than cognition in aging. People with MCR are susceptible to faster decline in visuospatial, executive, and language functions. This study adds important knowledge of trajectories of gait and cognitive decline in aging, and identifies MCR as a risk factor for accelerated cognitive decline.

Neurostimulation for cognitive enhancement in Alzheimer's disease (the NICE-AD study): a randomized clinical trial.

New therapies for symptoms in Alzheimer's disease (AD) are urgently needed. Prior studies suggest that transcranial direct current stimulation (tDCS), a noninvasive neuromodulatory method, may be a safe and potentially effective treatment, but conclusions have been limited by small-sample sizes and brief stimulation protocols. This double-blind randomized trial involving 100 older adults with mild-to-moderate AD examines effects of 6 months of at-home active tDCS or sham delivered over the dorsolateral prefrontal cortex. The primary outcome is global cognitive performance. Secondary outcomes include executive-control/spatial selective attention, functional neuroplasticity, depressive symptoms, quality of life and the durability of effects 3 months after the stimulation period. The results will provide evidence on the efficacy of multimonth at-home tDCS in the AD treatment. =Clinical trial identifier NCT04404153 (Clinicaltrials.gov).

Cross-Cultural Comparisons of Subjective Cognitive Complaints in a Diverse Primary Care Population.

BACKGROUND: Very few studies have explored the utility of subjective cognitive complaints (SCCs) in primary care settings. OBJECTIVE: We aim to investigate associations between SCCs (item-level), objective cognitive function (across domains and global), and mood in a diverse primary care population, including subjects with mild cognitive impairment. METHODS: We studied 199 (75.9%females; 57.8%Hispanics; 42.2%African Americans) older adults (mean age 72.5 years) with memory concerns at a primary care clinic. A five-item SCC questionnaire, and objective cognitive assessments, including the Montreal Cognitive Assessment (MoCA) and the Geriatric Depression Scale, were administered. RESULTS: Logistic regression analyses showed associations between SCC score and depressive symptoms. A memory-specific ("memory worsening") SCC predicted scores on the MoCA (p = 0.005) in Hispanics. CONCLUSION: SCCs are strongly linked to depressive symptoms in African Americans and Hispanics in a primary care setting; a specific type of SCC is related to global cognitive function in Hispanics.

Telehealth for the cognitively impaired older adult and their caregivers: lessons from a coordinated approach.

The Covid-19 pandemic forced providers to alter their delivery of care to special populations, including older adults with cognitive impairment. The Montefiore-Einstein Center for the Aging Brain, a specialty multidisciplinary center for the evaluation and management of patients with neurodegenerative disorders, developed a coordinated approach (Coordinated Care At Risk/Remote Elderly program [CCARRE]) to reach our diverse population during the initial Covid-19 crisis in New York City, USA. In the tele-evaluation of the first 85 patients seen with CCARRE, we recognized unique factors that could improve patient care, lessen burden and optimize access to community resources. Lessons learned from the experience are shared.

Plasma proteomic profile of age, health span, and all-cause mortality in older adults.

Aging is a complex trait characterized by a diverse spectrum of endophenotypes. By utilizing the SomaScan® proteomic platform in 1,025 participants of the LonGenity cohort (age range: 65-95, 55.7% females), we found that 754 of 4,265 proteins were associated with chronological age. Pleiotrophin (PTN; ß[SE] = 0.0262 [0.0012]; p = 3.21 × 10-86 ), WNT1-inducible-signaling pathway protein 2 (WISP-2; ß[SE] = 0.0189 [0.0009]; p = 4.60 × 10-82 ), chordin-like protein 1 (CRDL1; ß[SE] = 0.0203[0.0010]; p = 1.45 × 10-77 ), transgelin (TAGL; ß[SE] = 0.0215 [0.0011]; p = 9.70 × 10-71 ), and R-spondin-1(RSPO1; ß[SE] = 0.0208 [0.0011]; p = 1.09 × 10-70 ), were the proteins most significantly associated with age. Weighted gene co-expression network analysis identified two of nine modules (clusters of highly correlated proteins) to be significantly associated with chronological age and demonstrated that the biology of aging overlapped with complex age-associated diseases and other age-related traits. The correlation between proteomic age prediction based on elastic net regression and chronological age was 0.8 (p < 2.2E-16). Pathway analysis showed that inflammatory response, organismal injury and abnormalities, cell and organismal survival, and death pathways were associated with aging. The present study made novel associations between a number of proteins and aging, constructed a proteomic age model that predicted mortality, and suggested possible proteomic signatures possessed by a cohort enriched for familial exceptional longevity.

Insulin-like Growth Factor-1 and IGF Binding Proteins Predict All-Cause Mortality and Morbidity in Older Adults.

While the growth hormone/insulin-like growth factor-1 (GH/IGF-1) pathway plays essential roles in growth and development, diminished signaling via this pathway in model organisms extends lifespan and health-span. In humans, circulating IGF-1 and IGF-binding proteins 3 and 1 (IGFBP-3 and 1), surrogate measures of GH/IGF-1 system activity, have not been consistently associated with morbidity and mortality. In a prospective cohort of independently-living older adults (n = 840, mean age 76.1 ± 6.8 years, 54.5% female, median follow-up 6.9 years), we evaluated the age- and sex-adjusted hazards for all-cause mortality and incident age-related diseases, including cardiovascular disease, diabetes, cancer, and multiple-domain cognitive impairment (MDCI), as predicted by baseline total serum IGF-1, IGF-1/IGFBP-3 molar ratio, IGFBP-3, and IGFBP-1 levels. All-cause mortality was positively associated with IGF-1/IGFBP-3 molar ratio (HR 1.28, 95% CI 1.05-1.57) and negatively with IGFBP-3 (HR 0.82, 95% CI 0.680-0.998). High serum IGF-1 predicted greater risk for MDCI (HR 1.56, 95% CI 1.08-2.26) and composite incident morbidity (HR 1.242, 95% CI 1.004-1.538), whereas high IGFBP-1 predicted lower risk for diabetes (HR 0.50, 95% CI 0.29-0.88). In conclusion, higher IGF-1 levels and bioavailability predicted mortality and morbidity risk, supporting the hypothesis that diminished GH/IGF-1 signaling may contribute to human longevity and health-span.