Importance:There is limited research on the long-term associations of plasma phosphorylated tau 217 (p-tau217) with mild cognitive impairment (MCI) and dementia. No study has evaluated whether such associations vary by race or hormone therapy (HT) use. Objective:To examine associations of baseline plasma p-tau217 with incident MCI and dementia and determine whether associations vary by age, race, APOE ε4 carrier status, or HT use. Design, Setting, and Participants:This cohort study examined women recruited from 39 US clinical sites between 1996 and 1999 into the Women's Health Initiative Memory Study who were randomized to either estrogen alone vs placebo or estrogen plus progestin vs placebo. Women were assessed for up to 25 years through 2021. Baseline plasma p-tau217 was measured in 2024 and analyzed between February and August 2025. Women aged 65 to 79 years who were cognitively unimpaired at baseline were included for this analysis. Exposure:Plasma p-tau217, quantified using the ALZpath Simoa assay. Main Outcomes and Measures:The primary outcome was the combined end point of incident MCI or probable dementia. Secondary outcomes included MCI and dementia examined separately. Cause-specific hazard ratios (HRs) and 95% CIs for the association of p-tau217 with MCI or dementia were estimated using Cox proportional hazards regression models. Results:Among 2766 participants (mean [SD] age, 69.9 [3.8] years; 486 [17.9%] Black, 196 [7.1%] Hispanic, and 2007 [73.9%] White), 1311 developed the combined end point of MCI or dementia (849 participants with MCI and 752 participants with dementia). Every 1-SD increase in log2-transformed p-tau217 was associated with incident MCI or dementia (HR, 2.43; 95% CI, 2.18-2.71) and each individual outcome (MCI: HR, 1.94; 95% CI, 1.72-2.20; dementia: HR, 3.17; 95% CI, 2.79-3.61). Associations of p-tau217 with dementia were larger in magnitude for women randomized to estrogen plus progestin (HR, 4.18; 95% CI, 3.41-5.13) vs placebo (HR, 3.07; 95% CI, 2.41-3.91) (P for interaction = .04) but did not significantly vary by estrogen alone vs placebo. P-tau217 associations with MCI or dementia were larger in magnitude for women older than 70 years (P for interaction = .04), APOE ε4 carriers (P for interaction = .02), and White women compared with Black women (P for interaction < .001). However, the combination of p-tau217 and age performed similarly in White women (area under the curve = 72.0%; 95% CI, 70.3%-73.6%) and Black women (area under the curve = 70.4%; 95% CI, 64.0%-78.0%). P-tau217 was not associated with incident MCI in Black women. Conclusions and Relevance:In this cohort study of cognitively unimpaired older women, p-tau217 was associated with incident MCI or dementia up to 25 years later. These findings suggest that age, race, APOE ε4, and HT use should be considered when examining associations of p-tau217 with cognitive outcomes.

BACKGROUND:Little is known about whether epigenetic age acceleration (EAA) clocks are capable of predicting exceptional longevity with or without preserved cognitive function. METHODS:We examined 5844 women from the Women's Health Initiative Memory Study. Fifteen epigenetic clocks were measured at baseline (1996-1999). Longevity outcomes were defined as: 1) survival to age 90 with preserved cognition (n = 1726, 29.5%); or 2) survival to age 90 with cognitive impairment (n = 956, 16.4%); vs. 3) death before age 90 (n = 2611, 44.7%). Logistic regression models examined associations between the 15 clocks and survival to age 90 (vs. death before age 90), adjusting for covariates. Multinomial logistic regression models examined associations with survival to age 90 without cognitive impairment and survival to age 90 with cognitive impairment (each vs. death before age 90), also adjusting for covariates. RESULTS:Each standard deviation increase in EAA for the first-generation clocks was associated with 7%-18% reduced odds of survival to age 90 vs. earlier death. Stronger associations were observed for second- and third-generation clocks, including AgeAccelGrim2 (OR = 0.66; 95% CI 0.61-0.71), PCGrimAge (OR = 0.64; 95% CI 0.59-0.69), PCPhenoAge (OR = 0.73; 95% CI 0.68-0.78) and DunedinPACE (OR = 0.77; 95% CI 0.72-0.82). None of the clocks was more strongly associated with survival to age 90 with preserved cognition than with survival to age 90 with cognitive impairment, relative to death before age 90. CONCLUSION:All epigenetic clocks were associated with exceptional longevity, but none were associated with cognitive healthspan. Developing clocks that can differentiate long survival with and without preserved cognitive function is critical.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by amyloid-β (Aβ) and tau accumulation. Dysregulation of the brain renin-angiotensin system, particularly hyperactivation of the angiotensin II type-1 receptor, contributes to AD pathogenesis. In contrast, activation of the angiotensin II type-2 receptor (AT2R) has been linked to neuroprotection and reduced Aβ accumulation. However, the underlying mechanisms of AT2R-related Aβ reduction and the role of AT2R-interacting protein (ATIP), also known as AT2R-binding protein, remain unclear. We aimed to explore the relationship between ATIP and Aβ and tau pathologies as well as brain AT2R protein levels in older adults with AD. Using TOMAHAQ, a method that enables precise examination of numerous peptides across various samples in a single mass spectrometry analysis, we identified a specific human tryptic peptide that enables ATIP quantification. We applied this method to postmortem frontal-cortex samples to measure ATIP levels. Sixty individuals with AD were included, half of whom were users of angiotensin receptor blockers (ARBs). The ATIP peptide was quantifiable in 12 participants. Among these individuals, higher ATIP levels were associated with lower Aβ burden in the frontal-cortex and across multiple brain regions. This association remained significant after adjustment for age and ARB use. In contrast, ATIP levels were not significantly associated with AT2R, which was quantified using TOMAHAQ. This suggests that the relationship between ATIP and Aβ burden may not depend on differences in AT2R abundance. Although causality cannot be established, these findings may suggest a potential protective role for ATIP in AD that warrants further investigation.

Although prior studies have examined associations of personality traits with sleep, most have investigated self-reported sleep, been cross-sectional, and focused on younger and middle-aged adults. We investigated associations of personality with actigraphic sleep parameters and changes in sleep in 398 cognitively normal adults aged 40–95 years (M ± SD = 70.1 ± 12.0) in the Baltimore Longitudinal Study of Aging. Participants completed the Revised NEO Personality Inventory (NEO-PI-R) and 6.61 days +/-1.01 nights of wrist actigraphy at the same study visit. Participants with wrist actigraphy at multiple study visits had actigraphy data at 3.11 ± 1.52 visits (follow-up = 2.35 ± 0.70 years). Adjusting for age, sex, race, education, depressive symptoms, comorbidities and interactions of these variables with time, greater extraversion was associated with higher sleep efficiency. After further adjustment for BMI, sleep medication use, and sleep apnea symptoms, greater extraversion was associated with shorter total sleep time, and greater openness was associated with shorter average wake bout length. We observed numerous interactions of personality with sex and age, with stronger personality-sleep associations generally present at younger ages (i.e., aged 50–60 vs. 70–80) and sex differences in associations. Middle-aged and older adults higher in extraversion and lower in openness may be more vulnerable to poor sleep and may benefit from screening for sleep disturbances.

BACKGROUND:Skeletal muscle dysfunction contributes significantly to disability, which is one of the most common complications of diabetes in older adults. We aimed to assess whether diabetes was associated with a steeper muscle strength decline and whether lower strength is related to a higher diabetes incidence in older adults. METHODS:A prospective analysis of data from two Italian population-based studies in older adults (the Invecchiare in Chianti and Progetto Veneto Anziani studies). Diabetes was assessed at baseline and after a median of 4.4 (first follow-up) and 6.3 years (second follow-up) using multiple sources of information. Muscle function was assessed as handgrip strength. RESULTS:The sample comprised 3927 participants (58.6% females) with a mean age of 75.5 years (29.6% aged ≥80 years). After adjusting for potential confounders, the decline in muscle strength among individuals with diabetes exceeded that of those without diabetes by 0.70 kg (95% CI, -1.30 to -0.11) at the first follow-up and by 0.84 kg (95% CI, -1.61 to -0.07) at the second follow-up. In those taking oral antidiabetics, this association was even stronger. Over a median 5-year follow-up, 186 incident diabetes cases were recorded. In a multivariable Cox regression, each 1-SD higher in the handgrip/body weight ratio was associated with an 20% lower likelihood of incident diabetes (95% CI, 0.68-0.95, n = 3102). CONCLUSIONS:These findings demonstrate an independent circular relationship between diabetes and skeletal muscle strength. In older people, muscle dysfunction may be a long-term diabetes complication. Whether increasing muscle strength might reduce diabetes risk remains to be determined.

Spinal cord morphometry provides essential biomarkers of neurological health, but clinical interpretations are confounded by inter-subject variability and a lack of normative references across the full human lifespan. We address this gap by generating the first comprehensive lifespan charts for cervical spinal cord morphometry. We leveraged 30 population-based brain MRI datasets, aggregating 78,269 scans from 41,042 individuals (ages 0-100) whose imaging protocols included cervical cord coverage. To overcome contrast variability, we employed a state-of-the-art contrast-agnostic deep learning segmentation method, extracting cross-sectional area (CSA), anteroposterior (AP) and right-left (RL/transverse), and shape indices (compression ratio, eccentricity, and solidity) from C1 to C7. Normative trajectories were modeled using Generalized Additive Models for Location, Scale, and Shape (GAMLSS). The resulting charts reveal distinct non-linear lifespan changes: rapid growth through childhood and adolescence, peak maturation occurring in early-to-mid adulthood (e.g., mid-30s for CSA), followed by gradual decreases. Significant regional variations along the cervical cord and consistent sex differences (males > females for size metrics) were quantified. Spinal cord trajectories showed strong temporal coupling with brain white matter and brainstem volumes, suggesting integrated CNS development and aging. These lifespan charts provide a robust normative framework, enabling age- and sex-specific centile scoring of individual spinal cord morphometry. This resource offers a critical tool for differentiating typical variation from pathological changes, enhancing the clinical utility of spinal cord MRI in studies of development and neurodegeneration.

Objectives Tooth loss is linked to cognitive impairment and cognitive decline in older adults. Whether tooth loss is associated with loss of brain structure is unknown, particularly with respect to white matter integrity, which is vulnerable to inflammation and vascular pathology. Methods We examined the associations between clinically assessed tooth loss and subsequent changes in brain atrophy and microstructural integrity over an average follow-up of 4.8 (SD=3.6) years in 375 Baltimore Longitudinal Study of Aging participants (mean age=65.5 years, 53.6% women, average tooth loss: 3) using linear mixed-effects models, adjusted for age, sex, race, and scanner site. Brain volumes and microstructural integrity were assessed via 3T MRI volumetric scans and DTI, respectively, over up to 12 years between 2008 and 2020. Results More tooth loss was cross-sectionally associated with a larger 4th ventricle, smaller brain volumes in temporal areas, greater deep white matter signal abnormalities, and lower white matter integrity in the corpus callosum. Longitudinally, each tooth loss was associated with a faster increase in diffusivity in the corpus callosum and corona radiata (all p<0.01), suggesting loss of microstructural integrity. Tooth loss was also associated with higher white blood cell counts, neutrophil counts, and erythrocyte sedimentation rate, greater increases in white blood cell and neutrophil counts and greater decrease in albumin over time (all p<0.05). Adjustment for these markers did not alter the associations with neuroimaging outcomes. Conclusion Tooth loss may indicate subsequent white matter degradation, independent of inflammation markers. Future studies are warranted to elucidate the biological mechanisms driving these associations. Clinical significance Within aging, tooth loss may indicate an unfavorable brain structure which overlaps with the Alzheimer’s disease signature and indicate long-term degradation of white matter integrity and increased inflammation.

Cellular senescence increases in frequency with age and is implicated in age-related pathologies, and identifying circulating biomarkers of senescence holds great diagnostic potential. Circulating senescence signatures are predictive of many age-related traits and diseases, though cell type-specific senescence signatures have not been comprehensively explored. In this study, senescence signatures from the Senescence Catalog (SenCat), including 14 human cell types such as peripheral blood mononuclear cells, renal epithelial cells, vascular smooth muscle cells, among others, are examined for their clinical relevance in circulation in two longitudinal studies: 1,275 participants of the Baltimore Longitudinal Study of Aging (BLSA) and 997 participants of the Invecchiare in Chianti (InCHIANTI) study. Notably, pooled senescence proteins outperformed non-senescence proteins in predicting many clinical parameters such as age and hypertension, and in many instances cell type senescence signatures mapped most strongly to their corresponding health domain. Importantly, the immune cell senescence signature is associated with future onset of several diseases such as diabetes. This study demonstrates that circulating cell type-specific biomarkers of senescence can reveal higher resolution health status than previously attained.

BACKGROUND:Gait performance in older adults reflects the integrated function of balance, lower-extremity strength, and symptom-related factors such as musculoskeletal pain. However, commonly used clinical measures provide limited insight into the functional organization of gait control. OBJECTIVE:To develop and evaluate the Balance-Weighted Gait Score (BWGS), a composite index derived from simple clinical measures, and to examine its construct validity and associations with gait characteristics in older adults. METHODS:Participants aged 60-96 years from the Baltimore Longitudinal Study of Aging (BLSA) who completed balance assessments were included (n = 428). BWGS was derived using ordinary least squares regression, integrating chair-rise time, narrow-based walking performance, and knee pain. Construct validity was evaluated using one-leg stance time as an independent measure of balance performance. Associations between BWGS and spatiotemporal, kinematic, and kinetic gait parameters were analyzed. Fall history was included for descriptive comparison. RESULTS:Higher BWGS values were associated with faster gait speed, longer stride length, greater joint range of motion at the hip, knee, and ankle, increased mechanical work expenditure, and narrower stride width (all p < 0.05). Higher BWGS was also associated with one-leg stance performance, providing supportive evidence of construct validity. These associations showed distinct patterns when stratified by fall history. CONCLUSION:BWGS provides a simple and clinically interpretable index reflecting key biomechanical and control-related features of gait. By integrating multiple functional components into a single metric and demonstrating construct validity against independent balance performance, BWGS offers a practical tool for characterizing balance-related gait regulation in older adults.

Mitochondria play central roles in cellular metabolism and in key processes such as inflammation, stress response, cell death and signalling. Mitochondrial quality control (MQC) mechanisms continuously monitor organelle integrity and function, and repair or eliminate damaged mitochondria to replace them with newly formed, healthy organelles. MQC is particularly important under metabolic or environmental stress conditions. Failure of MQC paves the way to chronic diseases, such as diabetes, metabolic syndromes and immunosenescence. This Review summarizes our current understanding of MQC biology in the context of healthy human longevity. We explore the regulation of MQC in physiological conditions and explain how the dysregulation of MQC in ageing negatively impacts systemic metabolism and immune function. We discuss emerging therapeutic strategies-such as NAD+, AMPK activators and caloric restriction-that maintain a robust MQC to improve metabolic resilience and illustrate how preclinical and clinical studies can leverage MQC as a potential gerotherapeutic target.

Background Alzheimer’s disease (AD) pathology, particularly amyloid-β (Aβ) deposition, occurs years before clinical symptoms. Modifiable risk factors may influence cognitive trajectories during this preclinical stage, but whether amyloid status alters their effects remains unclear. Objectives To investigate interactions between amyloid pathology and modifiable risk factors in predicting longitudinal cognitive decline among cognitively unimpaired older adults. Design and Setting This study was a secondary analysis of data derived from two large multicenter longitudinal cohort studies, the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study. Participants A total of 1707 cognitively unimpaired adults aged 65–85 years were included, comprising 1169 amyloid-positive participants from the A4 Study (Aβ+) and 538 amyloid-negative participants from the LEARN Study (Aβ–). Measurements Cognitive function was assessed every six months using the Preclinical Alzheimer’s Cognitive Composite (PACC) over a mean follow-up of 4.9 years. Eight established modifiable risk factors—low education, alcohol use, diabetes, high cholesterol, high blood pressure, obesity, depressive symptoms, and physical inactivity—were evaluated. Linear mixed-effects models were applied to examine associations between each risk factor and longitudinal PACC decline, and to test interactions with amyloid status, adjusting for demographic and genetic covariates. Results Significant interactions between amyloid status and modifiable risk factors were observed for diabetes (adjusted β = −0.206, p = 0.032), high cholesterol (adjusted β = −0.155, p < 0.001), and physical inactivity (adjusted β = −0.161, p = 0.046), indicating combined effects rather than additive effects on cognitive decline among Aβ+ individuals. In the A4 study (Aβ+), low education, diabetes, high cholesterol, and physical inactivity were independently associated with accelerated cognitive decline, whereas obesity was linked to slower decline. In contrast, in the LEARN study (Aβ-), these associations were not statistically significant. Conclusions In conclusion, the significant interactions with amyloid status were observed for diabetes, high cholesterol, and physical inactivity, indicating that these risk factors were associated with faster cognitive decline specifically in Aβ+ individuals. The results suggest that consideration of amyloid status may be important when evaluating the potential role of metabolic and lifestyle risk factors in preclinical cognitive decline. In Aβ+ individuals, obesity was associated with slower cognitive decline, while low education was linked to lower baseline cognition or a reduced symptom threshold, without a significant interaction with amyloid status. Future studies should incorporate amyloid status and longitudinal biomarkers to assess whether modifying these factors can slow preclinical cognitive decline.

BACKGROUND:The energetic cost of walking increases with age and is linked to physical function impairment, but its relation to cognitive impairment is unknown. METHODS:A total of 687 initially cognitively normal older adults (mean age 74.0 ± 7.2 years, 52% women) underwent repeated walking energy expenditure assessments (V̇O2) and adjudicated cognitive diagnoses over 7.6 ± 3.8 years. We examined (1) trajectories in the energetic cost of walking prior to any clinical diagnosis of cognitive impairment, comparing adults who later developed cognitive impairment versus those who did not, and (2) the baseline energetic cost and future risk of cognitive impairment using linear mixed-effects and Cox regression models. RESULTS:Ninety-one participants (13%) progressed to cognitive impairment. Progressors exhibited a steeper increase in energetic cost than non-progressors (B = 0.13; p = 0.003). Higher baseline cost predicted impairment among adults ≥75 years (hazard ratio [HR] = 1.1, 95% confidence interval [CI] = 1.00 to 1.20, p = 0.039), but not those aged 65 to 74 (HR = 0.91, 95% CI = 0.81 to 1.01, p = 0.089). CONCLUSION:Walking efficiency provides a physiological link between mobility and cognitive health; preserving efficiency may reduce risk of Alzheimer's disease and related dementias.

The world is rapidly aging. It is projected that the “young old” (i.e., 60+ y) population will double by 2050 and the “older old” (i.e., 80+ y) will nearly triple. Greater life expectancy has been accompanied by more chronic health conditions and disabilities, especially those that are related to diet and lifestyle. Although people are living longer, their healthy life expectancy has not kept pace, meaning that more years are spent in poorer health—thus, the need to identify targets to increase “health span.” Nutrition plays a critical role in aging healthfully. However, the aging process is accompanied by unique physiological, social, and contextual factors that impact the nutritional needs of the aging population—requiring more specific and tailored dietary recommendations. To examine the complexity of diet within the aging population, the Nutrition and Wellness Science Forum: Exploring the Journey to Healthy Aging was held in Washington, D.C. to focus on scientific evidence and research gaps surrounding dietary intakes and nutrient adequacy among older adults, as well as the role of nutrition in musculoskeletal, cardiometabolic, and cognitive health. Discussions also addressed the need for culturally appropriate dietary assessment methods and interventions that reflect the heterogeneity and diversity of older adults, as well as the importance of the food system. This review summarizes the forum’s key themes, discussions, and identified research gaps.

Cellular senescence is implicated in age-related pathologies, and identifying circulating biomarkers of senescence holds great diagnostic potential. Circulating senescence signatures are predictive of age-related traits and diseases, though cell type senescence signatures have not been comprehensively explored. In this study, senescence signatures from the Senescence Catalog (SenCat), including 14 human cell types are examined in circulation for clinical relevance in two longitudinal studies—1,275 participants of the Baltimore Longitudinal Study of Aging (BLSA) and 997 participants of the Invecchiare in Chianti (InCHIANTI) study. Notably, pooled senescence proteins outperform non-senescence proteins in predicting many clinical parameters such as age and hypertension, and in many instances, cell type senescence signatures map most strongly to their corresponding health domain. Importantly, the immune cell senescence signature is associated with mortality and future disease onset. This study demonstrates that circulating cell type biomarkers of senescence can reveal higher resolution health status than previously attained.

BackgroundGait speed is an important indicator of functional status and health outcomes in older adults. Electronic gait mats are common in research, but stopwatches are more feasible in clinical practice. This study compared agreement between single task (ST) gait speed measured by stopwatch and gait mat and described single and dual task (DT) gait performance measured by gait mat.MethodsA subset of Atherosclerosis Risk in Communities (ARIC) Study Visit 8 participants completed ST cognitive (serial subtractions), ST gait speed, and DT gait (gait with serial subtractions) on an electronic gait mat; ST gait speed was also assessed by stopwatch. Bland Altman analyses examined agreement between ST gait speed methods. Adjusted linear mixed effects models estimated differences between ST and DT gait parameters.ResultsAmong 364 participants (mean 81.8 years, 54.7% female), faster gait mat gait speeds were associated with a greater discrepancy from stopwatch measurements (β: −0.24 [95%CI: −0.31, −0.17]), indicating stopwatch underestimation. Participants exhibited mutual interference under DT, walking slower (mean difference in gait speed: −25.0 cm/s [95%CI: −26.8, −23.2]) with shorter (mean difference in step length: −6.2 cm [95%CI: −6.8, −5.6]) and wider steps (mean difference in stride width: 1.6 cm [95%CI: 1.3, 1.9]).ConclusionGait mat and stopwatch measurements showed acceptable agreement, supporting clinical use. However, greater disagreement at faster speeds suggests gait mats may be more appropriate for faster walking speeds. These findings support future investigations of ST and DT gait performance within ARIC and other aging cohorts, including relationships with cognitive decline, mobility limitations, and adverse health outcomes.

Aging is associated with declining aerobic capacity, driven in part by impaired mitochondrial oxidative phosphorylation in skeletal muscle and other tissues. Although prior proteomic studies have demonstrated age-related reductions in mitochondrial proteins, how mitochondrial proteome remodeling is functionally coupled to energetic capacity and modified by habitual physical activity remains poorly understood. We examined the relationships among aging, habitual physical activity, cardiorespiratory fitness, in-vivo mitochondrial oxidative capacity, muscle respirometry, and mitochondrial proteomic profiles across skeletal muscle, PBMCs, naïve CD4⁺ and CD8⁺ T cells, and skin in GESTALT study (healthy 22-89 years old human cohort). Even among individuals who remained healthy into old age, we detected mitochondrial proteome remodeling that was highly selective rather than uniform. Aging preferentially depleted core bioenergetic and proteostatic modules and altered within-pathway protein correlation structure, indicating coordinated mitochondrial network remodeling that was not captured by differential abundance analysis alone. Habitual physical activity and fitness were associated with proteomic signatures that opposed age-related remodeling, particularly within oxidative phosphorylation, mitochondrial translation, and protein import pathways. This rescue signature was strongly linked to skeletal muscle energetic function measured in vivo by 31P magnetic resonance spectroscopy. Individuals with higher physical activity rescue scores exhibited more favorable energetic function across adulthood. Beyond skeletal muscle, aging was associated with coordinated remodeling of mitochondrial proteomic profiles across peripheral tissues, with activity selectively altering tissue-to-tissue mitochondrial correlations rather than a uniform increase in cross-tissue coordination. Mitochondrial proteome remodeling is thus a functionally meaningful axis of human aging and identifies habitual physical activity as a selective modifier of the mitochondrial programs most tightly linked to energetic function.

Chronic inflammation has long been recognized as a major risk factor for and a causal contributor to cardiovascular disease (CVD). However, advances in omics technologies and deepening insights into CVD pathogenesis have expanded our understanding of the underlying mechanisms. Inflammation is now seen not as an isolated cause, but as one of several biological responses to cumulative tissue damage over time. In this Review, we propose that inflammation initially functions as a resilience mechanism, acting to resolve molecular and cellular damage driven by environmental stressors and intrinsic age-related entropy. With ageing, however, this protective response can become dysregulated and maladaptive, promoting collateral pathological changes. We illustrate this theory through two examples, atherosclerosis and age-related impairment of tissue perfusion, and support these conceptual models using proteomic data from large population studies with cardiovascular outcomes. Our findings reaffirm the central role of inflammation in CVD pathophysiology, but also indicate that the upstream biological driver of inflammation is molecular damage that is either not readily prevented or repaired by inadequate resilience mechanisms. Understanding the coordination of these responses offers new opportunities for targeted prevention and treatment of CVD. In this Review, Ferrucci and colleagues propose that inflammation is a resilience mechanism that resolves molecular and cellular damage driven by environmental stressors. With ageing, however, this protective response can become dysregulated and maladaptive, promoting collateral changes central to the pathophysiology of cardiovascular disease.

Epigenetic clocks of biological aging have been associated with cognitive impairment and dementia. Less is known about whether they are associated with an older-appearing brain or with an atrophy pattern associated with dementia. We examined associations of five epigenetic clocks measured at baseline with the Spatial Pattern of Atrophy for Recognition of Brain Aging (SPARE-BA) and the Alzheimer's Disease Pattern Similarity Score (AD-PS) derived from structural MRIs obtained an average of 8 years later among 1,196 older women. Using linear regression models adjusting for relevant covariates, we observed no associations between any epigenetic clock and accelerated brain aging based on SPARE-BA. We observed a significant association between AgeAccelGrim2 and AD-PS (β = 0.015; 95% CI 0.004 to 0.027; p = 0.01). This association appeared to be primarily driven by the association of a DNA methylation marker of smoking pack years with frontal and temporal lobe volumes. AgeAccelGrim2 was not associated with volumes in regions implicated in early AD (hippocampus and entorhinal cortex). Taken together with prior findings, these results suggest that measures of epigenetic and brain age acceleration capture different aspects of biological aging, and that AgeAccelGrim2 is predictive of neurodegenerative changes associated with smoking that increase risk of dementia.

Background Eye movement is a vital indicator of neurodegenerative diseases, brain health, and behavior. However, existing knowledge is limited to patient populations or cross-sectional samples. Little is known about eye movement in association with longitudinal cognitive and mobility decline in aging. Objective Investigate relationships between eye movement features with cognitive impairment, including Alzheimer's disease (AD), and longitudinal decline in cognition and mobility. Methods In 543 Baltimore Longitudinal Study of Aging participants (mean age = 71 years), we examined associations of eye movements with cognitive impairment of any severity, vascular conditions, and falls using logistic regression, and up to 18-year longitudinal changes in cognition and mobility using linear mixed-effects models. Four eye movement features (saccade, smooth pursuit, vergence, optokinetic nystagmus) were derived from a portable eye-tracking perimeter (Neurolign Dx100) using machine learning Least Absolute Shrinkage Selection Operator regression. Results Higher saccade, smooth pursuit, and vergence were bivariately or marginally associated with lower odds of cognitive impairment, including AD, and vascular diseases. In age- and sex-adjusted models, higher saccade was associated with slower declines in cognition (attention: Trail Making Test-Part A), mobility, and balance. Higher smooth pursuit was associated with slower decline in mobility and balance. Higher vergence was associated with slower cognitive decline (executive function: Trail Making Test-Part B; visuoperceptual speed: Digit Symbol Substitution Test). Higher optokinetic nystagmus was associated with lower odds of falls and slower decline in balance. Conclusions Select eye movement features may be indicators of age-related cognitive and mobility decline. Future studies are warranted to investigate underlying neuroimaging markers and brain pathology.