Recent literature suggests potential associations between hallucinogen use and valvular heart disease (VHD) due to prolonged activation of serotonin 5-HT2B receptors, which may lead to valvular fibrosis - a condition also linked to drugs including fenfluramine and pergolide. Despite these concerns, epidemiological studies exploring this association are lacking. This exploratory analysis investigated associations between lifetime hallucinogen use and VHD using cross-sectional data from US adults with linked electronic health record data in the NIH All of Us Research Program who completed the Lifestyle survey. This survey included questions about lifetime hallucinogen use (lysergic acid diethylamide [LSD], mushrooms/psilocybin, 3,4-Methylenedioxymethamphetamine [MDMA]/ecstasy, ketamine, phencyclidine [PCP]). Multivariable logistic regression models examined the association between hallucinogen use and VHD, adjusting for sociodemographic factors and other confounding health conditions. Our sample comprised 286,842 adults (mean age 50.8 [SD 16.7], 61.4% female, 60.6% White). Among them, 13.2% reported lifetime hallucinogen use. Individuals with lifetime hallucinogen use had lower unadjusted VHD prevalence compared to those without lifetime hallucinogen use (3.6% vs. 4.7%, p < .001). However, after adjusting for confounders, models revealed modestly increased VHD odds (aOR = 1.08, 95% CI: 1.01-1.55, p = .017). This exploratory study found that hallucinogen use was associated with modestly increased VHD odds after adjustment, requiring confirmation through longitudinal research.

BACKGROUND:Stress is a risk factor for impaired cognitive function, but the mechanisms linking stress and cognitive function in older adults remain unclear. This study examined whether physical health and sleep quality mediate the relationship between stress and cognitive function in community-dwelling older adults. METHODS:Data were analyzed from 600 community-dwelling older adults aged 60 and above. Ordinary least squares regression models tested associations between stress, physical health, sleep quality, and cognitive function, while adjusting for age, gender, race, and education. Bootstrapped mediation analyses were conducted to estimate indirect effects of physical health and sleep quality on the stress-cognitive function relationship. RESULTS:Higher perceived stress was significantly associated with lower cognitive function in the adjusted model (B = -0.113, p = 0.013). Physical health showed a significant indirect effect (B indirect = -0.0443, 95% CI [-0.0775, -0.0147]), with higher stress associated with poorer physical health, which in turn predicted lower cognition. Sleep quality also showed a significant indirect effect in an inconsistent direction (B indirect = 0.0265, 95% CI [0.0029, 0.0542]), with opposing paths whereby higher stress was associated with more reported sleep problems, while greater sleep problems predicted improved cognition. CONCLUSIONS:Stress may affect cognition in older adults partly through sleep quality and physical health, suggesting modifiable pathways for promoting cognitive resilience and healthy aging.

Impaired glucose tolerance (IGT) and insulin resistance (IR), including prediabetes and diabetes, increase risk of developing age-related disorders, such as cardiovascular disorders, kidney disorders, and Alzheimer’s disease. We analyzed mitochondrial bioenergetics of platelets collected from 208 adults, 55 years and older, with IGT and IR and without normoglycemic (NG). Platelets from IGT participants exhibited unique mitochondrial bioenergetic profiles exemplified by higher mitochondrial respiration compared with NG. IGT platelets exhibited higher glucose-dependent maximal respiration (Max) and spare respiratory capacities (SRCs) and higher fatty acid oxidation (FAO)-dependent maximal coupled (MaxOXPHOS) and uncoupled (maximal electron transport system) respiration compared with NG. Correlating mitochondrial bioenergetics from all 208 participants with measures of glucose tolerance (oral glucose tolerance test values measured 120 min after glucose administration, and oral glucose tolerance test area under the curve), and historical glucose measures [hemoglobin A1 (HbA1c)] revealed significant positive associations. Most associations were unaltered with age, sex, and body mass index adjustments. Examining NG and IGT participants separately, we found platelet respiration and HbA1c exhibited positive association in NG participants. Significant positive associations emerged between platelet SRC, FAO, FAO+CI (oxygen flux due to FAO + complex I activities), and HbA1c. No significant associations were observed in the IGT group. Given the utilization of blood-based mitochondrial bioenergetic profiling strategies in clinical research, this work provides new insights into the clinical features of IR that can affect platelet mitochondrial bioenergetics.

Aging is typically accompanied by a progressive decline in cognitive function, yet some individuals maintain exceptional cognitive performance, even across the transition from middle to older age, defining exceptional cognitive resilience. While existing measures of resilience primarily rely on clinical assessments, its molecular determinants and early predictive markers remain poorly understood. Here, we performed untargeted LC-MS/MS profiling of longitudinal serum samples to identify metabolic signatures associated with cognitive resilience, which was established based on cognitive tests conducted over 28 years in a cohort of 237 participants. We observed associations across multiple chemical classes, including carnitines, glutamine conjugates, phosphocholines, as well as diet- and drug-derived metabolites. Chemical class-specific analyses revealed distinct metabolic profiles, including predominantly negative associations of medium-chain acylcarnitines with cognitive resilience, increased accumulation of glucuronide conjugates in individuals with low cognitive resilience, altered metabolism of the antihypertensive drug, metoprolol, and elevated levels of dietary compounds such as piperine and lutein in individuals with high cognitive resilience. By leveraging public metabolomics data, we further contextualized the metabolic signatures with respect to their organ specificity, microbial origin, and disease associations. Collectively, these metabolic features, including several previously underexplored compounds, represent promising candidates for functional characterization in mechanisms of aging biology and provide mechanistic insights into the molecular basis of cognitive resilience.

Mitochondrial dysfunction is recognized as a biological hallmark of aging; however, bioenergetic capacity across the healthy human life course remains insufficiently characterized. While aging is generally associated with a systemic decline in mitochondrial function ("age-related bioenergetic decline"), recent research suggests that age-related bioenergetic differences are context dependent. Blood cells are extensively utilized as accessible samples for human bioenergetic profiling; therefore, our goal was to characterize bioenergetic capacity in platelets, peripheral blood mononuclear cells (PBMCs), monocytes, and lymphocytes of healthy adults from the San Diego Nathan Shock Center Clinical Cohort representative of the adult life course (20-80+ years of age). In our sample of 72 adults, we found that chronological age was positively associated with PBMC (maximal respiration [Max] β = 0.147, p = 0.028) and lymphocyte respiratory capacity (Max β = 0.135, p = 0.041). Notably, the pattern of age-related differences varied by sex; age showed a weak positive association with platelet respiration (Max β = 0.219, p = 0.037) in men but not in women. Similarly, age showed a strong positive association with PBMC respiration (Max β = 0.206, p = 0.018) in women but not in men. We also explored the relationship between glycolysis and respiration and found strong positive associations in platelets, PBMCs, and monocytes, but not lymphocytes. It is possible that, despite our cohort consisting of healthy, disease-free individuals, the elevated respiratory capacity in older adults may be reflective of compensatory mechanisms that require further investigation. Nonetheless, these findings underscore the importance of considering biological context, such as donor health, sex, and tissue type, in understanding age-related bioenergetic differences.

Resting metabolic rate (RMR) accounts for the majority of the total energy expenditure. While RMR is known to decline with advancing age and is recognized to be lower in females compared to males, the mechanisms underlying these differences remain unclear. Changes in body composition are posited to account for age- and sex-related differences in RMR, but to what extent lacks consensus. We characterized 80 healthy adults aged 23-82 years from the San Diego Nathan Shock Center (SD-NSC) clinical cohort for body composition and RMR using dual-energy x-ray absorptiometry (DXA) and indirect calorimetry techniques, respectively. Body composition metrics-body surface area (BSA), lean tissue mass (LTM), and total body fat (TBF)-were modelled as predictive variables to assess their explanatory power against the age and sex effects on RMR. We found that the negative association between RMR and age persists even after adjusting for body composition and sex, with a predicted decrease in RMR per decade of 62.6 kcal/day (ꞵ = -62.6, P < 0.0001). While individual body composition metrics do not account for the observed sex differences in RMR, adjusting for all body composition metrics together explained the observation that females have lower RMR compared to males. Our results suggest that while differences in body composition can explain sex differences in RMR, additional factors independent of body composition contribute to age-related differences. These results provide new insights into RMR differences among healthy individuals across the human life-course, which may inform age-appropriate interventions for optimizing metabolism.

ABSTRACT Autophagy is widely proposed to decline with age; however, direct evidence for this across cell and tissue types in humans remains limited. Furthermore, it remains unknown whether interventions that improve physiological health during aging can modify autophagic activity in humans. Here, we performed transcriptomic and functional autophagy analyses across subject-matched human cell types from a healthy aging cohort spanning the adult lifespan. RNA-seq of primary dermal fibroblasts and induced neurons (iNs) revealed increased transcription of many autophagy-related genes with age, most markedly in fibroblasts. The impact of age on autophagic activity, measured using autophagy flux assays, was cell type- and sex-dependent, and uncoupled from autophagy-gene transcription. Autophagy flux decreased with age in male fibroblasts, was unchanged in female fibroblasts, and increased in female iNs. In freshly isolated peripheral blood mononuclear cells (PBMCs), autophagy flux became more heterogeneous with age and trended higher in older individuals, independent of sex. Although autophagy flux levels did not match across different cell types, higher autophagy flux in all cell types was associated with reduced physical function in older adults (≥70 years). Importantly, autophagy flux decreased following 12 weeks of mild exercise in parallel with improved physical function. These findings indicate that autophagy is regulated in a cell type-, sex-and physiological function-dependent manner during human aging, and highlight PBMC autophagy flux as a potentially modifiable, blood-accessible readout of physiological state in older adults.

The psychosocial impact of the COVID-19 pandemic on older adults is not fully understood. This study aims to explore the differences in emotional measures pre- and post-pandemic to assess the emotional burden of the COVID-19 pandemic on this population. We hypothesize that older adults will have a significant decrease in emotional wellbeing status post pandemic, with the highest impact on the 75+ older adult population. UCSD Successful Aging Evaluation (SAGE) longitudinal study is a prospective cohort study with a focus on the cognitive and emotional aspects of aging. This analysis utilized validated emotional measures: anxiety (BSIA), depression (CESD), self-compassion (NSCS), resilience (CDRS), and loneliness (UCLA Loneliness Scale). 248 community-dwelling participants were found eligible to be included in this study. Across all participants we observed a significant increase in anxiety (p = 0.0403), depression (p = 0.0707), and loneliness (p = 0.0111) and a significant decrease in self-compassion (p = 0.0441) and resilience (p = < 0.0001). The 50-74 population had higher levels of anxiety (p = 0.0055), depression (p = 0.0189), and loneliness (p = 0.0317) pre-pandemic than the 75+ population. Post-pandemic, the 75+ population experienced a greater change in emotional characteristics with significant changes in anxiety (p = < 0.0001), depression (p = < 0.0001), loneliness (p = 0.0099), self-compassion (p = 0.0006), and resilience (p = < 0.0001) with no significant changes in the 50-74 population. The 75+ population was significantly more affected by the psychosocial impact of the pandemic, indicating greater vulnerability of this population. Uncovering the emotional vulnerability of this population is critical to promote greater awareness and provide insight into potential intervention strategies to aid in full emotional recovery.

Resilience can change over time and in response to challenging life events, yet the underlying changes in older adulthood and the influence of demographic factors remain unclear. This study examined the 10-year trajectory of resilience in community-dwelling adults and its association with demographic factors and the experience of past-year life events. We analyzed self-report survey data from 1,081 adults in the Successful Aging Evaluation (SAGE) study, a longitudinal study in San Diego County, CA. Resilience was measured using the CD-RISC-10 scale and recent life events with the WHI-LES in all yearly surveys. Linear mixed-effects models assessed associations between recent life events (frequency and perceived impact), demographics, and resilience measured 6 times over 10 years. Results indicated that older age and socioeconomic factors, particularly gender and income, are associated with better resilience trajectories. While resilience showed a small decline with age (b=-0.02, p = 0.008), the decline was greater with a higher number of life events (b=-0.25, p<.001). Notably, the effect of life events on resilience trajectory was not as severe for adults over 65 (b = 0.003, p = 0.017). Household income above $75,000 was associated with greater resilience at baseline (b = 0.89, p = 0.001), underscoring the protective role of economic resources. Men reported significantly higher resilience trajectories than women (b = 0.86, p = 0.012). These findings highlight the dynamic nature of resilience in adulthood and the critical role of socioeconomic factors in fostering stability. Future research should explore protective factors that help sustain resilience across the lifespan and implement interventions to support individuals facing cumulative life challenges.

Systemic mitochondrial dysfunction is apparent in the pathophysiology of Alzheimer's disease (AD). However, the factors driving bioenergetic decline remain unclear. This study utilized serum samples from older adults with normal cognition, mild cognitive impairment, and dementia to identify circulating molecules that can drive mitochondrial dysfunction in the context of AD. We used mass spectrometry to measure the abundance of lipid metabolites and applied tiered selection criteria to identify candidate "mito-inhibitory" molecules. These criteria were based on correlations with (1) in vitro bioenergetic effects of whole serum samples on naïve cells, (2) the bioenergetic capacity of blood cells from the serum donor, and (3) cognition, as measured by the modified mini-mental state exam. Mito-inhibitory lipid candidates were validated by examining their bioenergetic effects on neurons, myoblasts, and fibroblasts in vitro. Our results indicate that nervonic acid and 15-epi Prostaglandin A1 (15-epi-PGA1) are elevated in participants with dementia compared to those with normal cognition. Importantly, both metabolites inhibited mitochondrial function across multiple cell types in vitro. High resolution respirometric analyses reveal that inhibitory effects from lipid treatment occur via broad inhibition of the electron transfer system (ETS) with no change in overall mitochondrial content. This study provides insights into the mechanisms underlying systemic bioenergetic decline associated with AD dementia. The identification of circulating factors that drive mitochondrial bioenergetic decline may inform the development of mitochondrial therapeutics for AD.

OBJECTIVE:Latinos/as comprise nearly 20% of the U.S. population; 25% report past-month binge drinking, and disparities in care persist. Culturally adapted interventions may improve outcomes and access. We tested the efficacy of a culturally adapted behavioral intervention to reduce unhealthy alcohol use, delivered in Spanish to Latino/a adults. METHOD:We conducted a parallel, two-group, randomized controlled trial with 12- and 26-week follow-ups to test a three-session intervention delivered by community health workers (CHWs) from a community-based agency in Los Angeles, California. The intervention combined culturally adapted Motivational Enhancement Therapy and Strengths-Based Case Management (CA-MET/SBCM) and was compared to the Rethinking Drinking booklet. Participants were 236 non-treatment-seeking Latino/a adults who exceeded National Institute on Alcohol Abuse and Alcoholism low-risk drinking limits. The primary outcome was the percentage of heavy drinking days (≥5 drinks for men, ≥4 drinks for women) in the past 90 days at 26 weeks. Secondary outcomes were the average number of drinks per week and alcohol-related problems. RESULTS:The CA-MET/SBCM group had greater reductions in heavy drinking days and average drinks per week at Week 26 compared with the Rethinking Drinking group (-21.7 vs. -12.9 for percent heavy drinking days; -15.9 vs. -9.8 for average drinks per week). At Week 12, heavy drinking days were also significantly reduced in the CA-MET/SBCM group (-18.5 vs. -10.3). CONCLUSIONS:A culturally adapted behavioral intervention, combining MET and SBCM, delivered by Spanish-speaking CHWs significantly reduced unhealthy alcohol use among Latinos/as. These results are promising in addressing health disparities, although continued research is essential to further reduce unhealthy drinking and advance health equity for Latinos/as.

Circulating non-cellular factors, such as plasma proteins, contribute to various features of aging. To determine the impacts of endogenous circulating factors on human age-related bioenergetic decline, we treated primary human fibroblasts with serum samples representing the adult life-course. Our results demonstrate that the maximal mitochondrial bioenergetic capacity of fibroblasts treated with serum is negatively correlated with the chronological and epigenetic age of the serum donor. Using targeted proteomics, we identified plasma proteins associated with the bioenergetic effects of serum. We then utilized elastic net, a linear regression modeling technique, to derive a novel proteomic signature of age-related mitochondrial differences. MitoAge is a 25-protein signature of age-related mitochondrial health that predicts the systemic bioenergetic effects of circulating factors and is related to differences in physical function across human aging. Signatures that report on cellular hallmarks of aging, such as mitochondrial function, represent a new generation of mechanistically-informed biomarkers of biological aging. GRAPHICAL ABSTRACT:In this study, we describe the development of a novel proteomic signature, MitoAge. This signature was developed by utilizing human primary fibroblasts treated with serum samples representing the adult human life-course and analyzing how resulting respirometry correlated with chronological age, epigenetic age, and abundance of serum proteins. Utilizing machine learning techniques, we derived a 25-protein signature which can predict bioenergetics and physical features related to aging. Application and utility of this signature may be used to identify novel drivers of health and longevity.

BACKGROUND:The potential impacts of drug-induced modulation of mitochondrial function in humans remain unclear despite the high prevalence of "mito-modulatory" medication use among older adults. Although these medications, such as statins and metformin, have undergone extensive characterization of their effects on mitochondrial function in vitro, the effects in humans are far more complex and poorly understood. METHODS:This study uses data from the Study of Muscle, Mobility, and Aging (SOMMA) to evaluate how mito-modulatory medication use is related to skeletal muscle bioenergetic capacity, measured by ex vivo high-resolution respirometry and in vivo phosphorus magnetic resonance spectroscopy in healthy older adults. RESULTS:We found that mito-modulatory medication use was related to lower maximal complex I & II supported oxidative phosphorylation (Max OXPHOS), maximal electron transfer system capacity (Max ETS), and maximal ATP production capacity (ATP Max) in men, but not in women. We also found this to be dependent on the number of medications used, in which higher mito-modulatory medication load was associated with lower Max OXPHOS, Max ETS, and ATP Max. CONCLUSIONS:Our results provide greater insight into the potential clinical effects of mito-modulatory medication use and highlight the need to test the impact of these medications on mitochondrial function in randomized trials.

Objectives The extent to which lifestyle shapes trajectories of normal cognitive aging, and the factors with highest potential for mitigating cognitive decline, remain poorly characterized.Methods Participants of the Rancho Bernardo Study underwent demographic, health, and behavioral characterization at baseline, along with up to 7 cognitive assessments over a 27-year follow-up period. Factor analysis of 24 baseline risk variables identified 9 composite factors. Mixed effects models on data from 1,489 participants (aged 45-95 years at baseline) assessed prediction of cognitive change by baseline factor scores. Models were repeated stratified by sex and APOE4 status.Results Factors of hyperlipidemia and obesity; marriage and depression; occupation and education; and physical activity and subjective health best predicted rates of decline across multiple cognitive domains. Distinct risk profiles were identified for women and men, and for APOE4 carriers and non-carriers. Models of composite risk estimated that potential savings could amount to 7-9.5 years of preserved cognitive health span for low- versus high-risk profiles. Magnitudes of aggregate risk effects were greater among women across cognitive domains, and for APOE4 carriers for memory and verbal fluency.Discussion Multifactorial life-course approaches to manage cardiometabolic health and promote physical, cognitive, and social engagement may help to mitigate cognitive decline with age, with composite risk associated with up to a decade of preserved cognitive health span. Differences by sex and APOE4 in risk profiles and their potential for risk reduction, highlight the importance of developing personalized recommendations for multidomain approaches to cognitive health maintenance throughout the life-course.

Multiple lines of evidence suggest that calorie restriction may slow biological processes related to aging and extend lifespan. To determine whether calorie restriction affects mitochondrial function, we treated fibroblasts from adult donors with serum samples obtained from participants of the CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) study. The CALERIE study enrolled healthy, non-obese middle-aged (average 38y.o) participants to examine the effects of long-term calorie restriction. We studied the serum samples of 177 participants (calorie restriction CR = 121, ad libitum AL = 56) who had specimens available at two timepoints (12 and 24 months). We assessed the basal and maximal mitochondrial respiration of fibroblasts treated with dilute serum for 24 hours. Our results show that the baseline basal and maximal mitochondrial respiration of fibroblasts is positively correlated with the adiposity of the serum donor (R = 0.112, P = 0.137; R = 0.183, P = 0.015, respectively). Interestingly, treatment of fibroblasts with serum collected after 12 months of calorie restriction causes a decrease in both basal and maximal mitochondrial respiration (P = 0.1854; P = 0.0623, respectively). Fibroblasts treated with serum collected after 24 months of calorie restriction exhibited a further reduction in both basal and maximal mitochondrial respiration (P = 0.0174; P = 0.0092, respectively). These findings suggest that the serum of individuals on long term calorie restriction diet comprises factors that can reduce oxidative phosphorylation. This reduction in bioenergetic capacity may align with the theory that calorie restriction leads to a cellular energy-conserving state, which could have implications for cellular aging and metabolism.

Abstract We previously showed peripheral blood mononuclear cell (PBMC) and platelet mitochondrial bioenergetic capacities are lower in older adults with Alzheimer’s disease (AD), with notable changes in fatty acid oxidation (FAO)-mediated respiration. The metabolic pathways underlying mitochondrial functional differences remain un-identified. This study investigated lipid metabolites that are differently expressed across different stages of cognitive impairment (CI). Targeted lipidomics analyzed 51 fatty acids (FAs) in PBMCs and platelets of older adults with normal cognition (NC), mild cognitive impairment (MCI), and AD dementia (DEM). 10 FAs were selected in each cell type based on significant concentration differences between different cognitive groups. In PBMCs, 9 FAs exhibited higher concentrations in MCIs than NC and DEM, with significantly lower concentration in DEM than MCI, while 1 FA exhibited progressively declining concentrations from NC to MCI to DEM. Significant positive correlations were observed between FA concentrations and FAO and maximal mitochondrial respiration (Max). In platelets, 7 FAs showed progressively declining concentrations from NC to MCI to DEM, and significant positive correlations with FAO and Max, while 3 FAs showed progressively increasing concentrations with cognitive impairment, and significant negative correlations with FAO and Max. Significant negative correlations were also observed with mPACC5 cognitive assessment scores and hippocampal volumes. Pathway analyses identified FA biosynthesis, alpha-linolenic acid, and alpha-linoleic acid metabolism as involved pathways differently impacted across cognitive groups. These findings emphasize the importance of FAs and related metabolic pathways in systemic bioenergetic decline in CI, and may facilitate development of preventative, diagnostic, and therapeutic approaches in AD.

Abstract Alzheimer’s disease (AD) dementia associates with systemic mitochondrial bioenergetic decline. We previously showed blood cell mitochondrial bioenergetics recapitulates bioenergetic capacity of highly metabolically active organs like brain, liver, and skeletal muscles, and peripheral blood mononuclear cell (PBMC) mitochondrial function relates to brain morphology. More recently, we examined PBMC and platelet bioenergetics in a cohort of older adults with dementia due to AD. We assessed mitochondrial function using complementary respirometric approaches in intact and permeabilized PBMCs and platelets from individuals with normal cognition (NC), mild cognitive impairment (MCI), and dementia due to probable AD (DEM). Cognitive abilities were assessed using Modified Preclinical Alzheimer’s Cognitive Composite (mPACC5) scores, and brain morphology using MRI. Our results indicate blood cells exhibit lower bioenergetic capacity associated with cognitive decline in MCI and DEM, with lowest capacities in DEM. Specifically, glucose-mediated respiration was significantly lower in DEM compared to NC. PBMC fatty-acid oxidation (FAO)-mediated respiration were progressively lower with MCI and DEM compared to NC, while platelet FAO-mediated respiration exhibited higher maximal respiration in MCI than NC and DEM. PBMC and platelet respiration positively correlated with mPACC5 scores and hippocampal volume, and negatively correlated with white matter hyperintensities. These findings indicate mitochondrial bioenergetic differences associated with cognitive abilities are systemic and blood-based bioenergetic profiling can be used as a minimally invasive approach for measuring mitochondrial alterations associated with dementia. Studies are underway to identify circulating factors underlying systemic bioenergetic decline and cellular mechanisms mediating mitochondrial dysfunction in PBMCs and platelets from older adults with cognitive impairment.