Molecular mechanisms of organismal and cell aging remain incompletely understood. We, therefore, generated a body-wide map of noncoding RNA (ncRNA) expression in aging (16 organs at ten timepoints from 1 to 27 months) and rejuvenated mice. We found molecular aging trajectories are largely tissue-specific except for eight broadly deregulated microRNAs (miRNAs). Their individual abundance mirrors their presence in circulating plasma and extracellular vesicles (EVs) whereas tissue-specific ncRNAs were less present. For miR-29c-3p, we observe the largest correlation with aging in solid organs, plasma and EVs. In mice rejuvenated by heterochronic parabiosis, miR-29c-3p was the most prominent miRNA restored to similar levels found in young liver. miR-29c-3p targets the extracellular matrix and secretion pathways, known to be implicated in aging. We provide a map of organism-wide expression of ncRNAs with aging and rejuvenation and identify a set of broadly deregulated miRNAs, which may function as systemic regulators of aging via plasma and EVs.

Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with ageing^1,2. Here we engineered bioorthogonal tools³ that enabled us to tag the nascent neuronal proteome and study its turnover with ageing, its propensity to aggregate and its interaction with microglia. We show that neuronal protein half-life approximately doubles on average between 4-month-old and 24-month-old mice, with the stability of individual proteins differing among brain regions. Furthermore, we describe the aged neuronal ‘aggregome’, which encompasses 1,726 proteins, nearly half of which show reduced degradation with age. The aggregome includes well-known proteins linked to diseases and numerous proteins previously not associated with neurodegeneration. Notably, we demonstrate that neuronal proteins accumulate in aged microglia, with 54% also displaying reduced degradation and/or aggregation with age. Among these proteins, synaptic proteins are highly enriched, which suggests that there is a cascade of events that emerge from impaired synaptic protein turnover and aggregation to the disposal of these proteins, possibly through microglial engulfment of synapses. These findings reveal the substantial loss of neuronal proteome maintenance with ageing, which could be causal for age-related synapse loss and cognitive decline.

Aging is asynchronous across cells and organs. Here we tested whether plasma proteomics can be used to analyze cell type-specific aging. From analyses of over 7,000 plasma proteins measured in 60,542 individuals, we developed machine learning models to estimate the biological age of over 40 cell types spanning neuronal, immune, glial, endocrine, epithelial and musculoskeletal origins. We observed that 20–25% of individuals exhibited accelerated aging in a single cell type and 1–3% in 10 or more cell types. Cellular aging signatures were associated with disease status and predicted incident disease and mortality over 15 years of follow-up. Individuals with the APOE4 genotype showed older astrocytes but younger macrophages compared to APOE3 carriers, whereas the APOE2 genotype had inverse associations. Moreover, extreme astrocyte aging tripled the risk of incident Alzheimer’s Disease in individuals with two APOE4 alleles, while youthful astrocytes reduced risk. Individuals with extremely aged compared to youthful skeletal myocytes exhibited a 12.7-fold higher risk of developing amyotrophic lateral sclerosis. In individuals who smoked, extreme respiratory epithelial cell aging was associated with a 58% higher lung cancer risk compared to smoking alone. Specific cellular vulnerabilities and cumulative cellular aging burden influenced survival, with youthful immune and neuronal cell types conferring protective effects. Finally, we developed a polycellular aging risk score that stratified mortality risk across cohorts and proteomics platforms. These findings establish a framework for quantifying human physiology at cellular resolution, revealing heterogeneous aging trajectories and their impact on disease susceptibility and resilience.

Background: Turner Syndrome (TS) is a relatively rare X-chromosomal disease with increased cardiovascular morbidity and mortality. This study aimed to identify whether the circulating miR-126-3p/5p are involved in the pathophysiology of vascular dysfunction in TS. Methods: Using the RT-qPCR, the abundance levels of miR-126-3p and miR-126-5p were determined in 33 TS patients and 33 age-matched healthy volunteers (HVs). Vascular screening, including the assessment of blood pressure, pulse wave velocity, augmentation index, aortic deformation, arterial distensibility, and arterial elastance, was conducted in TS patients and HVs. Results: The abundance levels of miR-126-3p and miR-126-5p were significantly higher in TS patients compared to HVs (p < 0.0001). Within the TS cohort, miR-126-3p/5p correlated significantly with aortic deformation (r = 0.47, p = 0.01; r = 0.48, p < 0.01) and arterial distensibility (r = 0.55, p < 0.01; r = 0.48, p < 0.01). In addition, a significant negative correlation was demonstrated between miR-126-3p and arterial elastance (r = −0.48, p = 0.01). The receiver operating characteristic analysis showed that miR-126-3p and miR-126-5p separated the tested groups with high sensitivity and specificity. Conclusions: The abundance levels of miR-126-3p and miR-126-5p were significantly higher in TS patients compared to HVs. Within the TS cohort, a lower abundance level of miR-126-3p and miR-126-5p was linked with a significantly higher aortic stiffness.

Little is known about abundance level changes of circulating microRNAs (miRNAs) and messenger RNAs (mRNA) in patients with Ebstein’s anomaly (EA). Here, we performed an integrated analysis to identify the differentially abundant miRNAs and mRNA targets and to identify the potential therapeutic targets that might be involved in the mechanisms underlying EA. A large panel of human miRNA and mRNA microarrays were conducted to determine the genome-wide expression profiles in the blood of 16 EA patients and 16 age and gender-matched healthy control volunteers (HVs). Differential abundance level of single miRNA and mRNA was validated by Real-Time quantitative PCR (RT-qPCR). Enrichment analyses of altered miRNA and mRNA abundance levels were identified using bioinformatics tools. Altered miRNA and mRNA abundance levels were observed between EA patients and HVs. Among the deregulated miRNAs and mRNAs, 76 miRNAs (49 lower abundance and 27 higher abundance, fold-change of ≥2) and 29 mRNAs (25 higher abundance and 4 lower abundance, fold-change of ≥1.5) were identified in EA patients compared to HVs. Bioinformatics analysis identified 37 pairs of putative miRNA-mRNA interactions. The majority of the correlations were detected between the lower abundance level of miRNA and higher abundance level of mRNA, except for let-7b-5p, which showed a higher abundance level and their target gene, SCRN3, showed a lower abundance level. Pathway enrichment analysis of the deregulated mRNAs identified 35 significant pathways that are mostly involved in signal transduction and cellular interaction pathways. Our findings provide new insights into a potential molecular biomarker(s) for the EA that may guide the development of novel targeting therapies.

Aging is asynchronous across cells and organs, but whether plasma proteins can capture cell type-specific aging and predict disease and mortality remains unknown. We developed machine learning models to estimate the biological age of more than 40 distinct cell types—spanning neuronal, immune, glial, endocrine, epithelial, and musculoskeletal origins—using over 7,000 plasma proteins measured in 60,000 individuals across three cohorts, comprising the largest human plasma proteomics aging study to date. Individuals showed heterogeneous aging profiles, with 20-25% exhibiting accelerated aging in a single cell type and 1-3% across ten or more cell types. APOE genotype showed antagonistic aging effects in different cell types: APOE4 carriers exhibited older astrocytes but younger macrophages, while APOE2 carriers showed the inverse. Cellular aging signatures were uniquely associated with disease status and predicted incident disease and mortality over 15 years of follow-up. Amyotrophic lateral sclerosis (ALS) showed the strongest association with skeletal myocyte aging (hazard ratio = 12.7 for extreme accelerated versus youthful aging). In Alzheimer’s disease (AD), prevalent cases showed accelerated aging across multiple neural and peripheral cell types, with extreme astrocyte aging conferring AD risk comparable to APOE4 carrier status. Moreover, extreme astrocyte aging increased AD risk in APOE4/4 carriers threefold, while youthful astrocytes strikingly reduced risk. Beyond neurodegeneration, respiratory cell aging identified smokers at 58% higher lung cancer risk, and myeloid aging identified normoglycemic individuals at higher diabetes risk. Both specific cellular vulnerabilities and cumulative aging burden influenced survival, wherein youthful immune or neuronal profiles were protective. A polycellular aging risk score provided robust mortality risk stratification across platforms and cohorts. These findings establish a framework for quantifying biological aging at the cellular resolution using plasma proteomics, revealing heterogeneity in aging trajectories and their impact on disease susceptibility and resilience.