Longevity Papers

Sarcopenia, the age-related loss of muscle strength and mass, contributes to adverse health outcomes in older adults. While exercise mitigates sarcopenia by transiently activating calcium (Ca2+)- and reactive oxygen species (ROS)-dependent signaling pathways that enhance muscle performance and adaptation, these same signals become chronically elevated in aged skeletal muscle and promote functional decline. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a key transducer of both Ca2+ and ROS signals during exercise. Here we show that CaMKII is chronically activated in aged muscles, promoting muscle dysfunction. Muscle-specific expression of a constitutively active CaMKII construct in young mice recapitulates features of aging muscles, including impaired contractility, progressive atrophy, mitochondrial disorganization, formation of tubular aggregates, and an older transcriptional profile characterized by the activation of inflammatory and stress response pathways. Mediation analysis identified altered heme metabolism as a potential mechanism of CaMKII-induced weakness, independent of muscle atrophy. Conversely, partial inhibition of CaMKII in aged muscle improved contractile function and shifted the transcriptome toward a more youthful state without inducing hypertrophy. These findings identify chronic CaMKII activation as a driver of functional and molecular muscle aging and support the concept that CaMKII exemplifies antagonistic pleiotropy, whereby its beneficial roles in promoting muscle performance and adaptation during youth may incur deleterious consequences in aging. We propose that persistent CaMKII activation in aged skeletal muscle reflects unresolved cellular stress and promotes maladaptive remodeling. Enhancing physiological reserve capacity through exercise, in combination with temporally targeted CaMKII inhibition, may help restore adaptive CaMKII signaling dynamics and preserve muscle function in aging.

Mitochondrial heteroplasmy, the co-existence of different mitochondrial genomes within a cell, is linked to aging and disease. Patients with heteroplasmy due to mitochondrial mutations experience multiple organ complications, particularly poor bone health and bone structure defects. However, the mechanisms involved are generally unknown, due largely to the difficulty of manipulating mtDNA in vivo. To overcome this, we leveraged a heteroplasmic mouse model and discovered that mitochondrial heteroplasmy affects a fundamental developmental process. Specifically, the differentiation of osteoclasts, which resorb bone tissue and maintain bone homeostasis. Mechanistically, there was a reduced localization of specifically respiratory complex I subunits in mitochondria in heteroplasmic mice, disrupting ATP production and osteoclast differentiation. In addition, autophagic flux is exhausted, and the autophagy inducer spermidine restores mitochondrial health and rescues osteoclast activity, both in mice and in cells from patients with primary mitochondrial disease. Together, we identify the mechanisms by which mitochondrial heteroplasmy impacts osteoclastogenesis and discover spermidine as a modulator of this process, which presents a potential treatment for human heteroplasmic conditions such as mitochondrial diseases, which are largely untreatable.

As aging is the primary risk factor for many chronic diseases, geroscience aims to target aging to delay age-related decline. Here, we identify Cyrene (dihydrolevoglucosenone), a sustainable, biocompatible solvent, as a novel geroprotective compound. Cyrene extends lifespan and healthspan in C. elegans, improving locomotor function and resistance to oxidative, thermal, osmotic, genotoxic, and proteotoxic stress. It also confers protection in neurodegenerative models of Alzheimer\'s, Parkinson\'s, and Huntington\'s disease. Cyrene is effective when delivered during development or early adulthood and requires administration before day 8 to extend longevity. Its benefits are independent of bacterial metabolism and partially independent of the FOXO transcription factor DAF-16. Importantly, Cyrene also extends lifespan and enhances oxidative stress resistance in Drosophila melanogaster, demonstrating cross-species efficacy. These findings identify Cyrene as a novel geroprotective compound that promotes longevity, resilience, and neuroprotection. Conservation across species supports future work to dissect molecular mechanisms and test its potential in mammals.

Reproductive longevity is essential for female fertility and healthy aging; however, the role of stress response, especially stress granule accumulation, in ovarian aging remains elusive and interventions are lacking. Here, we identified deleterious mutations and decreased expression of NCOA7, a stress-response protein related to granulosa cell senescence in women with physiological and pathological ovarian aging. NCOA7 deletion accelerates oxidative stress-related cellular senescence, ovarian aging and fecundity decline in mice. Mechanistically, NCOA7 partitions into the stress granule containing G3BP1-V-ATPase and facilitates autophagic degradation of stress granules to relieve stress. Boosting granulophagy with rapamycin or lipid nanoparticle-based mRNA delivery of NCOA7 accelerates stress granule clearance, alleviating cellular senescence in human granulosa cells and delaying ovarian aging in mice. This study depicts a mechanism for ovarian resilience to stress and provides potential targets for therapeutic strategies to alleviate ovarian aging.

Telomere attrition stands as a fundamental hallmark of cardiovascular aging, driving cellular senescence and dysfunction across endothelial, cardiomyocyte, and vascular smooth muscle compartments. This review systematically examines: (1) molecular mechanisms linking telomere shortening to oxidative stress (NOX2/PRDX1 axis), epigenetic dysregulation (subtelomeric methylation, H3K9me3 loss), and mitochondrial dysfunction; (2) clinical evidence positioning leukocyte telomere length and telomere-associated proteins (eg, TRF2, POT1) as predictive biomarkers for coronary artery disease, heart failure, and hypertension; and (3) emerging therapeutic strategies ranging from telomerase activation (TA-65, GRN510) to senolytic cocktails (dasatinib + quercetin) and CRISPR (regularly interspersed short palindromic reportsclustered regularly interspaced short palindromic repeats)-based editing (6-29% efficiency in Chinese hamster ovary models). The review further addresses methodological challenges in telomere measurement (quantitative polymerase chain reaction (PCR) vs Flow-FISH standardization) and proposes an integrated risk assessment model combining leukocyte telomere length, oxidative markers (AGEs/sRAGE ratio), and epigenetic clocks. Translationally, we discuss tissue-specific delivery systems to mitigate oncogenic risks of telomerase therapies while emphasizing mitochondrial-targeted approaches for telomere stabilization. This synthesis bridges basic telomere science with clinical cardiology, offering a roadmap for personalized vascular rejuvenation strategies.

Aging is a major risk factor for neurodegeneration and is characterized by diverse cellular and molecular hallmarks. To understand the origin of these hallmarks, we studied the effects of aging on the transcriptome, translatome, and proteome in the brain of short-lived killifish. We identified a cascade of events in which aberrant translation pausing led to altered abundance of proteins independently of transcriptional regulation. In particular, aging caused increased ribosome stalling and widespread depletion of proteins enriched in basic amino acids. These findings uncover a potential vulnerable point in the aging brain's biology-the biogenesis of basic DNA and RNA binding proteins. This vulnerability may represent a unifying principle that connects various aging hallmarks, encompassing genome integrity, proteostasis, and the biosynthesis of macromolecules.

The gut microbiota both adapts to, and shapes, the metabolic state of individuals. This bidirectional relationship is mediated via circulating metabolites and gene regulatory networks and interacts with many organs, including by the gut-brain axis. Here, we have processed the cecum from 232 mice from our recent aging colony across age (6-24 months), diet (chow or high fat), and genetics (43 BXD strains) and sequenced their metagenome, metatranscriptome, and cecal transcriptome. We quantify changes in over 300 species caused by interactions between diet, age, and genetic background. Traditional bioinformatics approaches linked particular microbes to observed phenotypes, while newer machine learning models based microbial clusters accurately predicted host outcomes, including individual body weight (AUC = 0.92) and chronological age (AUC = 0.84). This was further enhanced by a compact 10-feature multi-omics model, combining our microbiome data with prior liver expression data to increase chronological age AUC to 0.95. Mechanistically, integrative network analyses identified dozens of significant links between particular bacterial taxa and gene expression, such as a strong negative correlation between host Ido1 expression and short-chain fatty acid (SCFA)-producing Lachnospiraceae, indicating dietary fat can modulate host tryptophan metabolism via microbiota shifts. Moreover, as our study uses inbred mice sampled across time, we have identified signature sets of taxonomies that provide excellent predictive value for future metabolic outcomes driven by metabolic networks connecting the microbiome to the host organism\'s tissues (here, cecum and liver from the same mice). By better understanding the gut-liver axis, we can understand the cellular etiologies of metabolic disease and identify earlier, personalized diagnostic biomarkers attuned to the genetic background and environmental state of the individual.

Mosaic loss of Y chromosome (mLOY) in blood cells is an age-related somatic mutation, but its relationship with pulmonary health remains undercharacterized. Leveraging mLOY assessment in over 12,000 men, including 5,097 from the COPDGene Study and 7,235 from six additional cohorts in Trans-Omics for Precision Medicine program, we investigated its association with respiratory outcomes and epigenetic aging. Cross-sectionally, mLOY was associated with airflow obstruction with prevalence increasing with age, particularly in men with a former smoking history. Longitudinally, mLOY associated with lung function decline. Notably, mLOY was also associated with greater CT-quantified lung emphysema and faster pace epigenetic aging. Prospectively, in participants with normal lung function at baseline, mLOY was associated with lower future lung function and faster pace of epigenetic aging. These associations remained robust after adjusting for clonal hematopoiesis and telomere length. Collectively, these findings position mLOY as a potential biomarker of respiratory aging and obstructive lung disease.

Retinal fundus images offer a non-invasive window into systemic aging. Here, we fine-tuned a foundation model (RETFound) to predict chronological age from color fundus images in 71,343 participants from the UK Biobank, achieving a mean absolute error of 2.85 years. The resulting retinal age gap (RAG), i.e., the difference between predicted and chronological age, was associated with cardiometabolic traits, inflammation, cognitive performance, mortality, dementia, cancer, and incident cardiovascular disease. Genome-wide analyses identified genes related to longevity, metabolism, neurodegeneration, and age-related eye diseases. Sex-stratified models revealed consistent performance but divergent biological signatures: males had younger-appearing retinas and stronger links to metabolic syndrome, while in females, both model attention and genetic associations pointed to a greater involvement of retinal vasculature. Our study positions retinal aging as a biologically meaningful and sex-sensitive biomarker that can support more personalized approaches to risk assessment and aging-related healthcare.

Proteins are the cornerstone of life. However, the proteomic blueprint of aging across human tissues remains uncharted. Here, we present a comprehensive proteomic and histological analysis of 516 samples from 13 human tissues spanning five decades. This dynamic atlas reveals widespread transcriptome-proteome decoupling and proteostasis decline, characterized by amyloid accumulation. Based on aging-associated protein changes, we developed tissue-specific proteomic age clocks and characterized organ-level aging trajectories. Temporal analysis revealed an aging inflection around age 50, with blood vessels being a tissue that ages early and is markedly susceptible to aging. We further defined a plasma proteomic signature of aging that matches its tissue origins and identified candidate senoproteins, including GAS6, driving vascular and systemic aging. Together, our findings lay the groundwork for a systems-level understanding of human aging through the lens of proteins.

Aging is associated with increased susceptibility to metabolic stress and chronic liver disease, yet the interactions between age and metabolic stressors and the potential for ameliorating interventions remain incompletely understood. Here, we examined the hepatic response of young (7-month-old) and old (25-month-old) C57BL/6 male mice to a 9-week high-fat diet (HFD) and assessed whether rapamycin, a well-established pro-longevity intervention, could mitigate age-exacerbated effects. While both age groups developed metabolic-associated steatohepatitis (MASH), older mice displayed more severe hepatic steatosis, inflammation, and transcriptional dysregulation. Transcriptomic profiling of whole livers and purified hepatocytes revealed that aging amplifies HFD-induced inflammatory and metabolic gene expression changes, including activation of immune pathways and suppression of metabolic pathways. Notably, treatment of aging mice with rapamycin reversed the majority of HFD-driven transcriptional alterations, including upregulation of pro-inflammatory regulators such as Stat1, and dysregulation of metabolic gene networks. Rapamycin also reduced hepatosteatosis, total body weight, and a tumorigenic transcriptomic signature associated with hepatocellular carcinoma risk. These findings demonstrate that aging intensifies hepatic sensitivity to metabolic stress and identify rapamycin as a promising therapeutic to counteract age-related liver dysfunction and MAFLD progression.