Longevity Papers

Endothelial metabolism underpins tissue regeneration, health, and longevity. We uncover a nuclear oxidative catabolic pathway linking cystine to gene regulation. Cells preparing to proliferate upregulate the SLC7A11 transporter to import cystine, which is oxidatively catabolized by cystathionine-γ-lyase (CSE) in the nucleus. This generates acetyl units via pyruvate dehydrogenase, driving site-specific histone H3 acetylation and chromatin remodeling that sustain endothelial transcription and proliferation. Combined loss of SLC7A11 and CSE abolishes cystine oxidative and reductive metabolism and causes embryonic lethality, whereas single deletions reveal distinct effects. SLC7A11 deficiency triggers compensatory cysteine de novo biosynthesis, partially maintaining angiogenesis, while CSE deletion disrupts nuclear cystine oxidative catabolism, transcription, and vessel formation. Therapeutically, cystine supplementation promotes vascular repair in retinopathy of prematurity, myocardial infarction, and injury in aging. These findings establish the role of cystine nuclear oxidative catabolism as a fundamental metabolic axis coupling nutrient utilization to gene regulation, with implications for vascular regeneration.

Forgetting is a critical component of memory, but its molecular regulation - particularly with age - is not well understood. Epigenetic modifications are a candidate for this regulation and may further drive age-related behavioral decline, as they are dramatically altered in the aging brain. We found that multiple components of the SET1/COMPASS complex, a conserved histone methyltransferase complex associated with active gene transcription, are upregulated with age in the C. elegans nervous system. Neuronal knockdown of the SET1/COMPASS components improves memory in young adult animals and slows memory decline in old animals. By pharmacological and genetic inhibition, optogenetics, and neuronal mRNA and chromatin profiling, we demonstrate that SET1/COMPASS-mediated active transcription promotes forgetting. SET1/COMPASS regulates the de novo activity-dependent transcription and release of a neuropeptidergic signal from the AWC olfactory sensory neuron, which erases the associative memory trace in downstream motor neurons, resulting in forgetting. We further found that increased SET1/COMPASS-dependent chromatin accessibility at these gene loci with age primes these loci for transcription, resulting in accelerated forgetting. Our results reveal the role of active gene transcription in the regulation of forgetting and altered SET1/COMPASS- mediated gene transcription as a mechanism of cognitive decline, implicating increased expression of COMPASS components as a driver of increased forgetting in the aging brain. This mechanism may offer a new target for slowing loss of cognitive function with age.

Skeletal muscle stem cells (MuSC) are the guardians of muscle regeneration, sustaining tissue integrity through a delicate balance of quiescence, activation, and lineage commitment. While numerous molecular cues have been implicated in regulating these processes, the influence of androgen receptor (AR) signaling, an essential hormonal pathway for male muscle physiology, has remained largely unexplored. Here, we show that AR expression defines quiescent MuSC and acts as a safeguard of their dormancy. Integrated multi-omic analyses reveal a redistribution of AR binding from quiescence-maintenance loci to regulatory elements driving activation and metabolic reprogramming during repair. Loss of AR at puberty disrupts this balance, precipitating premature cell-cycle entry, skewed divisions toward symmetric differentiation, depletion of the stem cell reservoir, and destabilization of the niche. These defects converge with hallmarks of aging-associated androgen decline, while androgen supplementation restores regenerative competence. Together, our findings establish AR signaling as a pivotal determinant of MuSC fate and a cornerstone of skeletal muscle homeostasis.

Aging is marked by the accumulation of cells expressing the cyclin-dependent kinase inhibitor p16Ink4a. These p16⁺ cells, largely senescent, contribute to inflammation and tissue dysfunction. While eliminating p16⁺ cells improves healthspan, sex-specific differences in their burden and clearance remain unclear. Through combined transcriptomic, proteomic, and functional analyses, we reveal distinct sex-dependent dynamics of p16⁺ cells during aging. Female mice accumulate significantly more p16⁺ cells across multiple tissues, particularly in the liver. In the p16-3MR model, selective ablation of these cells enhances grip strength, promotes skin regeneration, and reduces liver damage exclusively in females. Multi-omics profiling shows that p16⁺ cell removal shifts female liver expression toward youthful, health-associated profiles, marked by improved mitochondrial activity and reduced inflammatory signaling-molecular patterns resembling those induced by longevity interventions such as calorie restriction, rapamycin, and acarbose. Integrative analysis of our and independent datasets identifies a conserved transcriptional network involving Srm, Cd36, and Lrrfip1, suggesting shared mitochondrial-immune regulatory mechanisms. Overall, our findings establish p16⁺ cells as critical yet heterogeneous drivers of tissue aging, uncover sex-specific differences in their abundance and senolytic responsiveness, and support the development of precision senotherapeutics that consider sex as a key biological variable in aging and rejuvenation.

DNA damage is a key driver of aging, contributing to epigenetic erosion, senescence, and chronic inflammation. However, genoprotective strategies to counteract aging remain intangible. Here we show that FOXM1 repression during aging accounts for a global transcriptional shutdown of DNA repair genes and the accrual of DNA damage. Restored FOXM1 activity in aged cells reduces DNA damage and epigenetic alterations driving senescence. Mechanistically, FOXM1 drives the transcription of DNA repair genes, which prevents the DNA damage-driven degradation of the G9a methyltransferase and subsequent loss of H3K9me2 at the nuclear periphery. Remarkably, we show that amendment of the H3K9me2 guidepost for peripheral heterochromatin by FOXM1 induction in aged cells inactivates enhancers of the AP-1-driven senescence and inflammation program. These findings establish FOXM1 as an age-reversal factor capable of restoring (epi)genetic integrity to inhibit the senescence enhancer landscape, offering a promising therapeutic avenue to address the fundamental causes of aging.

Small vessel disease (SVD) impacts healthy aging of organs across the body, yet its contributions to adverse brain aging remain poorly defined. Here we show thromboinflammation, a core feature of SVD, as a driver of adverse brain aging. We identify cerebrospinal fluid fibrinogen as a marker of brain thromboinflammation and screen neurovascular biosignatures mediating its impact on synaptic vulnerability along the full spectrum of brain aging from cognitively typical, amyloid-negative to cognitively impaired, amyloid-positive older adults. We identified 53 proteins mediating the effect of fibrinogen on synaptic markers in 1,655 donors from three independent cohorts. Single-cell transcriptomic mapping revealed mediator enrichment in neurovascular unit cells. Pathway analysis demonstrated dysregulation of angiogenesis, fibrosis, and immune signaling. Vascular and microglial-enriched biosignatures associated with compromised white matter integrity. These findings implicate thromboinflammation as an early, amyloid-independent pathway to neurodegeneration and tauopathy, establishing vascular health as fundamental to preserving brain healthspan.

Aging research has primarily focused on adult aging clocks, leaving a critical gap in understanding a biological clock across the full life cycle, particularly during infancy and childhood. Here we introduce LifeClock, a biological clock model that predicts biological age across all life stages using routine electronic health records and laboratory test data. To enhance individualized predictions, we integrated virtual patient representations from 24,633,025 heterogeneous longitudinal clinical visits across 9,680,764 individuals and projected them into a latent space. Our approach leverages EHRFormer, a time-series transformer-based model, to analyze developmental and aging dynamics with high precision and develop accurate biological age clocks spanning infancy to old age. Our findings reveal distinct biological clock patterns across different life stages. The pediatric clock is strongly associated with children's development and accurately predicts current and future risks of major pediatric diseases, including malnutrition, growth and developmental abnormalities. The adult clock is strongly associated with aging and accurately predicts current and future risks of major age-related diseases, such as diabetes, renal failure, stroke and cardiovascular diseases. This work therefore distinguishes pediatric development from adult aging, establishing a novel framework to advance precision health by leveraging routine clinical data across the entire lifespan.

Increasing evidence suggests that the aryl hydrocarbon receptor (AHR) and poly (ADP-ribose) polymerase 1 (PARP1) are closely linked to aging and aging-related disorders. However, the underlying mechanisms of AHR-PARP1 axis-mediated DNA repair in countering aging remain largely unknown. In this study, it is found that both aged humans and mice exhibit marked intestinal aging, characterized by gut dysbiosis and dysfunction and DNA damage, compared to their young counterparts. Intriguingly, it is discovered that intestinal AHR activation by indole-3-acetic acid (IAA), which is derived from Lactobacillus salivarius rather than host cells, effectively mitigates intestinal aging by regulating DNA-damage responses. Mechanistically, activated AHR by IAA interacts with PARP1, potentiating PARP1 activity and the polymerization of poly (ADP-ribose) (PARylation) by binding to its promoter. This interaction enhances intestinal barrier function and suppresses inflammation and cell senescence. Finally, the interplay between AHR and PARP1 is confirmed by in vivo and in vitro experiments, including intestine-specific Ahr knockout mice, Ahr and Parp1 knockdown, and Parp1 overexpression in enterocytes. These findings provide a potential intervention strategy targeting AHR-PARP1 axis to mitigate age-related intestinal dysfunction.

A loss of proteostasis is a primary hallmark of ageing that has emerged from mechanistic studies in model organisms, but little is currently known about changes to proteostasis in the muscle of older humans. We used stable isotope labelling (deuterium oxide; D2O) in vivo, and peptide mass spectrometry of muscle samples to investigate differences in proteome dynamics between the muscle of younger (28 {+/-} 5 y; n=4) and older (69 {+/-} 3 y; n=4) men during either habitual activity or resistance exercise training. We quantified the abundance of 1787 proteins and the turnover rate of 1046 proteins in bi-lateral samples of vastus lateralis (n=32 samples total) taken before and after a 15-day program including 5 sessions of unilateral leg-press exercise (3 sets of 10 repetitions at 90% of 10 RM). Our protein abundance profiling revealed a stoichiometric imbalance within the proteostasis network in aged skeletal muscle, including subunits of eIF3, subunits of 40S and 60S ribosomal proteins. The rate of bulk, mixed-protein synthesis was not different between younger and older men, but most ribosomal proteins were less abundant in the muscle of older participants, suggesting ribosomes in older muscle may exhibit increased translational efficiency to maintain similar levels of protein turnover compared to ribosomes in younger muscle. Resistance exercise partially restored age-related disruptions to the proteostasis network. In older skeletal muscle, resistance exercise specifically increased the absolute turnover rate (ATR) of mixed mitochondrial proteins, with increased fractional turnover rate (FTR) of prohibitin 1 (PHB1) and profilin-1 (PROF1), and increased abundance of prohibitin 2 (PHB2). These adaptations may suggest resistance exercise promotes mitochondrial proteostasis by facilitating the synthesis and maintenance of key mitochondrial proteins. Thus, our Dynamic Proteome Profiling data provide an impetus for further exploration of the role of proteostasis in maintaining skeletal muscle quality and supports resistance exercise as a potential therapeutic strategy to promote healthy skeletal muscle ageing in humans.