Longevity Papers

Aging is a complex biological process involving coordinated changes across multiple molecular systems. Traditional reductionist approaches, while valuable, are insufficient to capture the full scope of aging's systemic nature. Multiomics - integrating data from genomics, transcriptomics, epigenomics, proteomics, and metabolomics - provides a comprehensive framework to study aging as an interconnected network. In this Perspective, I explore how multiomic strategies, particularly those leveraging epigenomic and single-cell data, are reshaping our understanding of aging biology. Epigenetic alterations, including DNA methylation and histone modifications, are not only hallmarks but also powerful biomarkers of biological age. I discuss advances in multiomic aging clocks, cross-tissue atlases, and single-cell spatial technologies that decode aging at unprecedented resolution. I also build on a prior review I wrote with colleagues, Epigenomics. 2023;15(14):741-754, which introduced the concept of pathological epigenetic events that are reversible (PEERs) - epigenetic alterations linked to early-life exposures that predispose to aging and disease but may be therapeutically modifiable. This Perspective examines how PEERs and multiomics intersect to inform biomarkers, geroprotective interventions, and personalized aging medicine. Finally, I highlight integration challenges, ethical concerns, and the need for standardization to accelerate clinical translation. Together, these insights position multiomics as a central pillar in the future of aging research.

Aging is associated with a decline in the regenerative capacity of many tissues. Central to this decline is a complex interplay between inflammation and stem cell function. How these two processes are linked and influence regenerative capacity remains unclear. Here, we undertake a comprehensive assessment of age-related changes in the mouse colon at single-cell resolution. A survey of immune and epithelial compartments revealed a hyperactivated inflammatory state in the colon of old mice characterized by the induction of an interferon {gamma} (IFN{gamma}) response signature in immune cells. This does not result in increased inflammation under homeostasis, but triggers a disproportionate inflammatory response, disrupting regeneration after challenge with the enteropathogen Citrobacter rodentium. Colons of old mice exhibit higher production of IFN{gamma} by T and innate lymphoid cells (ILCs) that are associated with reduced Lgr5+ stem cells and decreased epithelial proliferation. Interestingly, we find aged intestinal epithelial cells to be hypersensitive to IFN{gamma} signaling, inducing a regeneration-associated fetal-like gene expression signature that, in turn, renders these cells more sensitive to IFN{gamma}-induced apoptosis. Our findings reveal an age-related imbalance in the interaction between the immune and epithelial compartments in the colon, priming the system for excessive inflammatory responses and the emergence of a hypersensitive epithelial cell state thus derailing proper repair of the intestinal epithelium after injury.

Muscle regeneration is impaired with aging, due to both intrinsic defects of muscle stem cells (MuSCs) and alterations of their niche. Here, we monitor the cells constituting the MuSC niche over time in young and old regenerating mouse muscle. Aging alters the expansion of all niche cells, with prominent phenotypes in macrophages that show impaired resolution of inflammation. RNA sequencing of FACS-isolated mononucleated cells uncovers specific profiles and kinetics of genes and molecular pathways in old versus young muscle cells, indicating that each cell type responds to aging in a specific manner. Moreover, we show that macrophages have an altered expression of Selenoprotein P (Sepp1). Macrophage-specific deletion of Sepp1 is sufficient to impair the acquisition of their restorative profile and causes inefficient skeletal muscle regeneration. When transplanted in aged mice, bone marrow from young WT mice, but not Sepp1-KOs, restores muscle regeneration. This work provides a unique resource to study MuSC niche aging, reveals that niche cell aging is asynchronous and establishes the antioxidant Selenoprotein P as a driver of age-related decline of muscle regeneration.

Background. Age is one of the major risk factors for a wide range of diseases. Nevertheless, some individuals can better cope with these changes and become centenarians. We hypothesize that their blood transcriptome may provide insights into the mechanisms contributing to healthy aging, as well as enable the discovery of candidate therapeutic targets. The Long-Life Family Study (LLFS), which includes participants from families enriched with long-lived individuals, serves as a valuable dataset for achieving these objectives. Methods. To identify transcripts associated with age, we analyzed the association between age at blood draw and 16,284 RNAseq-based blood transcriptomic data from 2,167 LLFS participants with ages ranging from 18 to 107. We used linear mixed-effect models controlling for familial relatedness and adjusted for genetic, socioeconomic, and technical confounders. We validated results in a dataset of 20,884 RNAseq-based blood transcriptomic data from 434 participants of the Integrative Longevity Omics Study, and compared findings to a published reference aging signature. We integrated the results by building a transcriptomic aging clock. We also identified transcripts associated with mortality risk using a Cox-proportional hazard model. Results. We identified 4,227 transcripts increasing and 4,044 transcripts decreasing with age. Age-associated expression patterns were significantly replicated in external datasets, with high correlation (R = 0.78 - 0.94). Enrichment analysis revealed age-related upregulation of inflammatory and senescence-related pathways (e.g., IFN-{gamma} response, TNF-/NF-{kappa}B signaling), and downregulation of MYC and Wnt/{beta}-catenin targets, among others. WGCNA identified co-expression modules reflecting inflammation, immune signaling, and decreased protein synthesis. We also identified 314 transcripts significantly associated with mortality risk and found that pro-survival gene sets included NK cell-mediated cytotoxicity and GPCR signaling. A subset of transcripts showed age associations unique to longevity-enriched cohorts and not present in non-longevity populations, implicating IL6-Jak-Stat3, mitotic spindle, and p53 pathways. Finally, transcriptomic age (delta-age) was strongly associated with increased mortality (HR = 1.108, p = 3.33e-18), with significant survival differences between delta-age groups. Conclusions. This study identified robust transcriptomic signatures of aging and mortality in a longevity-enriched population, highlighting key biological pathways such as immune modulation, inflammation, and senescence. Age-associated expression profiles that are unique to long-lived individuals may represent resilience mechanisms distinct from general aging trends. Transcriptomic age acceleration is a strong predictor of mortality, reinforcing its utility as a molecular biomarker of biological aging.

Targeting Endoplasmic Reticulum Oxidoreductase 1 Alpha (ERO1A) offers therapeutic potential for ER stress-related conditions, including motor neurone diseases and congenital muscle disorders. However, selective ERO1A inhibitors remain unavailable. Here, we developed a multi-modal discovery pipeline combining molecular docking with in vitro and in vivo assays, screening 401,824 natural products from the COCONUT database. We identified two compounds, S88 and geniposide, that inhibited ERO1A in vitro, reduced tunicamycin-induced ER stress markers in human neurons, and improved locomotion and neuromuscular junctions in UBQLN2ALS Drosophila. S88 maintained efficacy in late-stage disease and extended lifespan in a D-galactose aging model. In fly brains, S88 selectively reduced phosphorylated eIF2a; without lowering its downstream effector ATF4, suggesting engagement of alternative mechanisms preserving ATF4 homeostasis. These findings highlight S88 as a promising lead for treating ER stress-associated neuromuscular disorders and demonstrate the utility of this integrative discovery pipeline for identifying bioactive natural compounds with disease-modifying potential.

Reproduction and immunity are fundamental, energy intensive processes that often compete for resources, leading to trade-offs observed across diverse species. Lipid metabolism plays a crucial role in integrating these processes, particularly during stressful conditions such as pathogenic infections. Yet the molecular mechanisms governing this integration remain poorly understood. TCER-1, the C. elegans homolog of mammalian TCERG1, suppresses immunity and promotes fertility, especially upon maternal infection. Here, we show that TCER-1 regulates two conserved lysosomal lipases, lipl-1 and lipl-2, to balance reproduction, immunity and lifespan. Using transcriptomic, lipidomic, and molecular-genetic analyses, we demonstrate that while both lipl-1 and lipl-2 mediate infection-induced lipid remodeling, lipl-1 enhances immunity and catalyzes the accumulation of ceramide species linked to stress response and longevity, whereas, lipl-2 unexpectedly does not. Both lipases contribute towards fertility outcomes, but lipl-2 is especially critical for maintaining embryonic-eggshell integrity during maternal infection and aging. Strikingly, expression of human lysosomal acid lipase (LAL), the ortholog of lipl genes, rescues the immune defects triggered by lipl-l loss and enhances immune resilience. Together, these findings uncover functionally distinct roles for lipl-1 and lipl-2 in modulating lipid species that shape immune fitness, healthspan and reproductive health, and suggest a potentially conserved mechanism by which lipid metabolism links fertility and immunity.

Osteoarthritis (OA) is a challenging degenerative joint disease with limited treatment options. Subchondral bone plays a critical role in maintaining joint homeostasis and influencing OA progression. Here, we investigated the role of senescence in mesenchyme-derived stem/progenitor cells (MDSPCs) during OA progression, aiming to identify potential therapeutic targets. Histopathological evaluations and bioinformatic analyses of OA samples from both humans and mice revealed that EGFR

Astrocytes, the most abundant glial cells in the central nervous system, play essential roles in maintaining neuronal homeostasis, synaptic regulation, and blood-brain barrier integrity. However, these cells can undergo senescence, a cellular state characterized by irreversible growth arrest and the secretion of proinflammatory factors, in response to aging, and pathological stressors, contributing to synaptic dysfunction and neurodegenerative diseases. This review examines the molecular mechanisms driving astrocytic senescence, including oxidative stress, DNA damage, and inflammatory signaling pathways such as NF-κB and the senescence-associated secretory phenotype (SASP). A particular focus is placed on the diverse array of known chemical inducers of astrocyte senescence such as pesticides and heavy metals, which provide critical insights into the processes governing cellular aging in the brain. By analyzing the effects of these inducers, we highlight their implications for neurodegenerative disease progression and brain aging. Understanding astrocytic senescence offers new insights into age-related neuropathology and presents promising avenues for targeted therapies in neurodegenerative disorders induced by environmental toxicants.

Stress response pathways are emerging as conserved modulators of lifespan. The prevailing hypothesis is that activation of stress responsive pathways, including the amino acid deprivation arm of the integrated stress response (ISR; the GCN2-ATF4 pathway) is pro-longevity. Activation of ATF4 orthologs extends lifespan in Saccharomyces cerevisiae (yeast) and Caenorhabditis elegans, but its role in other longer-lived organisms remains unclear. We comprehensively tested the role of the GCN2-ATF4 pathway in the fly (Drosophila melanogaster) for the first time. We used conditional genetic manipulation of dGCN2 and its downstream effector Drosophila ATF4 (crc; dATF4). In contrast to previous studies, we show that overexpression of dGCN2 and dATF4 significantly reduces lifespan, while knockdown (in vivo RNAi) of dATF4 extends lifespan. We confirmed dATF4 activity was successfully modulated using a fluorescent dATF4 activation reporter. Borrelidin, a tRNA synthetase inhibitor, significantly reduced lifespan in a both dATF4 and diet-dependent manner, independent of microbial load, showing our modulation of dATF4 altered nutrient to ISR signalling. We further conducted long-read RNA sequencing and found that our manipulation of dATF4 changed global transcription in opposite directions, including known ATF4 target genes. Enrichment analysis revealed that dATF4 overexpression may drive metabolic stress, while dATF4 knockdown upregulates proteostasis and DNA repair pathways. Our work reveals that ATF4 exhibits a dual, dose- and context-dependent role in ageing. Chronic dATF4 activation is detrimental in flies, while chronic suppression is pro-longevity. The GCN2-ATF4 pathway thus qualifies as a modifiable control of lifespan with cross-species relevance.

The misclassification of functional genomic loci as pseudogenes has long obscured critical regulators of cellular homeostasis, particularly in aging-related pathways. One such locus, originally annotated as RPL29P31, encodes a 17-kDa protein now redefined as PERMIT (Protein that Mediates ER-Mitochondria Trafficking). Through rigorous experimental validation-including antibody development, gene editing, lipidomics, and translational models-p17/PERMIT has emerged as a previously unrecognized mitochondrial trafficking chaperone. Under aging or injury-induced stress, p17 mediates the ER-to-mitochondria translocation of Ceramide Synthase 1 (CerS1), facilitating localized C18-ceramide synthesis and autophagosome recruitment to initiate mitophagy. Loss of p17 impairs mitochondrial quality control, accelerating neurodegeneration, and sensorimotor decline in both injury and aging models. This Perspective highlights p17 as a paradigm-shifting discovery at the intersection of lipid signaling, mitochondrial biology, and genome reannotation, and calls for a broader reassessment of the "noncoding" genome in aging research. We summarize a rigorous multi-platform validation pipeline-including gene editing, antibody generation, lipidomics, proteomics, and functional rescue assays-that reclassified p17 as a bona fide mitochondrial trafficking protein. Positioned at the intersection of lipid metabolism, organelle dynamics, and genome reannotation, p17 exemplifies a growing class of overlooked proteins emerging from loci historically labeled as pseudogenes, urging a systematic reevaluation of the "noncoding" genome in aging research.

Early detection of cognitive impairment in assisted living is hindered by time intensive tools like MMSE and MoCA. We present a 60-second voice based screening model that analyzes picture descriptions to estimate dementia risk. Using transcripts from the DementiaBank corpus, our model integrates traditional linguistic features (pause rate, pronoun use, syntactic complexity) with latent semantic dimensions extracted from language model embeddings. These semantic axes, interpretable constructs like "Drift & Hesitation" or "Over detailed Narration", consistently emerged as top predictors and may represent novel linguistic biomarkers of early decline. The final ElasticNet classifier is sparse, interpretable, and outperforms known non deep learning baselines (AUC = 0.858), exceeding MMSE. Its simplicity enables deployment in mobile apps or in-room monitors, offering scalable, low burden screening for early dementia. This work supports a shift toward linguistically grounded, tech enabled cognitive care in aging populations.

The nuclear chromatin landscape changes with age. Here, we investigate whether chromatin alterations distinguish also animals with unusual aging rates, focusing on Caenorhabditis elegans with reduced insulin/IGF-like signaling (IIS), i.e., daf-2 mutants. In these animals, enhancer regions that close with age tend to open and become transcriptionally active. We identify LIN-39 as a transcription factor (TF) binding these regions and being required for the longevity of daf-2 mutants. LIN-39 acts during late development in hermaphrodite-specific VC motor neurons - at a time when these undergo maturation. LIN-39-mediated longevity requires DAF-16/FOXO, suggesting cooperation of both TFs in VC neurons to open enhancers. Our findings argue that longevity of daf-2 mutant hermaphrodites relies on a signal emitted by properly matured VC neurons, and due to its essential role in this maturation process LIN-39 becomes a rare example of a development-specific lifespan determinant.

The faithful transmission of genomic DNA over succeeding generations is an essential prerequisite for species maintenance. The germplasm theory by August Weismann has been foundational for the current understanding of heredity; it proposed that genetic inheritance is exclusively mediated by germ cells while they are protecting heritable germline genomes from the phylogenetic influences of an individual's life history. However, recent studies on the inheritance of epigenetic variation have challenged the traditional dogma of heredity and opened new perspectives on molecular mechanisms of inheritance. This review highlights the current knowledge about heritable memories of the ancestral lifestyle and discusses emerging frontiers in soma-germline circuits with a focus on the control of the integrity of heritable genomes as well as their implications for somatic and reproductive aging.

Aging induces substantial structural and functional decline in the retina, yet the molecular drivers of this process remain elusive. In this study, we used heterochronic parabiosis (HP) combined with single-cell RNA sequencing to generate comprehensive transcriptomic profiles of murine retinas from young, aged, and HP pairs, aiming to identify antiaging targets. Our analysis revealed extensive transcriptional alterations across retinal cell types with aging. HP experiments demonstrated that systemic factors from young mice rejuvenated aged retinas and alleviated senescent phenotypes, while aged blood accelerated aging in young mice. Integrative analysis pinpointed adiponectin receptor 1 (AdipoR1) and the downstream adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling pathway as central to the molecular mechanisms underlying retinal rejuvenation. Treatment with the AdipoR1 agonist AdipoRon reversed retinal aging. Mechanistically, AdipoR1-AMPK activation promoted mitochondrial function, contributing to the restoration of youthful cellular phenotypes. Together, our study identifies AdipoR1 as a therapeutic target for retinal aging and provides insights into the molecular programs driving retinal rejuvenation.

Aging is associated with the accumulation of molecular damage, functional decline, increasing disease prevalence, and ultimately mortality. Although our system-wide understanding of aging has significantly progressed at the genomic and transcriptomic levels, the availability of large-scale proteomic datasets remains limited. To address this gap, we have conducted an unbiased quantitative proteomic analysis in male C57BL/6J mice, examining eight key organs (brain, heart, lung, liver, kidney, spleen, skeletal muscle, and testis) across six life stages (3, 5, 8, 14, 20, and 26-month-old animals). Our results reveal age-associated organ-specific as well as systemic proteomic alterations, with the earliest and most extensive changes observed in the kidney and spleen, followed by liver and lung, while the proteomic profiles of brain, heart, testis, and skeletal muscle remain more stable. Isolation of the non-blood-associated proteome allowed us to identify organ-specific aging processes, including oxidative phosphorylation in the kidney and lipid metabolism in the liver, alongside shared aging signatures. Trajectory and network analyses further reveal key protein hubs linked to age-related proteomic shifts. These results provide a system-level resource of protein changes during aging in mice, and identify potential molecular regulators of age-related decline.

Cerebral glucose metabolism (CMRGlc) systematically decreases with advancing age. We sought to identify correlates of decreased CMRGlc in the spectral properties of fMRI signals imaged in the task-free state. Lifespan resting-state fMRI data acquired in 455 healthy adults (ages 18-87 years) and cerebral metabolic data acquired in a separate cohort of 94 healthy adults (ages 25-45 years, 65-85 years) were analyzed. The spectral properties of the fMRI data were characterized in terms of the relative predominance of slow versus fast activity using the spectral slope (SS) measure. We found that the relative proportion of fast activity increases with advancing age (SS flattening) across most cortical regions. The regional distribution of spectral slope was topographically correlated with CMRGlc in young adults. Notably, whereas most older adults maintain a youthful pattern of SS topography, a distinct subset of older adults significantly diverged from the youthful pattern. This subset of older adults also diverged from the youthful pattern of CMRGlc metabolism. This divergent pattern was associated with T2-weighted signal changes in frontal lobe white matter, an independent marker of small vessel disease. These findings suggest that BOLD signal spectral slope flattening may represent a biomarker of age-associated neurometabolic pathology.

Pathogenic germline variants causing excessive telomere shortening may result in bone marrow failure, hematopoietic malignancy, and extramedullary complications, such as pulmonary fibrosis, liver cirrhosis, and solid tumors. Patients with short telomeres also develop immunodeficiency with low CD4+ T cells and impaired general immunosurveillance, particularly against solid neoplasms. We investigated a broad spectrum of lymphocyte subsets and myeloid immune cells from human patients with telomere biology disorders (TBDs) and matched healthy volunteers to understand further how the immune system is affected by telomere dysfunction. We employed mass cytometry (CyTOF) for deep-immunophenotyping peripheral blood mononuclear cells (PBMCs), followed by high-dimensional data analysis. Cytokines, chemokines, and growth factors were assessed in serum. Our results showed profound immune alterations in TBD beyond those observed in aging, with low naïve lymphocytes and thymic hypofunction. We further observed that T helper subsets were markedly skewed, with an inverted TH2/TH1 ratio and low TH17 and TH17.1 levels. T cell activation and exhaustion markers were upregulated, whereas circulating mucosal-associated invariant T (MAIT) cells were significantly decreased and overactivated. Several serum cytokine levels were positively correlated with telomere length and blood counts, suggesting an association with marrow function. In aggregate, these findings suggest a pro-inflammatory profile in TBDs. Our data provide new details on how TBD affects immune cells, particularly lymphocytes, which may contribute to the clinical phenotypes.

Age-related diseases and syndromes result in poor quality of life and adverse outcomes, representing a challenge to healthcare systems worldwide. Several pharmacological interventions have been proposed to target the aging process to slow its adverse effects. The so-called geroprotectors have been proposed as novel molecules that could maintain the organism's homeostasis, targeting specific aspects linked to the hallmarks of aging and delaying the adverse outcomes associated with age. On the other hand, machine learning (ML) is revolutionising drug design by making the process faster, cheaper, and more efficient.