Longevity Papers

Leveraging clinical phenotypes, neuroimaging, proteomics, metabolomics, and epigenetics, biological aging clocks across organ systems and tissues have advanced our understanding of human aging and disease. In this study, we expand this biological aging clock framework to multi-organ magnetic resonance imaging (MRI) by developing 7 organ-specific MRI-based biological age gaps (MRIBAGs), including the brain, heart, liver, adipose tissue, spleen, kidney, and pancreas. Leveraging imaging, genetic, proteomic, and metabolomic data from 313645 individuals curated by the MULTI consortium, we link the 7 MRIBAGs to 2923 plasma proteins, 327 metabolites, and 6477810 common genetic variants. These associations reveal organ-specific and cross-organ interconnection landscapes, identifying distinct molecular signatures related to organ aging. Genome-wide associations identify 53 MRIBAG-locus pairs. Genetic correlation and Mendelian randomization analyses further support organ-specific and cross-organ interconnections with 9 phenotype-based, 11 proteome-based, and 5 metabolome-based aging clocks, as well as 525 disease endpoints. Through functional gene mapping and Bayesian colocalization analysis linking evidence from genetics, proteomics, and metabolomics, we prioritize 9 druggable genes as targets for future anti-aging treatments. Finally, we demonstrate the clinical relevance of the 7 MRIBAGs in predicting disease endpoints (e.g., diabetes mellitus), all-cause mortality, and capturing differential and heterogeneous cognitive decline trajectories over 240 weeks of treatment with the Alzheimers disease drug (Solanezumab). Sex differences are evident across multiple organ systems, manifesting at structural, molecular, and genetic levels. In summary, we developed 7 MRI-based aging clocks that enhance the existing multi-organ biological aging framework, offer multi-scale insights into aging biology, and demonstrate clinical potential to advance future aging research.

Aging is the largest risk factor for the development of osteoarthritis (OA), a major contributor to increased years lived with disability. This review reflects on how age-related changes relevant to OA have been measured at various length scales. Key discoveries include increased chondrocyte DNA damage with age and the disruption of matrix homeostasis by cellular senescence. Epigenetic clocks have yet to show predictive value for OA, while transcriptomic changes and miRNA profiles are linked to aging and senescence. Protein biomarkers have gained traction in the context of post-traumatic OA and may also be useful in understanding risk profiles for age-related OA. Post-translational modifications provide insights into protein aging and the rate of matrix turnover at different joint sites. Non-enzymatic crosslinks also increase with age and may be responsible for changes to the mechanical properties of joint tissues. Finally, the walking speed declines with age and predicts incident OA. Despite these advances, more research is needed on age-related changes in tissues beyond cartilage. Efforts should be directed toward identifying biomarkers of aging that can integrate large studies on genetic risk factors with the deep phenotyping done in longitudinal cohort OA studies. Early intervention is crucial for treating OA and other age-related diseases, highlighting the importance of validating sensitive and predictive biomarkers that could support new treatment paradigms. Finally, reversing at least some aspects of age-related decline may be critical for improving joint function. Promising approaches include effective delivery of targeted senolytics and the use of partial reprogramming to rejuvenate chondrocytes.

The aging process is often accompanied by hepatic metabolic dysregulation and related complications, including lipid accumulation and fibrosis. Nutritional interventions are crucial for maintaining metabolic health. This study explored the effects of exogenous nucleotides (NTs) on liver health in aged SAMP8 mice over 9 months. Results demonstrated dietary NTs effectively improved liver pathology, increased body mass, enhanced antioxidant capacity, reduced lipid accumulation, downregulated lipid synthesis genes, and lowered fibrosis-related markers. Mechanistically, NTs downregulated purine biosynthesis, modulating lipid metabolism-related transcription factors to reduce lipid accumulation. Additionally, NTs enhanced the efficiency of glycolysis and increased ATP synthesis. Thus, NTs exhibited substantial effects in regulating energy metabolism, suppressing lipid synthesis, and combating fibrosis. However, the effects displayed a nonlinear dose-dependent relationship, and the precise impact of NT dosage on health remains challenging. This study advances our understanding of NTs' role in aging and metabolic dysregulation.

The nutritional environment in early life, referred to as the nutrition history, exerts far-reaching health effects beyond the developmental stage. Here, with Drosophila melanogaster as a model, we fed larvae on diets consisting of a variety of yeast mutants and explored the resulting histories that impacted adult lifespan. A larval diet comprised of yeast nat3 KO shortened the lifespan of male adults; and remarkably, this diet diminished the function of histone acetyltransferase Gcn5 in larvae. Concordantly, perturbation of Gcn5-mediated gene regulation in the larval whole body or neurons significantly contributed to the earlier death of adults. The nat3 KO diet is much more abundant in long-chain fatty acids and branched-chain amino acids (BCAAs) than the control yeast diet. Supplementing the control diet with a combination of oleic acid, valine, and acetic acid recapitulated the effects of the nat3 KO diet on the larval transcriptome and the lifespan of males. Our findings strongly suggest a causal link between a fatty acids- and BCAA-rich diet in developmental stages and lifespan reduction via the adverse effect on the Gcn5 function.

Hematopoietic stem cells (HSCs) are responsible for sustaining hematopoietic system throughout life, and their functional decline contributes to hematological disorders and organismal aging. Understanding the molecular mechanisms that govern HSC function is critical for developing interventions for treating and preventing aging-related diseases. Here, we show that DCAF8, a substrate recognition component of Cullin-RING E3 ubiquitin ligases, is highly expressed in HSCs and undergoes a progressive decline with age. Loss of DCAF8 in mice results in impaired function in HSCs, characterized by increased number yet decreased self-renewal capacity, which associates with cellular senescence and elevated DNA damage. Mechanistically, DCAF8 mediates the degradation of DOCK11, a guanine nucleotide exchange factor for CDC42. In the absence of DCAF8, DOCK11 accumulates, leading to elevated CDC42 activity and consequential loss of polarity of HSCs. Knocking out Dock11 mitigates the senescence, DNA damage, and self-renewal defects of Dcaf8-/- HSCs. This study highlights a critical role of DCAF8 in preventing HSC senescence via the DOCK11-CDC42 axis and suggests potential therapeutic targets for preventing functional decline in HSCs.

Cellular senescence represents a permanent state of cell cycle arrest, also observed in neurodegenerative disorders. As p300 has been identified as an epigenetic driver of replicative senescence, we aimed to investigate whether in vitro p300 inhibition could rescue the stress-induced premature senescence (SIPS) phenotype. We exploited 2D and 3D (brain organoids) in vitro models of SIPS using two different stressor agents. In addition, we combined the treatment with a p300 inhibitor and validated p300 role in SIPS by analyzing different senescence markers and the transcriptome in our models. Interestingly, p300 inhibition can counteract the DNA damage and SIPS phenotype, detecting a dysregulation of gene expression and protein translation associated with the senescence program. These findings highlight both the molecular mechanisms underlying senescence and p300 as a possible pharmacological target. Thus, targeting p300 and, by extension, senescent cells could represent a promising therapeutic strategy for age-related diseases such as neurodegenerative disorders.

Ovarian aging is a critical yet understudied driver of systemic aging in female bodies, with profound implications for female health and longevity. Despite its significance, we still know little about ovarian aging and its systemic effects on aging trajectories. With new efforts over the past few years, interest in the field has been growing and there is momentum to address these questions. This review highlights the importance of leveraging modern tools and approaches to better understand ovarian aging and its impact on health span. Specifically, we believe it will be useful for both aging researchers looking to go into research on ovarian aging and reproductive researchers looking to adopt more modern toolkit. We focus on menopause-a key marker of ovarian aging-as a lens through which to examine the current state of the field, identify limitations in existing research, and outline goals for future progress. By emphasizing cutting-edge techniques and emerging models, we seek to illuminate new pathways for research that could lead to improved strategies for managing ovarian aging and enhancing overall female health.

Ultraviolet (UV) radiation from the sun causes adverse skin changes such as premature aging. UVA radiation is the primary factor for photoaging due to its deep penetration into the dermis, and UV-induced mitochondrial DNA (mtDNA) alterations, including deletions, contribute to photoaging and cellular dysfunction. The most frequent mtDNA rearrangement is the common deletion (CD), characterized by the loss of nearly one-third of the genome, 4,977 base pairs. UV radiation exposure leads to the formation of the CD, however, a distinct characterization of UV-induced CD and the underlying molecular mechanisms driving its initiation remains unexplored. In this study, we showed that increasing doses of UV radiation led to an increase in the CD in human skin fibroblasts. We found that UVA induce the formation of the CD by increasing the cellular reactive oxygen species (ROS) and oxidized bases content in the mtDNA. Preconditioning cells with antioxidants prevented the accumulation of the UVA-induced CD, suggesting that this mutational mechanism is ROS-dependent. In stark contrast, UVB did not alter cellular ROS levels but increased the formation of cyclobutane pyrimidine dimers (CPD), leading to CD generation though a ROS-independent mechanism. We corroborated our findings by using a 3D human full-thickness skin equivalent model, where we detected UVA-dependent CD formation in both the epidermal and dermal layers of the skin. By analyzing bulk RNA from UVA-exposed human skin fibroblasts by RNA-Seq, we found that UVA led to the upregulation of genes encoding mitochondrial DNA replication proteins and to the downregulation of genes involved genes encoding mtDNA repair factors. Taken together, our findings provide insight into how UVA and UVB differ in their detrimental effects on mtDNA, with UVA impacting mtDNA maintenance and transcription via a ROS-dependent mechanism. Our findings also established the mtDNA CD as a novel potential biomarker for monitoring UVA-induced oxidative stress and photoaging in skin cells in vitro and in vivo.

Plasma proteins derived from specific organs can estimate organ age and mortality, but their sensitivity to environmental factors and their robustness in forecasting onset of organ diseases and mortality remain unclear. To address this gap, we estimate the biological age of 11 organs using plasma proteomics data (2,916 proteins) from 44,498 individuals in the UK Biobank. Organ age estimates were sensitive to lifestyle factors and medications and were associated with future onset (within 17 years' follow-up) of a range of diseases, including heart failure, chronic obstructive pulmonary disease, type 2 diabetes and Alzheimer's disease. Notably, having an especially aged brain posed a risk of Alzheimer's disease (hazard ratio (HR) = 3.1) that was similar to carrying one copy of APOE4, the strongest genetic risk factor for sporadic Alzheimer's disease, whereas a youthful brain (HR = 0.26) provided protection that was similar to carrying two copies of APOE2, independent of APOE genotype. Accrual of aged organs progressively increased mortality risk (2-4 aged organs, HR = 2.3; 5-7 aged organs, HR = 4.5; 8+ aged organs, HR = 8.3), whereas youthful brains and immune systems were uniquely associated with longevity (youthful brain, HR = 0.60 for mortality risk; youthful immune system, HR = 0.58; youthful both, HR = 0.44). Altogether, these findings support the use of plasma proteins for monitoring of organ health and point to the brain and immune systems as key targets for longevity interventions.

N6-methyladenosine (m6A), as the most common RNA modification at the post-transcriptional level, plays a role in various pathophysiological processes. However, its underlying mechanism in skin aging remains enigmatic. Here, we identified that fat mass and obesity-associated protein (FTO) serves as a protective factor against skin aging. FTO expression is downregulated in aging skin tissues and senescent fibroblasts. Furthermore, the depletion or inhibition of FTO exacerbates dermal fibroblasts senescence and accelerates skin aging. Additionally, RNA-seq combined with MeRIP-seq revealed that lysine acetyltransferase 8 (KAT8) is the downstream target of FTO. FTO deficiency leads to an increase in m6A levels and a decrease in mRNA stability of KAT8 in a m6A-YTHDF2-dependent manner. Notably, our integrated analysis of m6A sequencing and acetylation proteomics links changes in heterochromatin structure with aging. Mechanistically, KAT8 depletion leads to heterochromatin loss and the subsequent aging by acetylating remodeling and spacing factor 1 (RSF1) at K1050. Overall, our finding reveals a pivotal role of FTO-mediated m6A modification in the skin aging by regulating KAT8/RSF1-involved heterochromatin formation. It provides new insights into the mechanisms and strategies for delaying aging and improving healthspan.

Background: Leukocyte telomere length (LTL) has been implicated in aging and age-related diseases, including chronic respiratory diseases (CRDs). However, the extent and mechanisms of shared genetic architecture between LTL and respiratory health indicators (such as CRDs and lung function parameters) remain incompletely understood. Methods: We first systematically characterized the genetic correlations and genetic overlaps between LTL and multiple respiratory health indicators. We then performed horizontal pleiotropy analysis by integrating SNP-level functional annotation, gene mapping, and pathway analysis to identify candidate pleiotropic loci, genes, and shared biological pathways. Finally, we assessed the causal relationships among these trait pairs using the latent causal variable (LCV) and MRlap. Results: There was extensive genetic overlap between LTL and respiratory health indicators, regardless of whether these trait pairs had significant genetic associations. We identified 27,885 candidate pleiotropic loci and 82 pleiotropic genes. Notably, five key genes, such as STN1, MPHOSPH9, MTRFR, MAX, and UCKL1, showed significant pleiotropic effects in multiple phenotype pairs and mediated different patterns of genetic associations. Pathway enrichment analysis of these pleiotropic genes highlighted the close association of specific trait pairs with RNA metabolism and telomere maintenance. Finally, vertical pleiotropy analysis revealed negative causal associations of LTL-idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease-LTL. Conclusions: Our findings reinforce the roles of telomere biology and RNA processing in the pathogenesis of chronic lung diseases and support a shared genetic basis for common molecular pathways.

Cellular senescence is a process in which the cell cycle becomes permanently arrested, thereby inhibiting cell division, proliferation and growth. Various cellular stresses, such as DNA damage, telomere shortening and oxidative stress, can trigger cellular senescence. Physiologically, cellular senescence contributes to tissue development, repair and critical biological processes such as embryogenesis, whereas, pathologically, it plays a key role in diverse disease subsets. To this end, elucidating the underlying mechanisms and molecular regulation of senescence is crucial. Here, in this Review, we explore recent key findings on cellular senescence in experimental and human disease models, focusing on its molecular mechanisms, regulation and future research directions to advance the field and facilitate therapeutic translation.

Aging is an inherent phenomenon that is highly important in the pathological development of numerous diseases. Aging is a multidimensional phenomenon characterized by the progressive impairment of various cellular structures and organelle functions. The basis of human organ senescence is cellular senescence. Currently, with the increase in human life expectancy and the increasing proportion of the elderly population, the economic burden of diseases related to aging is becoming increasingly heavy worldwide, and an in-depth study of the mechanism of cellular aging is urgently needed. Aging, a multifactor-driven biological process, is closely related to mitochondrial dysfunction, which is the core pathological basis of a variety of age-related diseases. This article systematically reviews the molecular pathways by which mitochondrial dysfunction drives aging through multidimensional mechanisms such as metabolic reprogramming, epigenetic regulation, telomere damage, autophagy imbalance, and the senescence-associated secretory phenotype. Metabolic reprogramming promotes tumor progression and exacerbates energy metabolism disorders through abnormal activation of the PI3K/Akt/mTOR signaling pathways. The sirtuin family (such as SIRT1 and SIRT3) maintains mitochondrial homeostasis by regulating PGC-1α, FOXO3 and other targets. Telomere shortening directly inhibits mitochondrial biosynthesis through the p53-PGC-1α axis, leading to oxidative stress accumulation and a decline in organ function. The dual roles of autophagy (removing damaged mitochondria or inducing apoptosis) suggests that its homeostasis is essential for delaying aging. The SASP mediates the inflammatory microenvironment through the cGAS‒STING pathway, which is not only a marker of aging but also a driving force of disease progression. Future studies need to integrate multiomics techniques to analyze the interaction network between mitochondria and other organelles, such as the endoplasmic reticulum and lysosomes, and explore precise intervention strategies targeting sirtuins, AMPK and telomerase. Combined therapies targeting metabolic reprogramming or SASP inhibition are expected to provide new ideas for delaying aging and preventing age-related diseases.

Adaptive behavior depends on the brains capacity to vary its activity across multiple spatial and temporal scales. Yet, how distinct facets of this variability evolve from childhood to older adulthood remains poorly understood, limiting mechanistic models of neurocognitive aging. Here, we characterize lifespan neural variability using an integrated empirical-computational approach. We analyzed high-density EEG cohort data spanning 111 healthy individuals aged 9-75 years, recorded at rest and during passive and attended auditory oddball stimulation task. We extracted scale-dependent measures of EEG fluctuations amplitude and entropy, together with millisecond-resolved phase-synchrony networks in the 2-20 Hz range. Multi-condition partial least squares decomposition analysis revealed two independent lifespan trajectories. First, slow-frequency power, variance and complexity at longer timescales declined monotonically with age, indicating a progressive dampening of low-frequency fluctuations and large-scale coherence. Second, the temporal organization of phase-synchrony reconfigurations followed an inverted U-trend: young adults exhibited the slowest yet most diverse switching--characterized by low mean but high variance and low kurtosis of jump lengths at 2-6 Hz and the opposite pattern at 8-20 Hz--whereas children and older adults showed faster, more stereotyped dynamics. To mechanistically account for these patterns, we fitted a ten-node phase-oscillator model constrained by the human structural connectome. Only an intermediate, metastable coupling regime reproduced the empirical combination of reduced low-frequency variability and maximally heterogeneous synchrony dynamics observed in young adults, while deviations toward weaker or stronger coupling mimicked the childrens and older adults profiles. Our results demonstrate that development and aging entail changes in the switching dynamics of EEG phase synchronization, by differentially sculpting stationary and transient aspects of neural variability. This establishes time-resolved phase-synchrony metrics as sensitive, mechanistically grounded markers of neurocognitive status across the lifespan.

Shifts in the skin microbiome have shown a close link to chronological age. However, the contribution of skin microbiome in skin aging phenotypes remains unclear. To explore this, we performed phenotypic, metabolomic, metagenomic, and functional analyses on a cohort with divergent skin aging phenotypes. Genome-scale metabolic models (GEMs) integrated with metabolomic analysis revealed that Stenotrophomonas maltophilia, enriched in the younger group (categorized by AI-predicted age and skin elasticity), utilizes the glutathione cycle to maintain redox homeostasis. Cellular experiments showed its metabolites enhanced GSH synthesis and alleviated oxidative stress-induced skin aging by upregulating key genes in fibroblasts, including GCLM, PGD, SOD2, and NQO1. Additionally, GEMs highlighted its potential anti-aging roles in regulating host metabolic pathways involving betaine, lysolecithin, and porphyrin. In parallel, Acinetobacter guillouiae was found to influence host melanin metabolism by degrading dopamine (DA) and 3-methoxytyramine (3-MT), offering potential therapeutic strategies for mitigating pigmentation. Our findings highlight the dynamic interplay between skin microbiota and the host in aging, offering new insights for designing targeted anti-aging interventions.

Aging is a degenerative process, and while Rosa roxburghii Tratt has demonstrated notable anti-aging and antioxidant properties, the precise anti-aging effects of its seeds are not yet fully understood. The aim of this study was to employ a blend of in "dry" and "wet" approaches to investigate the anti-aging activity and underlying mechanisms of the polyphenol-rich extract from these seeds, Rosa roxburghii Tratt seed polyphenol extract (RRTSPE). UPLC-Q-Exactive Orbitrap/MS was employed to identify the chemical constituents of RRTSPE, resulting in the identification of 33 chemical components. Subsequent in vitro antioxidant assays demonstrated RRTSPE's moderate antioxidant capacity, and in vivo evaluations using Caenorhabditis elegans (C. elegans) confirmed its ability to extend lifespan, reduce lipofuscin accumulation, and enhance resistance to oxidative and heat stress. Network pharmacology analysis suggests that RRTSPE's anti-aging effects may involve key proteins linked to metabolic and inflammatory diseases. The predictions regarding the anti-aging effects of RRTSPE were further substantiated using mutant C. elegans strains (DR26, VC475, TJ1052, and CB1370), which confirmed the engagement of the insulin/IGF-1 signaling (IIS) pathway in RRTSPE's anti-aging effects. RRTSPE demonstrates its anti-aging effects in C. elegans through a multifaceted approach, which includes scavenging free radicals, diminishing reactive oxygen species (ROS), enhancing DAF-16 nuclear translocation, and modulating IIS pathway-related proteins like SOD-3 and HSP-16.2. It is the synergistic effect of these actions that underpins the broad-spectrum anti-aging potential of RRTSPE. Taken together, this study not only provides a scientific foundation for the utilization of Rosa roxburghii Tratt seeds as a natural anti-aging agent but also paves the way for further research and development in leveraging their potential health benefits.

Aging leads to a gradual decline in muscle function, yet the mechanisms by which different skeletal muscles respond to aging remain unclear. Here, we constructed transcriptional maps of 11 skeletal muscles with extensive transcriptional diversity from young and old mice. Age-related changes in gene expression displayed distinct tissue-specific patterns, involving muscle diseases and metabolic processes. Notably, the mitochondrial-enriched soleus muscle exhibited superior resistance to aging compared to other skeletal muscles. Further, we generated a single-nuclei transcriptomic atlas on representative skeletal muscles, analyzing 73,170 nuclei. We found the age-related changes in the cellular composition of different skeletal muscles and the emergence of new cell states in aged mice. Among different types of myonuclei, type II myonuclei showed particular sensitivity to aging, with reduced metabolic activity of IIb myonuclei with age. We also found cell-specific changes occurring across nonmuscle nuclei populations, including adipocytes, fibro-adipogenic progenitors, and immune cells, accelerating muscle aging and associated pathologies. Intercellular communication analysis revealed more intensive intercellular interactions in aged skeletal muscles, particularly between myonuclei and other cell types. Specifically, we validated the regulatory role of the EGF/EGFR axis in age-related inflammatory processes. These findings provide insight into muscle biology and aging and highlight potential therapeutic targets for age-associated muscle disorders.