Longevity Papers

RNA engineering has yielded a new class of medicines but faces limitations depending on RNA size and function. Here we demonstrate the synthesis and enzymatic stabilization of telomerase RNA component (TERC), a therapeutically relevant long non-coding RNA (lncRNA) that extends telomere length and replicative lifespan in human stem cells. Compared with therapeutic mRNAs, engineered TERC RNA (eTERC) depends on avoiding nucleoside base modifications and incorporates a distinct trimethylguanosine 5' cap during in vitro transcription. We show that the non-canonical polymerase TENT4B can be repurposed to enzymatically stabilize synthetic RNAs of any size by catalysing self-limited 2'-O-methyladenosine tailing, which is critical for optimal eTERC function in cells. A single transient exposure to eTERC forestalls telomere-induced senescence in telomerase-deficient human cell lines and lengthens telomeres in induced pluripotent stem cells from nine patients carrying different mutations in telomere-maintenance genes, as well as primary CD34

Heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutations are key drivers of mitochondrial diseases, yet their tissue-specific and cell-specific accumulation patterns during aging and the mechanistic links to pathology remain poorly understood. In this study, we employed DddA-derived cytosine base editor technology to generate three mouse models harboring distinct pathogenic mitochondrial tRNA mutations. These mutations exhibited age-dependent accumulation in the kidneys, leading to severe kidney defects that well recapitulate human mitochondrial kidney disease. Mitochondrial single-cell assay for transposase-accessible chromatin with sequencing (mtscATAC-seq) revealed unique heteroplasmy dynamics across different kidney cell types: podocytes exhibited a positive selection for mutant mtDNA, whereas tubular epithelial cells displayed neutral drift of mutations during aging. Integrative analyses combining mtscATAC-seq, single-cell RNA sequencing and spatially enhanced resolution omics sequencing further identified molecular changes in high-mutant defective cells, including increased AP-1 family transcription factor activity, tubular epithelial cell proliferation and immune activation, which contribute to disease progression. Our study underscores the importance of kidney function monitoring in patients with mitochondrial disease, particularly in older adults, and establishes robust preclinical models to facilitate the development of therapeutic strategies.

Muscle atrophy around joints is a common issue for people with osteoarthritis (OA), but its causes are poorly understood. Here we demonstrate that chronic inflammation in quadriceps muscle coincides with OA in mice, characterized by an increase in macrophages, activation of inflammatory pathways and tissue vascularization. We show that, during OA progression, macrophages progressively exhibit increasing phenotypes of senescence and promote muscle atrophy through paracrine induction of ferroptosis. Mechanistically, iron overload-induced mitochondrial damage results in reduced asparagine metabolites, impairing coenzyme Q10 (CoQ10) synthesis by inhibiting mTORC1-HMGCR signaling. Ultimately, this cascade enhances lipid peroxidation and promotes ferroptosis in skeletal muscle cells. We show that the cardiac medication CoQ10 can attenuate muscle atrophy by inhibiting ferroptosis, thereby reducing pathological damage to OA joints. Our findings offer insights for the potential management of muscle atrophy in patients with OA.

Diabetes has long-term, potentially severe implications for healthspan and lifespan and imposes an immense burden on global healthcare, the economy and society. Although a repertoire of medications is available to treat diabetes, these do not properly address the eventual lack of functional pancreatic beta cells that are needed to secrete insulin and maintain glucose homeostasis. Human islet cell transplantation from deceased donors is an established treatment for insulin-requiring type 1 diabetes, but demand outstrips supply. Substantial scientific and clinical progress has occurred in the last decade toward deriving pancreatic islet-like cells from human pluripotent stem cells, suggesting a potentially limitless solution to the supply issue and a new era in cell therapy for diabetes. Here, we critically review the scientific advances, the clinical trials and the various regulatory considerations that will need to be overcome for human stem cell-derived pancreatic islet-like cells to become the next cell therapy breakthrough for diabetes treatment.

Aging is characterized by progressive functional decline driven by stem cell exhaustion, chronic inflammation, and cellular senescence. Mesenchymal progenitor cells (MPCs), which play a central role in tissue repair, are particularly vulnerable to age-associated dysfunction. Lei et al. (Cell 188:1-22, 2025) address this limitation by engineering human embryonic stem cell-derived MPCs with enhanced FOXO3 activity (termed SRCs). Intravenous administration of FOXO3-SRCs to aged cynomolgus macaques significantly slowed aging across multiple organs compared to wild-type MPCs. SRC treatment improved cognitive performance, preserved brain structure, protected bone integrity, and rejuvenated immune function. Transcriptomic and DNA methylation aging clocks revealed substantial reductions in biological age, with the most pronounced rejuvenation observed in the reproductive system, skin, lung, muscle, and hippocampus. These effects were partly attributed to SRC-derived exosomes enriched in gero-protective proteins and metabolites. Importantly, SRCs exhibited robust safety, showing no tumorigenicity or immunogenicity. This work positions FOXO3-enhanced MPCs and their exosomes as promising candidates for systemic anti-aging interventions, shifting the therapeutic paradigm from treating individual diseases to targeting the aging process itself.

The circadian clocks of the cell orchestrate a daily transcriptional rhythm that schedules key activities of the cell to maintain homeostasis and support resilience. Circadian rhythm is driven by the periodic oscillations of transcriptional activators and translational repressors, occurring in both the central and peripheral clocks. Accumulating evidence shows that aging impairs the functional synchrony of the circadian system which further escalate age-related disorders. In addition, the technological aspects of modern society, including constant work schedules and extensive use of personal electronics, have led to a significant rise in circadian disorders. Circadian dysfunction seems to adversely impact aging and longevity in animal models. Therefore, it is essential to conduct comprehensive studies to identify factors that worsen with aging and to discover therapeutic options for promoting healthy aging. This review examines how aging affects circadian function and the reciprocal effects of circadian disruption (CD) on aging and longevity. Further, we highlight the recent findings on non-pharmacological aspects such as dietary restrictions and physical exercise as a regulator of circadian rhythms, aging attenuation, and extending lifespan in mammals. Thus, resetting the circadian clock may lead to better synchrony in cellular homeodynamics and physiology which offers healthy aging and increased life span.

Assessing and validating circulating biomarkers is essential for the development of pre-clinical biomarkers that predict biological aging and aging-phenotypes in mice. However, comprehensive proteomics of serum, especially in longitudinal mouse studies, is limited by low volumes of samples. In this study, we develop a workflow for comprehensive and quantitative proteomic analysis of low volume mouse serum and demonstrate its utility and performance in identifying and evaluating key associations with aging phenotypes. Notably, a nanoparticle (NP)-based serum processing workflow coupled to mass spectrometry (MS) increases proteomic coverage by 2 to 4-fold across a range of volumes and provides a quantitative and reproducible (CV < 10%) pipeline for NP-based studies. In a study of 30 mice (aged 12, 24, and 30 months), we uncovered 3992 protein groups across all samples (2235 on average) in 20uL of serum and highlight novel insights into aging-associated changes in serum and associations with glucose and body composition. With 1uL additional serum, a 48-cytokine assay quantified 39 additional proteins not identified by MS. This study establishes a powerful workflow that enables deep quantitative proteomics of biologically relevant proteins in volumes feasibly obtained from mice (20 uL of serum) and presents fundamental insights into the aging serum proteome.

Small non-coding RNAs coordinate essential cellular processes, including gene expression regulation, genome stability maintenance, and transposon suppression. These processes determine aging, lifespan, and resistance of cells and organisms to stress. In this work, we conducted a comprehensive study of the geroprotective effects of overexpression of two Dicer family genes (Dcr-1 and Dcr-2, which are responsible for the biogenesis of miRNAs and siRNAs) in different tissues of Drosophila melanogaster (nervous system, fat body, intestine, muscles). Activation of the Dicer genes affected the lifespan in a tissue- and sex-depending manner. Females with Dcr-1 overexpression in the nervous system exhibited a significant and reproducible increase in both median (10.0-13.4%, p < 0.001) and maximum lifespan (10.0-13.4%, p < 0.01). However, in other cases, the effect was insignificant or negative. Additionally, flies with neuronal Dcr-1 activation had increased expression of several longevity genes (Sirt1, bsk, tgo, Gadd45, Xpc, Azot, foxo, Hsf, Tsc1) and significantly increased survival after acute exposure to 700 Gy γ-radiation (40-200%, p < 0.05). But they had reduced resistance to starvation. This indicates a crucial role of the miRNA machinery and the Dicer family in providing protection against genotoxic effects and coordinating metabolic processes.

The antagonistic pleiotropy theory of aging predicts genetic trade-offs between early-life and late-life fitness. However, empirical evidence for such trade-offs in vertebrates remains scarce, particularly in the context of ecologically relevant life histories. Here, we identify vestigial-like 3 (vgll3), a transcription cofactor previously linked to age at maturity in humans and male Atlantic salmon through GWAS, as an antagonistically pleiotropic gene in the turquoise killifish (Nothobranchius furzeri). Selective disruption of vgll3 isoforms accelerates male growth and maturation in an isoform- and dose-dependent manner. Transcriptomic analysis, supported by cellular and physiological phenotypes, indicated increased cell proliferation and elevated germline production. However, early-life maturation incurs a late-life cost, linked to altered DNA damage response. Older mutant males develop melanoma-like tumors, validated via transplantation into immunodeficient rag2 models, and exhibit elevated age-related mortality rate. These findings highlight vgll3 as a key regulator of vertebrate life-history trade-offs, balancing early-life fitness with late-life disease risks.

α-ketoglutaric acid (AKG), a tricarboxylic acid cycle metabolite central to aerobic metabolism and longevity, retains unresolved anti-aging protein targets. Here, we demonstrate that reduced isocitrate dehydrogenase 1 (IDH1) expression during senescence lowers AKG production, accelerating the aging of mesenchymal stem cells (MSCs). Exogenous AKG or IDH1 overexpression restores AKG levels, enabling 2-oxoglutarate and Fe(II)-dependent oxygenase domain-containing protein 1 (OGFOD1)-catalyzed hydroxylation of ribosomal protein S23 (RPS23) at proline 62. Mechanistically, AKG stabilizes the OGFOD1-RPS23 complex, enhancing translation accuracy to limit misfolded protein accumulation while sustaining synthesis rates, thereby balancing proteostasis. The natural flavonoid scutellarin (Scu), identified as an IDH1 agonist, elevates AKG to delay MSC senescence. In aged mice, Scu improves cognitive function, reduces osteoporosis and skin aging, and suppresses senescence-associated secretory phenotype. Our findings identify the AKG-IDH1-RPS23 axis as a regulator of stem cell senescence and we propose metabolic reprogramming strategies for anti-aging therapies.

Dysregulation of redox homeostasis is implicated in the ageing process and the pathology of age-related diseases. To study redox signalling by H

Background: Chronic heart failure (CHF), the terminal phase of cardiovascular disease progression, has emerged as an increasingly severe global public health concern. Despite current therapeutic approaches aimed at symptom relief, their long-term effectiveness remains limited, urgently necessitating the exploration of novel treatment strategies. This study endeavored to explore the role of cellular senescence in CHF, identify the characteristic genes linked to cellular senescence, and predict potential therapeutic agents. Methods: We acquired CHF-related datasets from the Gene Expression Omnibus database and cell senescence-related genes from the CellAge database to identify differentially expressed cell senescence-related genes. We then conducted Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses to elucidate the functions of these differentially expressed genes, constructed a protein-protein interaction network, and screened hub genes. Using receiver operating curve (ROC) analysis, we developed a diagnostic model based on these hub genes. Furthermore, we constructed networks for the hub genes involving miRNAs, lncRNAs, transcription factors, and drugs. Subsequently, we explored the potential mechanism of action of metformin in the treatment of CHF through molecular docking studies. Lastly, we verified the expression of the hub genes in a doxorubicin-induced CHF model in rats. Results: We ultimately identified nine hub genes associated with cellular senescence: STAT1, MMP9, MAP2K1, SOCS1, SDC1, MET, EIF4EBP1, ATF3, and NAMPT. These genes exhibited significant differential expression between CHF and normal tissues. The constructed diagnostic model demonstrated robust diagnostic performance in ROC curve analysis, with an area under the curve exceeding 0.7, thereby providing biomarker support for early CHF diagnosis. Furthermore, we identified a regulatory network comprising 94 lncRNAs, 63 miRNAs, and 11 transcription factors and screened 42 potential therapeutic drugs. Subsequent molecular docking simulations revealed that metformin could effectively bind to the hub genes. Finally, we validated the expression of some hub genes in a rodent CHF model, in which gene expression regulation varied across diverse experimental settings. Conclusions: Our research identified nine genes cellular senescence-related genes with potential roles in CHF pathogenesis, offering fresh perspectives concerning the diagnosis and treatment of CHF.

Sirtuins are NAD+-dependent histone deacetylases that play a key role in metabolism. Sirtuin activity is compromised in aging and metabolic disorders, and pharmacological strategies that promote sirtuin function including NAD+ boosting approaches show potential as therapeutics. To study the impact of nicotinamide mononucleotide (NMN) supplementation in mice in high fat diet (HFD) induced obesity and the role of SIRT1, a sirtuin family member, in mediating the NMN response, we administered NMN to mice in drinking water to boost NAD+ in control and in inducible SIRT1 knock-out mouse models and performed a combination of metabolic phenotyping, lipid profiling and plasma proteomics in these mice. We discovered that supplementation with NMN mitigated diet induced weight gain by enhancing energy expenditure, corrected dyslipidemia, and reversed perturbations in fasting blood glucose, all in a SIRT1-dependent manner. On the other hand, NMN-induced reductions in fat mass, fluid mass, eWAT and mesenteric WAT were SIRT1 independent. Proteomic approaches in plasma samples using O-Link and mass-spectrometry provided novel insights into key obesity- and NMN-dependent changes in circulating molecules with potential relevance to inflammation, liver function, and dyslipidemia. We discovered SIRT1 dependent and independent alterations in key circulating plasma proteins and identified key metabolic and molecular pathways that were significantly affected by HFD, several of which were reverted by oral NMN administration. Glucose metabolism, cholesterol metabolism and immune-related pathways are among the most significantly affected changes. Causal analysis of proteomic data suggests that observed effects could be mediated by transcription regulators FBXW7, ADIPOR2 and PRDM16. Collectively, our data support the hypothesis that promoting SIRT1 function by boosting NAD+ levels in vivo may be a useful strategy to mitigate obesity and associated cardiovascular complications such as dyslipidemia.

Lens epithelial cell (LEC) senescence is one of the key pathological processes of age-related cataract (ARC) and is associated with oxidative stress, mitochondrial dysfunction, and protein aggregation. This study aimed to elucidate the pathogenesis of LEC senescence in ARC. The protein expression level of silencing regulatory protein 1 (SIRT1) and aptamer protein (p66Shc) was quantified. Reactive oxygen species (ROS) and mitochondrial superoxide levels were measured to evaluate cellular oxidative stress. Senescence-associated protein expression (p21 and p53) and SA-β-galactosidase staining were employed to assess the aging status of LEC. Targeted metabolic analysis was conducted to explore energy changes during LEC senescence, and mitochondrial morphology and function were assessed in the cell models. The aging and damage conditions of the lens in ARC rats were evaluated through histological staining, transmission electron microscopy, expression of senescence-related proteins, and oxidative stress markers. We comprehensively investigated the downregulation of SIRT1 expression and the upregulation of p66Shc expression in human cataract samples, UVB-induced rat cataract models, and UVB-treated LEC. SIRT1 could alleviate UVB-induced oxidative stress, as well as mitochondrial dysfunction, inhibiting p66Shc expression in LEC. Nicotinamide mononucleotide (NMN) effectively alleviated the abnormal expression of aging-related proteins and inhibited mitochondrial morphological and functional disorders by activating SIRT1. In conclusion, NMN activated SIRT1, inhibiting mitochondrial dysfunction, oxidative stress, and senescence in LEC, delaying lens opacity. This mechanism could be associated with the onset and progression of ARC, providing a new strategy for its prevention and treatment.

Age-related macular degeneration (AMD) is a leading cause of blindness in people over 50. AMD and cardiovascular disease share risk factors including age, impaired lipid metabolism, and extracellular lipid deposition. Because of its importance in age-related diseases, we hypothesize that apolipoprotein M (ApoM), a lipocalin that binds sphingosine-1-phosphate (S1P), might restore lipid homeostasis and retinal function in AMD. In support, we find that human patients with AMD demonstrate significantly reduced ApoM compared to controls. In mice with impaired retinal cholesterol efflux, ApoM improves retinal pigment epithelium (RPE) function and lipotoxicity in an S1P- and S1P receptor 3-dependent manner. Ultrastructural evidence of enhanced melanosome-lipid droplet interactions led us to hypothesize and demonstrate that ApoM-S1P signaling drives RPE-specific lysosomal lipid catabolism. RPE-specific knockout of lysosomal acid lipase recapitulates features of AMD. Our study defines a novel role for ApoM/S1P signaling in AMD driven by RPE lipotoxicity, mediated by cell-autonomous lysosomal lipid catabolism.

Protein homeostasis controlled by the 26S proteasome plays a pivotal role in the adaption of plants to environmental stress, contributing to survival and longevity. During ageing in animals, proteasome activity declines resulting in senescence, however, in plants this is so far largely unexplored. Both in Arabidopsis and barley we found that genes encoding for proteasomal subunits are upregulated at the transcript level during the onset of leaf senescence. In contrast, at the protein level a decrease in proteasomal subunit abundance was observed. Moreover, in Arabidopsis 26S proteasome capacity deteriorates with leaf age, while 20S proteasome activity increases. In contrast, in barley a potential increase in proteasome activity was observed with age. As ribosome-associated RNAs levels of proteasomal subunits increase in Arabidopsis during senescence, it suggests a high-turnover. Furthermore, chemical inhibition of the proteasome results in accelerated leaf senescence in Arabidopsis and barley. In Arabidopsis, 26S proteasome activity could be restored by external cytokinin application, resulting in delayed senescence. Finally, we identified several senescence-associated transcription factors that acts as novel transcriptional regulator of proteasomal genes in Arabidopsis. Taken together, this work provides new insights into the dynamic regulation of proteasome activity which deepens our understanding on leaf senescence in plants.

While aging is a natural biological process, it is associated with a greater risk for multiple diseases, including cancer, neurodegeneration, and cardiovascular disease. Thus, it is important to study the biochemical mechanisms involved in aging to understand how to treat and prevent these health conditions. The discovery that calorie restriction (CR) promoted longevity in various organisms is a major breakthrough for aging research. Molecular studies of CR have revealed that it mediates its anti-aging effects by activating key signaling pathways, including the AMPK pathway. This pathway is important for regulating various processes, including energy homeostasis, metabolism, and proteostasis. Despite the advantages associated with CR, this practice can have detrimental effects, including decreased liver, body, and muscle mass. Additionally, CR is difficult to track and maintain, limiting its long-term potential. Interestingly, direct activation of the AMPK pathway offers a potential approach to increase longevity and quality of life without dietary restrictions. Remarkably, a recent discovery revealed that lithocholic acid (LCA), a metabolite from bile acid, could directly activate the AMPK pathway. Activation of the AMPK pathway by LCA leads to the beneficial effects of CR without the negative effects. These recent findings point to the possibility that supplementation of specific doses of LCA could offer a novel approach to induce anti-aging pathways that lead to increased longevity and improved quality of life.

Biological aging is a complex non-linear process, with markedly distinct starting and end points, yet the biomarkers of its progression remain elusive. A key assumption of most machine learning (ML) approaches for age clocks is that predictive biomedical features can be identified via mathematical transformations of data to favor a linear transition from start to end, even if they erase any natural biological pattern. It is given that expected correlations, e.g., time lived (age) and time left to live (mortality), would persist in such mathematically optimized models, biologically meaningful or not. Here, we further clarify the workings of the clocks, explain the trade-off between mathematical optimization and biological interpretability, and discuss a hallmark of aging, inflammaging, that age clocks struggle to detect. We expand on the negative consequences of incoherence in linear models where some DNA methylation (DNAm) features increase with aging and disease, while others correspondingly decrease, yet positive weights are assigned to both. We quantify the misalignment between major DNAm clocks and actual changes in DNAm, providing an interactive visualization of these errors for each model. We demonstrate that major conventional age clocks are both incoherent and skewed toward leukocyte fractions and that rectifying incoherence makes the model balanced and not skewed toward neutrophils and better detects inflammaging. We briefly outline non-linear ML age clocks and the advantages of identifying a natural trajectory of aging directly from the primary data.

Aging is an unavoidable process associated with a progressive decline of muscle mass, strength, and regenerative ability. Satellite cells are a muscle stem cell (MuSC) population that plays a key role in mammalian muscle regeneration, by awakening from quiescence and then migrating to sites of damage, expanding in number to generate progenitor cells, and then either differentiating to rebuild the muscle tissue or self-renewing to repopulate the stem cell pool. Emerging evidence suggests that the aging process impairs the activation potential and the regenerative capacity of MuSCs. This review explores some of the recent discoveries of how mis-regulation of intrinsic and extrinsic mechanisms drive the decline of MuSC function in aging muscles, and we discuss new strategies to rejuvenate aged MuSC function for regenerative medicine. Understanding these processes will speed up the development of novel therapeutics for counteracting muscle loss and improve muscle healing in the elderly.

Adipose tissue, a pivotal player in whole-body energy homeostasis and insulin sensitivity, undergoes considerable remodelling throughout the ageing process, a facet that has garnered little attention until the past decade. This Review comprehensively summarizes the dynamic metabolic, cellular and functional changes that occur in white and thermogenic adipose tissue during distinct ageing stages, across different adipose tissue depots. We emphasize the influence of ageing on different cell types within adipose tissue, including adipocytes, adipocyte progenitors, immune cells and senescent cells, and their collective effect on adipose tissue function and systemic metabolism. We also decipher the correlation between adipose tissue ageing and prevalent age-related conditions such as metabolic dysfunction-associated fatty liver disease and cardiovascular diseases. Finally, the Review delves into the potential of current anti-ageing interventions to beneficially affect adipose tissue, encompassing caloric restriction, metformin, glucagon-like peptide 1 receptor agonists and senolytics. The discussion extends to the exploration of whether targeting adipose tissue through such interventions could emerge as a prominent therapeutic strategy for mitigating age-related diseases and enhancing the healthspan and lifespan of the ageing population.

Geroprotectors, a class of compounds that ameliorate molecular, cellular, or physiological aging-related alterations, have garnered significant attention in the quest to promote healthy aging and extend the human health span. Among these, Calorie Restriction Mimetics (CRMs) have emerged as promising candidates due to their potential to mimic the benefits of calorie restriction, a dietary approach involving reduced calorie intake without malnutrition. Prospective CRMs may include biguanides (metformin and aminoguanidine), which exert effects on the insulin signaling pathway; rapamycin, which interacts with mTOR signaling pathways; and stilbenes (resveratrol), which influences stress signaling pathways and promotes the activation of AMPK, impacting mitochondrial metabolism in addition to the activity of FOXO and sirtuin. Other compounds, such as glycolytic inhibitors, carbohydrate and lipid absorption blockers, polyamines, and polyphenols, which collectively modulate pathways regulating the effects of free radicals, are also under consideration. To propose prospective geroprotective strategies, this article focuses on analyzing the functions of potential CRMs and their mechanisms demonstrating health benefits, the same as that of CR (Calorie Restriction), but without undesirable side effects.

Jingfang Granule (JFG), a traditional Chinese medicine preparation, is widely used in clinical practice. It has been shown to extend both lifespan and healthspan in the Caenorhabditis elegans model. However, the molecular mechanisms of its main constituents and their targets remain unclear. In this study, through network pharmacology, molecular docking, and experiments on C. elegans including lifespan assays and stress resistance assays, the bioactive compounds of JFG and their targets were screened. Network analysis identified a total of 187 candidate components and 150 drug-disease related targets, among which TP53, STAT3, IL6, TNF, AKT1, ESR1, CCND1, BCL2, MAPK1, and MAPK3 were the core nodes. Gene Ontology (GO) enrichment analysis revealed that these targets were mainly involved in aging-related and anti-apoptotic processes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that the AGE-RAGE signaling pathway, which is crucial in diabetic complications, might be involved. Experiments on Caenorhabditis elegans further confirmed that neohesperidin, kaempferol, and stigmasterol in Jingfang Granule exhibited good anti-aging effects and stress resistance. They could extend the lifespan of Caenorhabditis elegans by activating the target genes of the transcription factors DAF-16, HSF-1, and SKN-1. By combining the strategies of network pharmacology and molecular biology, this study elucidated the anti-aging mechanisms of the Jingfang Granule formula and its bioactive compounds. Therefore, the Jingfang Granule formula and its bioactive compounds hold potential for lifespan extension, healthspan improvement, and enhanced stress resistance.

Many long-lived plant species exhibit notable patterns in phylogenies, such as short molecular branch lengths and high gene-tree conflict. However, it is not clear what biological properties of long-lived plant species or concomitant processes acting within these lineages generate these patterns. To explore this mystery, we implemented an agent-based model and conducted simulations to investigate how longevity affects molecular evolution and population dynamics. Through these simulations, we demonstrated that the patterns exhibited in empirical datasets for long-lived species can be explained by their lifespan and overlapping generations. We also show that somatic mutations can exacerbate these patterns, although evidence for substantive rates in empirical systems high enough to impact phylogenetic patterns is scarce. We discuss several empirical datasets containing life history shifts that exhibit diverse phylogenomic patterns. The variation produced through different parameterizations of our simulations reflects the diversity of patterns found in empirical datasets. Our results have broad implications for phylogenomic patterns and population genetics in general, as well as for specifically explaining patterns of evolution in long-lived lineages.

Along with organismal aging, multiple compartments of the immune system undergo a progressive functional degeneration that may contribute to - or at least allow for - disease, a scenario that is commonly known as "immunosenescence". While not all immune cell populations suffer from organismal aging through similar mechanisms, immunosenescence appears to involve numerical alterations in specific immune cell types that - at least in some settings - result from the unscheduled activation of regulated cell death (RCD), often along with unbalanced hematopoietic output downstream of thymic involution and bone marrow defects. Here, we critically discuss core RCD mechanisms including apoptosis, necroptosis, ferroptosis, pyroptosis and NETosis as key regulators of global immune homeostasis in the context of immunosenescence.

Dietary restriction (DR) extends lifespan in animals and plants, but its evolutionary causes are elusive. Adaptive hypotheses posit that DR extends lifespan because organisms reallocate resources from reproduction to survival (\"disposable soma\") or recycle cellular waste to maximize either their immediate reproduction (\"nutrient recycling\") or survival (\"clean cupboards\"). We developed an experimental paradigm that tricks Caenorhabditis elegans nematodes into increasing their reproductive effort under DR via food odour, thus allowing us to test these hypotheses. We found that experimentally increased reproduction under DR does not affect immediate or long-term survival benefits compared to DR animals that did not reproduce, thus refuting all three adaptive hypotheses. Our data suggest that a large part of suppressed fertility under DR is a result of organisms refraining from producing offspring in a poor environment. We developed a model based on Hamiltonian forces of selection to show that lifespan extension under DR evolves because DR suppresses fertility, directly increasing selection against mortality in DR environment. Our analytical approach suggests that DR-driven lifespan extension can evolve under a broader range of conditions not previously anticipated, such as a relaxed need for physiological or genetic trade-offs. Instead, we show how reduced survival on plentiful food can evolve via mutation accumulation.

Age-related changes in circulating metabolites influence systemic physiology and may contribute to diseases such as sarcopenia. Although metabolic dysregulation is closely linked to sarcopenia, the roles of specific metabolites remain unclear. In this study, we performed comprehensive plasma metabolomic and lipidomic analyses across two cohorts comprising 1,013 individuals, uncovering the metabolic characteristics of sarcopenia, including a notable decline in plasma sarcosine levels in both aging patients and those with sarcopenia. Functional studies in mice showed that sarcosine helps maintain muscle mass homeostasis during aging, promotes adipose thermogenesis and enhances muscle regeneration. We demonstrate here that sarcosine activated the GCN2 signaling pathway to enhance anti-inflammatory macrophage polarization, promoting adipose thermogenesis and muscle regeneration. These effects may increase energy expenditure and restore metabolic balance to reduce chronic inflammation and improve insulin sensitivity, which are crucial for managing sarcopenia. This study underscores the potential of sarcosine supplementation as an adjunctive strategy via macrophage modulation for preventing sarcopenia in older adults.

The accumulation of senescent cells (SEN) with aging produces a chronic inflammatory state that accelerates age-related diseases. Eliminating SEN has been shown to delay, prevent, and in some cases reverse aging in animal disease models and extend lifespan. There is thus an unmet clinical need to identify and target SEN while sparing healthy cells. Here, we show that Lysosomal-Associated Membrane Protein 1 (LAMP1) is a membrane-specific biomarker of cellular senescence. We have validated selective LAMP1 upregulation in SEN in human and mouse cells. Lamp1

As individuals age, they often experience persistent, unresolved pain, impacting their quality of life. Aging as a process is accompanied by "inflammaging," a state of chronic, low-grade systemic inflammation contributing to various diseases. Understanding the functional link between inflammaging and age-related development of pain is crucial for identifying novel therapeutic targets. We hypothesized that the circulatory milieu plays a role in regulating pain and that inflammaging contributes to changes in pain behavior with age. To test these hypotheses, we monitored nociception and postsurgical pain in male and female mice aged 3 and 24 months and analyzed their serum proteome, including cytokine/chemokine profiles. Our results demonstrated that compared with young mice, aging mice were hyposensitive to mechanical stimulation, yet their pain response to incision was aggravated and prolonged. Serum proteomic analysis revealed sex-specific inflammaging patterns. To explore the link between inflammaging and age-related alteration in pain behavior, we applied a rejuvenation strategy by transferring serum from 3-month-old mice to 19- to 21-month-old mice. Young serum normalized mechanical sensitivity in aged mice, alleviated postsurgical mechanical pain, and promoted recovery. Alongside the improvements in pain behavior phenotype, young serum recalibrated the aging serum profile. It reduced age-associated increases of cytokine/chemokine levels in male mice and rescued age-related, female-selective downregulation of inflammatory pathways such as liver X receptor/retinoid X receptor activation, D24-dehydrocholesterol reductase, and complement signaling. Our findings suggest that the circulatory environment, notably inflammaging, plays a significant role in altered pain behavior of aging mice. The sex-specific signature of age-dependent systemic inflammation highlights the importance of investigating inflammaging through the lens of sexual dimorphism.

Aneuploid cells are known to increase with age. Previously, we demonstrated that aneuploid cells increase in fibroblasts from aged mice due to chromosomal instability (CIN), which is caused by oxidative stress. It is unclear whether this phenomenon also occurs in human cells, which are more resistant to oxidative stress than mouse cells. Here, we found that fibroblasts from aged individuals exhibited an increase in aneuploid cells. The frequency of chromosome missegregation and micronuclei increased in these cells, indicating CIN. A DNA fiber assay revealed the presence of replication stress, accompanied by an increase in 53BP1 nuclear bodies and ultrafine bridges. Increased levels of reactive oxygen species derived from mitochondria, along with reduced mitochondrial membrane potential, imply that these cells experienced oxidative stress due to mitochondrial functional decline. Antioxidant treatment reduced the frequency of chromosome missegregation and micronuclei, suggesting that oxidative stress causes CIN. Oxidative stress also causes replication stress, which precedes CIN. Spindle microtubules were stabilized in fibroblasts from aged individuals, which was alleviated by antioxidant treatment. Taken together, these findings suggest that aging-related CIN in human fibroblasts is caused by oxidative stress associated with mitochondrial dysfunction, which induces replication stress that in turn causes CIN through microtubule stabilization. Although human fibroblasts are more resistant to the ambient oxygen environment than mouse fibroblasts, our findings showed that they undergo oxidative stress that causes CIN with age in a manner similar to mouse fibroblasts, revealing a conserved phenomenon in mammalian cells.